dopamine hypothesis psychology studies

Schizophrenia A-level Revisions Notes

Bruce Johnson

A-level Psychology Teacher

B.A., Educational Psychology, University of Exeter

Bruce Johnson is an A-level psychology teacher, and head of the sixth form at Caterham High School.

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Saul Mcleod, PhD

Editor-in-Chief for Simply Psychology

BSc (Hons) Psychology, MRes, PhD, University of Manchester

Saul Mcleod, PhD., is a qualified psychology teacher with over 18 years of experience in further and higher education. He has been published in peer-reviewed journals, including the Journal of Clinical Psychology.

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What do the examiners look for?

• Accurate and detailed knowledge
• Clear, coherent, and focused answers
• Effective use of terminology (use the “technical terms”)

In application questions, examiners look for “effective application to the scenario” which means that you need to describe the theory and explain the scenario using the theory making the links between the two very clear. If there is more than one individual in the scenario you must mention all of the characters to get to the top band.

Difference between AS and A level answers

The descriptions follow the same criteria; however you have to use the issues and debates effectively in your answers. “Effectively” means that it needs to be clearly linked and explained in the context of the answer.

Read the model answers to get a clearer idea of what is needed.

Exam Advice

You MUST revise everything – because the exam board could choose any question, however, it does make sense to spend more time on those topics which have not appeared for a while.

With these particular questions there is a sizeable risk that people don’t understand the difference between the questions, and then write about the wrong thing.

Make sure you know which is which, for example do you understand the difference between “genetic explanation” and “neural correlates explanation”, and do you have a model essay for each?

Schizophrenia is a severe mental illness where contact with reality and insight are impaired, an example of psychosis.

Section 1: Diagnosis and Classification of Schizophrenia

Classification is the process of organising symptoms into categories based on which symptoms cluster together in sufferers. Psychologists use the DSM and ICD to diagnose a patient with schizophrenia.

Diagnosis refers to the assigning of a label of a disorder to a patient. The ICD-10 (only negative symptoms need to be present) is used worldwide and the DSM-5 (only positive symptoms need to be present) is used in America.

In order to diagnose Schizophrenia the Mental Health Profession developed the DSM (Diagnostic and Statistical Manual) still used today as a method of classifying mental disorders (particularly in the USA).

It is also used as a basis for the ICD (International Classification of Diseases) used by the World Health Organisation in classifying all disorders (mental and physical).

Note: you may come across the terms DSM-IV and ICD-10. These refer to the latest editions of the two classification systems.

Positive Symptoms

an excess or distortion of normal functions: including hallucinations and delusions.

Positive symptoms are an excess or distortion of normal functions, for example hallucinations, delusions and thought disturbances such as thought insertion.

• Hallucinations are usually auditory or visual perceptions of things that are not present. Imagined stimuli could involve any of the senses. Voices are usually heard coming from outside the person’s head giving instructions on how to behave. • Delusions are false beliefs. Usually the person has convinced him/herself that he/she is someone powerful or important, such as Jesus Christ, the Queen (e.g. Delusions of Grandeur). There are also delusions of being paranoid, worrying that people are out to get them. • Psychomotor Disturbances: Stereotypyical – Rocking backwards and forwards, twitches, & repetitive behaviors. Catatonia- staying in position for hours/days on end, cut off from the world.

Negative Symptoms

where normal functions are limited: including speech poverty and avolition.

Negative symptoms are a diminution or loss of normal functions such as psychomotor disturbances, avolition (the reduction of goal-directed behavior), disturbances of mood and thought disorders.

• Thought disorder in which there are breaks in the train of thought and the person appears to make illogical jumps from one topic to another (loose association). Words may become confused and sentences incoherent (so called ‘word salad). Broadcasting is a thought disorder whereby a person believes their thoughts are being broadcast to others, for example over the radio or through TV. Alogia – aka speech poverty – is a thought disorder were correct words are used but with little meaning. • Avolition: Lack of volition (i.e. desire): in which a person becomes totally apathetic and sits around waiting for things to happen. They engage in no self motivated behavior. Their get up and go has got up and gone!

Classification

Slater & Roth (1969) say that hallucinations are the least important of all the symptoms, as they are not exclusive to schizophrenic people.

Classification and diagnosis does have advantages as it allows doctors to communicate more effectively about a patient and use similar terminology when discussing them. In addition, they can then predict the outcome of the disorder and suggest related treatment to help the patient.

Scheff (1966) points out that diagnosis classification labels the individual, and this can have many adverse effects, such as a self-fulfilling prophecy (patients may begin to act how they are expected to act), and lower self-esteem.

Ethics – do the benefits of classification (care, treatment, safety) outweigh the costs (possible misdiagnosis, mistreatment, loss of rights and responsibility, prejudice due to labelling).

Reliability and Validity in Diagnosis and Classification of Schizophrenia

with reference to co-morbidity, culture and gender bias and symptom overlap.

Reliability

For the classification system to be reliable, differfent clinicians using the same system (e.g. DSM) should arrive at the same diagnosis for the same individual.

Reliability is the level of agreement on the diagnosis by different psychiatrists across time and cultures; stability of diagnosis over time given no change in symptoms.

Diagnosis of schizophrenia is difficult as the practitioner has no physical signs but only symptoms (what the patient reports) to make a decision on.

Jakobsen et al. (2005) tested the reliability of the ICD-10 classification system in diagnosing schizophrenia. A hundred Danish patients with a history of psychosis were assessed using operational criteria, and a concordance rate of 98% was obtained. This demonstrates the high reliability of the clinical diagnosis of schizophrenia using up-to-date classification.

Comorbidity describes people who suffer from two or more mental disorders. For example, schizophrenia and depression are often found together. This makes it more difficult to confidently diagnose schizophrenia. Comorbidity occurs because the symptoms of different disorders overlap. For example, major depression and schizophrenia both involve very low levels of motivation. This creates problems of reliability. Does the low motivation reflect depression or schizophrenia, or both?

Gender bias: Loring and Powell (1988) found that some behavior which was regarded as psychotic in males was not regarded as psychotic in females.

Validity – the extent to which schizophrenia is a unique syndrome with characteristics, signs and symptoms.

For the classification system to be valid it should be meaningful and classify a real pattern of symptoms, which result from a real underlying cause.

The validity of schizophrenia as a single disorder is questioned by many. This is a useful point to emphasise in any essay on the disorder. There is no such thing as a ‘normal’ schizophrenic exhibiting the usual symptoms.

Since their are problems with the validity of diagnois classification, unsuitable treatment may be administered, sometimes on an involuntary basis. This raises practical and ethical issues when selecting different types of tretment.

Problems of validity: Are we really testing what we think we are testing? In the USA only 20% of psychiatric patients were classed as having schizophrenia in the 1930s but this rose to 80% in the 1950s . In London the rate remained at 20%, suggesting neither group had a valid definition of schizophrenia.

Neuropsychologist Michael Foster Green suggests that neurocognitive deficits in basic functions such as memory, attention, central executive and problem solving skills may combine to have an outcome which we are labelling “Schizophrenia” as if it was the cause when in fact it is simply an umbrella term for a set of effects.

Predictive validity. If diagnosis leads to successful treatment, the diagnosis can be seen as valid. But in fact some Schizophrenics are successfully treated whereas others are not. Heather (1976) there is only a 50% chance of predicting what treatment a patient will receive based on diagnosis, suggesting that diagnosis is not valid.

Aetiological validity – for a diagnosis to be valid, all patients diagnosed as schizophrenic should have the same cause for their disorder. This is not the case with schizophrenia: The causes may be one of biological or psychological or both.

David Rosenhan (1973) famous experiment involving Pseudopatients led to 8 normal people being kept in hospital despite behaving normally. This suggests the doctors had no valid method for detecting schizophrenia. They assumed the bogus patients were schizophrenic with no real evidence. In a follow up study they rejected genuine patients whom they assumed were part of the deception.

Culture – One of the biggest controversies in relation to classification and diagnosis is to do with cultural relativism and variations in diagnosis. For example in some Asian countries people are not expected to show emotional expression, whereas in certain Arabic cultures public emotion is encouraged and understood. Without this knowledge a person displaying overt emotional behavior in a Western culture might be regarded as abnormal. Cochrane (1977) reported that the incidence of schizophrenia in the West Indies and the UK is 1 %, but that people of Afro-Caribbean origin are seven times more likely to be diagnosed as schizophrenic when living in the UK.

Cultural bias – African Americans and those of Afro-carribean descent are more likely to be diagnosed than their white counterparts but diagnostic rates in Africa and the West Indies is low – Western over diagnosis is a result of cultural norms and the diagnosis lacks validity.

Section 2: Biological Explanations for Schizophrenia

Family studies find individuals who have schizophrenia and determine whether their biological relatives are similarly affected more often than non-biological relatives.

There are two types of twins – identical (monozygotic) and fraternal (dizygotic). To form identical twins, one fertilised egg (ovum) splits and develops two babies with exactly the same genetic information.

• Gottesman (1991) found that MZ twins have a 48% risk of getting schizophrenia whereas DZ twins have a 17% risk rate. This is evidence that the higher the degree of genetic relativeness, the higher the risk of getting schizophrenia. • Benzel et al. (2007) three genes: COMT, DRD4, AKT1 – have all been associated with excess dopamine in specific D2 receptors, leading to acute episodes, positive symptoms which include delusions, hallucinations, strange attitudes. • Research by Miyakawa et al. (2003) studied DNA from human families affected by schizophrenia and found that those with the disease were more likely to have a defective version of a gene, called PPP3CC which is associated with the production of calcineurin which regulates the immune system. Also, research by Sherrington et al. (1988) has found a gene located on chromosome 5 which has been linked in a small number of extended families where they have the disorder. • Evidence suggests that the closer the biological relationship, the greater the risk of developing schizophrenia. Kendler (1985) has shown that first-degree relatives of those with schizophrenia are 18 times more at risk than the general population. Gottesman (1991) has found that schizophrenia is more common in the biological relatives of a schizophrenic, and that the closer the degree of genetic relatedness, the greater the risk.

Very important to note genetics are only partly responsible, otherwise identical twins would have 100% concordance rates.

One weakness of the genetic explanation of schizophrenia is that there are methodological problems. Family, twin and adoption studies must be considered cautiously because they are retrospective, and diagnosis may be biased by knowledge that other family members who may have been diagnosed. This suggests that there may be problems of demand characteristics.

A second weakness is the problem of nature-v-Nurture. It is very difficult to separate out the influence of nature-v-nurture. The fact that the concordance rates are not 100% means that schizophrenia cannot wholly be explained by genes and it could be that the individual has a pre-disposition to schizophrenia and simply makes the individual more at risk of developing the disorder. This suggests that the biological account cannot give a full explanation of the disorder.

A final weakness of the genetic explanation of schizophrenia is that it is biologically reductionist. The Genome Project has increased understanding of the complexity of the gene. Given that a much lower number of genes exist than anticipated, it is now recognised that genes have multiple functions and that many genes behavior.

Schizophrenia is a multi-factorial trait as it is the result of multiple genes and environmental factors. This suggests that the research into gene mapping is oversimplistic as schizophrenia is not due to a single gene.

The Dopamine Hypothesis

• Dopamine is a neurotransmitter. It is one of the chemicals in the brain which causes neurons to fire. The original dopamine hypothesis stated that schizophrenia suffered from an excessive amount of dopamine. This causes the neurons that use dopamine to fire too often and transmit too many messages. • High dopamine activity leads to acute episodes, and positive symptoms which include: delusions, hallucinations, confused thinking. • Evidence for this comes from that fact that amphetamines increase the amounts of dopamine . Large doses of amphetamine given to people with no history of psychological disorders produce behavior which is very similar to paranoid schizophrenia. Small doses given to people already suffering from schizophrenia tend to worsen their symptoms. • A second explanation developed, which suggests that it is not excessive dopamine but that fact that there are more dopamine receptors. More receptors lead to more firing and an over production of messages. Autopsies have found that there are generally a large number of dopamine receptors (Owen et al., 1987) and there was an increase in the amount of dopamine in the left amygdale (falkai et al. 1988) and increased dopamine in the caudate nucleus and putamen (Owen et al, 1978).

One criticism of the dopamine hypothesis is there is a problem with the chicken and egg. Is the raised dopamine levels the cause of the schizophrenia, or is it the raised dopamine level the result of schizophrenia?

It is not clear which comes first. This suggests that one needs to be careful when establishing cause and effect relationships in schizophrenic patients.

One of the biggest criticisms of the dopamine hypothesis came when Farde et al found no difference between schizophrenics’ levels of dopamine compared with ‘healthy’ individuals in 1990.

Noll (2009) also argues around one third of patients do not respond to drugs which block dopamine so other neurotransmitters may be involved.

A final weakness of the dopamine hypothesis is that it is biologically deterministic. The reason for this is because if the individual does have excessive amounts of dopamine then does it really mean that thy ey will develop schizophrenia? This suggests that the dopamine hypothesis does not account for freewill.

Neural Correlates

• Neural correlates are patterns of structure or activity in the brain that occur in conjunction with schizophrenia • People with schizophrenia have abnormally large ventricles in the brain . Ventricles are fluid filled cavities (i.e. holes) in the brain that supply nutrients and remove waste. This means that the brains of schizophrenics are lighter than normal. The ventricles of a person with schizophrenia are on average about 15% bigger than normal (Torrey, 2002).

A strength is that the research into enlarged ventricles and neurotransmitter levels have high reliability. The reason for this is because the research is carried out in highly controlled environments, which specialist, high tech equipment such as MRI and PET scans.

These machines take accurate readings of brain regions such as the frontal and pre-frontal cortex, the basil ganglia, the hippocampus and the amygdale. This suggests that if this research was tested and re-tested the same results would be achieved.

Supporting evidence for the brain structure explanation comes from further empirical support from Suddath et al. (1990). He used MRI (magnetic resonance imaging) to obtain pictures of the brain structure of MZ twins in which one twin was schizophrenic.

The schizophrenic twin generally had more enlarged ventricles and a reduced anterior hypothalamus. The differences were so large the schizophrenic twins could be easily identified from the brain images in 12 out of 15 pairs.

This suggests that there is wider academic credibility for enlarged ventricles determining the likelihood of schizophrenia developing.

A second weakness of the neuroanatomical explanations is that it is biologically deterministic. The reason for this is because if the individual does have large ventricles then does it really mean that they will develop schizophrenia? This suggests that the dopamine hypothesis does not account for freewill.

Section 3: Psychological Explanations for Schizophrenia

Family dysfunction.

Family Dysfunction refers to any forms of abnormal processes within a family such as conflict, communication problems, cold parenting, criticism, control and high levels of expressed emotions. These may be risk factors for the development and maintenance of schizophrenia.

• Laing and others rejected the medical / biological explanation of mental disorders. They did not believe that schizophrenia was a disease. They believed that schizophrenia was a result of social pressures from life. Laing believed that schizophrenia was a result of the interactions between people, especially in families. • Bateson et al. (1956) suggested the double bind theory, which suggests that children who frequently receive contradictory messages from their parents are more likely to develop schizophrenia. For example parents who say they care whilst appearing critical or who express love whilst appearing angry. They did not believe that schizophrenia was a disease. They believed that schizophrenia was a result of social pressures from life. • Prolonged exposure to such interactions prevents the development of an internally coherent construction of reality; in the long run, this manifests itself as typically schizophrenic symptoms such as flattening affect, delusions and hallucinations, incoherent thinking and speaking, and in some cases paranoia. • Another family variable associated with schizophrenia is a negative emotional climate, or more generally a high degree of expressed emotion (EE). EE is a family communication style that involves criticism, hostility and emotional over-involvement. The researchers concluded that this is more important in maintaining schizophrenia than in causing it in the first place, (Brown et al 1958). Schizophrenics returning to such a family were more likely to relapse into the disorder than those returning to a family low in EE. The rate of relapse was particularly high if returning to a high EE family was coupled with no medication.

One strength of the double bind explanation comes from further empirical support provided by Berger (1965). They found that schizophrenics reported a higher recall of double bind statements by their mothers than non-schizophrenics.

However, evidence may not be reliable as patient’s recall may be affected by their schizophrenia. This suggests that there is wider academic credibility for the idea of contradictory messages causing schizophrenia.

A second strength of the research into expressed emotion (EE) is that it has practical applications. For example Hogarty (1991) produced a type of therapy session, which reduced social conflicts between parents and their children which reduced EE and thus relapse rates.

This suggests that gaining an insight into family relationships allows psychiatric professionals to help improve the quality of patient’s lives.

Individual differences – EE is associated with relapse but not all patients who live in high EE families relapse and not all patients in low EE families avoid relapse – Family dysfunction is an incomplete explanation for schizophrenia.

A weakness of the family relationsships appraoch is that there is a problem of cause and effect. Mischler & Waxler (1968) found significant differences in the way mothers spoke to their schizophrenic daughters compared to their normal daughters, which suggests that dysfunctional communication may be a result of living with the schizophrenic rather than the cause of the disorder.

This suggests that there is a problem of the chicken and egg scenario in relation to expressed emotion causing schizophrenia.

A second weakness of the double bind theory is that there are ethical issues. There are serious ethical concerns in blaming the family, particularly as there is little evidence upon which to base this.

Gender bias is also an issue as the mother tends to be blamed the most, which means such research is highly socially sensitive. This suggests that the research therefore does not protect individuals from harm.

Cause and effect – It remains unclear whether cognitive factors cause schizophrenia or if schizophrenia causes these cognitions – Family dysfunction may not be a valid explanation for schizophrenia.

Cognitive explanations

including dysfunctional thought processing.

Cognitive approaches examine how people think, how they process information. Researchers have focused on two factors which appear to be related to some of the experiences and behaviors of people diagnosed with schizophrenia.

First, cognitive deficits which are impairments in thought processes such as perception, memory and attention. Second, cognitive biases are present when people notice, pay attention to, or remember certain types of information better than other.

Cognitive Deficits

• There is evidence that people diagnosed as schizophrenic have difficulties in processing various types of information, for example visual and auditory information. Research indicates their attention skills may be deficient – they often appear easily distracted. • A number of researchers have suggested that difficulties in understanding other people’s behavior might explain some of the experiences of those diagnosed as schizophrenic. Social behavior depends, in part, on using other people’s actions as clues for understanding what they might be thinking. Some people who have been diagnosed as schizophrenic appear to have difficulties with this skill. • Cognitive deficits have been suggested as possible explanations for a range of behaviors associated with schizophrenia. These include reduced levels of emotional expression, disorganised speech and delusions.

Cognitive Biases

• Cognitive biases refer to selective attention. The idea of cognitive biases has been used to explain some of the behaviors which have been traditionally regarded as ‘symptoms’ of ‘schizophrenia’. • Delusions: The most common delusion that people diagnosed with schizophrenia report is that others are trying to harm or kill them – delusions of persecution. Research suggests that these delusions are associated with specific biases in reasoning about and explaining social situations. Many people who experience feelings of persecution have a general tendency to assume that other people cause the things that go wrong with their lives.

A strength of the cognitive explanation is that it has practical applications. Yellowless et al. (2002) developed a machine that produced virtual hallucinations, such as hearing the television telling you to kill yourself or one person’s face morphing into another’s.

The intention is to show schizophrenics that their hallucinations are not real. This suggests that understanding the effects of cognitive deficits allows psychologists to create new initiatives for schizophrenics and improve the quality of their lives.

A final strength is that it takes on board the nurture approach to the development of schizophrenia. For example, it suggests that schizophrenic behavior is the cause of environmental factors such as cognitive factors.

One weakness of the cognitive explanation is that there are problems with cause and effect. Cognitive approaches do not explain the causes of cognitive deficits – where they come from in the first place.

Is it the cognitive deficits which causes the schizophrenic behavior or is the schizophrenia that causes the cognitive deficits? This suggests that there are problems with the chicken and egg problem.

A second weakness of the cognitive model is that it is reductionist. The reason for this is because the approach does not consider other factors such as genes.

It could be that the problems caused by low neurotransmitters creates the cognitive deficits. This suggests that the cognitive approach is oversimplistic when consider the explanation of schizophrenia.

Section 4: Drug Therapy: typical and atypical antipsychotics

Drug therapy is a biological treatment for schizophrenia. Antipsychotic drugs are used to reduce the intensity of symptoms (particularly positive symptoms).

Typical Antipsychotics

• First generation Antipsychotics are called “Typical Antipsychotics” Eg. Chlorpromazine and Haloperidol. • Typical antipsychotic drugs are used to reduce the intensity of positive symptoms, blocking dopamine receptors in the synapses of the brain and thus reducing the action of dopamine. • They arrest dopamine production by blocking the D2 receptors in synapses that absorb dopamine, in the mesolimbic pathway thus reducing positive symptoms, such as auditory hallucinations. • But they tended to block ALL types of dopamine activity, (in other parts of the brain as well) and this caused side effects and may have been harmful.

Atypical Antipsychotics

• Newer drugs, called “atypical antipsychotics” attempt to target D2 dopamine activity in the limbic system but not D3 receptors in other parts of the brain. • Atypical antipsychotics such as Clozapine bind to dopamine, serotonin and glutamate receptors. • Atypical antipsychotic drugs work on negative symptoms, improving mood, cognitive functions and reducing depression and anxiety. • They also have some effect on other neurotransmitters such as serotonin . They generally have fewer side effects eg. less effect on movement Eg. Clozapine, Olazapine and Risperidone.

Since the mid-1950s antipsychotic medications have greatly improved treatment. Medications reduce positive symptoms particularly hallucinations and delusions; and usually allow the patient to function more effectively and appropriately.

Antipsychotic drugs are highly effective as they are relatively cheap to produce, easy to administer and have a positive effect on many sufferers. However they do not “cure” schizophrenia, rather they dampen symptoms down so that patients can live fairly normal lives in the community.

Kahn et al. (2008) found that antipsychotics are generally effective for at least one year, but second- generation drugs were no more effective than first-generation ones.

Some sufferers only take a course of antipsychotics once, while others have to take a regular dose in order to prevent symptoms from reappearing.

There is a sizeable minority who do not respond to drug treatment. Pills are not as helpful with other symptoms, especially emotional problems.

Older antipsychotics like haloperidol or chlorpromazine may produce side effects Sometimes when people with schizophrenia become depressed, so it is common to prescribe anti-depressants at the same time as the anti-psychotics.

All patients are in danger of relapsing but without medication the relapses are more common and more severe which suggests the drugs are effective.

Clozapine targets multiple neurotransmitters, not just dopamine, and has been shown to be more effective than other antipsychotics, although the possibility of severe side effects – in particular, loss of the white blood cells that fight infection.

Even newer antipsychotic drugs, such as risperidone and olanzapine are safer, and they also may be better tolerated. They may or may not treat the illness as well as clozapine, however.

Meta–analysis by Crossley Et Al (2010) suggested that Atypical antipsychotics are no more effective, but do have less side effects.

Recovery may be due to psychological factors – The placebo effect is when patients’ symptoms are reduced because they believe that it should.

However, Thornley et al carried out a meta-analysis comparing the effects of Chlorpromazine to placebo conditions and found Chlorpromazine to be associated with better overall functioning – Drug therapy is an effective treatment for SZ.

RWA – Offering drugs can lead to an enhanced quality of life as patients are given independence – Positive impact on the economy as patients can return to work and no longer need to be provided with institutional care.

Ethical issues – Antipsychotics have been used in hospitals to calm patients and make them easier for staff to work with rather than for the patients’ benefit – Can lead to the abuse of the Human Rights Act (no one should be subject to degrading treatment).

Severe side effects – Long term use can result in tardive dyskinesia which manifests as involuntary facial movements such as blinking and lip smacking – While they may be effective, the severity of the side effects mean the costs outweigh the benefits therefore they are not an appropriate treatment.

In most cases the original “typical antipsychotics” have more side effects, so if the exam paper asks for two biological therapies you can write about typical anti-psychotics and emphasise the side effects, then you can write about the atypical antipsychotics and give them credit for having less side effects.

Section 5: Psychological Therapies for Schizophrenia

Family therapy.

Family therapy is a form of therapy carried out with members of the family with the aim of improving their communication and reducing the stress of living as a family.

Family Therapy aims to reduce levels of expressed emotion, and reduced the likelihood of relapse.

Aims of Family Therapy

• To educate relatives about schizophrenia. • To stabilize the social authority of the doctor and the family. • To improve how the family communicated and handled the situation. • To teach patients and carers more effective stress management techniques.

Methods used in Family Therapy

• Pharoah identified examples of how family therapy works: It helps family members achieve a balance between caring for the individual and maintaining their own lives, it reduces anger and guilt, it improves their ability to anticipate and solve problems and forms a therapeutic alliance. • Families taught to have weekly family meetings solving problems on family and individual goals, resolve conflict between members, and pinpoint stressors. • Preliminary analysis: Through interviews and observation the therapist identifies strengths and weaknesses of family members and identifies problem behaviors. • Information transfer – teaching the patient and the family the actual facts about the illness, it’s causes, the influence of drug abuse, and the effect of stress and guilt. • Communication skills training – teach family to listen, to express emotions and to discuss things. Additional communication skills are taught, such as “compromise and negotiation,” and “requesting a time out” . This is mainly aimed at lowering expressed emotion.

A study by Anderson et al. (1991) found a relapse rate of almost 40% when patients had drugs only, compared to only 20 % when Family Therapy or Social Skills training were used and the relapse rate was less than 5% when both were used together with the medication.

Pharaoh et al. (2003) meta – analysis found family interventions help the patient to understand their illness and to live with it, developing emotional strength and coping skills, thus reducing rates of relapse.

Pharoah identified examples of how family therapy works: It helps family members achieve a balance between caring for the individual and maintaining their own lives, it reduces anger and guilt, it improves their ability to anticipate and solve problems and forms a therapeutic alliance.

Economic Benefits: Family therapy is highly cost effective because it reduces relapse rates, so the patients are less likely to take up hospital beds and resources. The NICE review of family therapy studies demonstrated that it was associated with significant cost savings when offered to patients alongside the standard care – Relapse rates are also lower which suggests the savings could be even higher.

Lobban (2013) reports that other family members felt they were able to cope better thanks to family therapy. In more extreme cases the patient might be unable to cope with the pressures of having to discuss their ideas and feelings and could become stressed by the therapy, or over-fixated with the details of their illness.

Token Economy

• Token economies aim to manage schizophrenia rather than treat it. • They are a form of behavioral therapy where desirable behaviors are encouraged by the use of selective reinforcement and is based on operant conditioning. • When desired behavior is displayed eg. Getting dressed, tokens (in the form of coloured discs) are given immediately as secondary reinforcers which can be exchanged for rewards eg. Sweets and cigarettes. • This manages schizophrenia because it maintains desirable behavior and no longer reinforces undesirable behavior. • The focus of a token economy is on shaping and positively reinforcing desired behaviors and NOT on punishing undesirable behaviors. The technique alleviates negative symptoms such as poor motivation, and nurses subsequently view patients more positively, which raises staff morale and has beneficial outcomes for patients. • It can also reduce positive symptoms by not rewarding them, but rewarding desirable behavior instead. Desirable behavior includes self-care, taking medication, work skills, and treatment participation.

Paul and Lentz (1977) Token economy led to better overall patient functioning and less behavioral disturbance, More cost-effective (lower hospital costs)

Upper and Newton (1971) found that the weight gain associated with taking antipsychotics was addressed with token economy regimes. Chronic schizophrenics achieved 3lbs of weight loss a week.

McMonagle and Sultana (2000) reviewed token economy regimes over a 15-year period, finding that they did reduce negative symptoms, though it was unclear if behavioral changes were maintained beyond the treatment programme.

It is difficult to keep this treatment going once the patients are back at home in the community. Kazdin et al. Found that changes in behavior achieved through token economies do not remain when tokens are with¬drawn, suggesting that such treatments address effects of schizophrenia rather than causes. It is not a cure.

There have also been ethical concerns as such a process is seen to be dehumanising, subjecting the patient to a regime which takes away their right to make choices.

In the 1950s and 60s nurses often “rewarded” patients with cigarettes. Due to the pivotal role of dopamine in schizophrenia this led to a culture of heavy smoking an nicotine addiction in psychiatric hospitals of the era.

Ethical issues – Severely ill patients can’t get privileges because they are less able to comply with desirable behaviors than moderately ill patients – They may suffer from discrimination

Cognitive Behavioral Therapy

In CBT, patients may be taught to recognise examples of dysfunctional or delusional thinking, then may receive help on how to avoid acting on these thoughts. This will not get rid of the symptoms of schizophrenia but it can make patients better able to cope with them.

Central idea: Patients problems are based on incorrect beliefs and expectations. CBT aims to identify and alter irrational thinking including regarding:

• General beliefs.
• Self image.
• Beliefs about what others think.
• Expectations of how others will act.
• Methods of coping with problems.

In theory, when the misunderstandings have been swept away, emotional attitudes will also improve.

Assessment : The therapist encourages the patient to explain their concerns.

• describing delusions • reflecting on relationships • laying out what they hope to achieve through the therapy.

Engagement :

The therapist wins the trust of the patient, so they can work together. This requires honesty, patience and unconditional acceptance. The therapist needs to accept that the illusions may seem real to the patient at the time and should be dealt with accordingly.

ABC : Get the patients to understand what is really happening in their life:

A: Antecedent – what is triggering your problem ? B: behavior – how do you react in these situations ? C: Consequences – what impact does that have on your relationships with others?

Normalisation :

Help the patient realise it is normal to have negative thoughts in certain situations. Therefore there is no need to feel stressed or ashamed about them.

Critical Collaborative Analysis :

Carrying on a logical discussion till the patient begins to see where their ideas are going wrong and why they developed. Work out ways to recognise negative thoughts and test faulty beliefs when they arise, and then challenge and re-think them.

Developing Alternative Explanations :

Helping the patient to find logical reasons for the things which trouble them Let the patient develop their own alternatives to their previous maladaptive behavior by looking at coping strategies and alternative explanations.

Another form of CBT: Coping Strategy Enhancement (CSE)

• Tarrier (1987) used detailed interview techniques, and found that people with schizophrenia can often identify triggers to the onset of their psychotic symptoms, and then develop their own methods of coping with the distress caused. These might include things as simple as turning up the TV to drown out the voices they were hearing! • At least 73% of his sample reported that these strategies were successful in managing their symptoms. • CSE aims to teach individuals to develop and apply effective coping strategies which will reduce the frequency, intensity and duration of psychotic symptoms and alleviate the accompanying distress. There are two components: 1. Education and rapport training: therapist and client work together to improve the effectiveness of the client’s own coping strategies and develop new ones. 2. Symptom targeting: a specific symptom is selected for which a particular coping strategy can be devised Strategies are practised within a session and the client is helped through any problems in applying it. They are then given homework tasks to practice, and keep a record of how it worked.

CBT does seem to reduce relapses and readmissions to hospital (NICE 2014). However, the fact that these people were on medication and having regular meetings with doctors would be expected to have that effect anyway.

Turkington et al. (2006) CBT is highly effective and should be used as a mainstream treatment for schizophrenia wherever possible.

Tarrier (2005) reviewed trials of CBT, finding evidence of reduced symptoms, especially positive ones, and lower relapse rates.

Requires self-awareness and willingness to engage – Held back by the symptoms schizophrenics encounter – It is an ineffective treatment likely to lead to disengagement.

Lengthy – It takes months compared to drug therapy that takes weeks which leads to disengaged treatment as they don’t see immediate effects – A patient who is very distressed and perhaps suicidal may benefit better in the short term from antipsychotics.

Addington and Addington (2005) claim that CBT is of little use in the early stages of an acute schizophrenic episode, but perhaps more useful when the patient is more calm and beginning to worry about how life will be after they recover. In other words, it doesn’t cure schizophrenia, it just helps people get over it.

Research in Hampshire, by Kingdon and Kirschen (2006) found that CBT is not suitable for all patients, especially those who are too thought disorientated or agitated, who refuse medication, or who are too paranoid to form trusting alliances with practitioners.

As there is strong evidence that relapse is related to stress and expressed emotion within the family, it seems likely that CBT should be employed alongside family therapy in order to reduce the pressures on the individual patient.

Section 6: Interactionist Approach

The Interactionist approach acknowledges that there are a range of factors (including biological and psychological) which are involved in the development of schizophrenia.

The Diathesis-stress Model

• The diathesis-stress model states that both a vulnerability to SZ and a stress trigger are necessary to develop the condition. • Zubin and Spring suggest that a person may be born with a predisposition towards schizophrenia which is then triggered by stress in everyday life. But if they have a supportive environment and/or good coping skills the illness may not develop. • Concordance rates are never 100% which suggests that environmental factors must also play a role in the development of SZ. MZ twins may have the same genetic vulnerability but can be triggered by different stressors. • Tienari Et. A. (2004): Adopted children from families with schizophrenia had more chance of developing the illness than children from normal families. This supports a genetic link. However, those children from families schizophrenia were less likely to develop the illness if placed in a “good” family with kind relationships, empathy, security, etc. So environment does play a part in triggering the illness.

Holistic – Identifies that patients have different triggers, genes etc. – Patients can receive different treatments for their SZ which will be more effective.

Falloon et al (1996) stress – such as divorce or bereavement, causes the brain to be flooded with neurotransmitters which brings on the acute episode.

Brown and Birley (1968) 50% people who had an acute schizophrenic episode had experienced a major life event in 3 weeks prior.

Substance abuse: Amphetamine and Cannabis and other drugs have also been identified as triggers as they affect serotonin and glutamate levels.

Vasos (2012) Found the risk of schizophrenia was 2.37 times greater in cities than it was in the countryside, probably due to stress levels. Hickling (1999) the stress of urban living made African-Carribean immigrants in Britain 8 to 10 times more likely to experience schizophrenia.

Faris and Dunham (1939) found clear pattern of correlation between inner city environments and levels of psychosis. Pederson and Mortensen (Denmark 2001) found Scandanavian villages have very LOW levels of psychosis, but 15 years of living in a city increased risk.

Fox (1990): It is more likely that factors associated with living in poorer conditions (e.g. stress) may trigger the onset of schizophrenia, rather than individuals with schizophrenia moving down in social status.

Bentall’s meta-analysis (2012) shows that stress arising from abuse in childhood increases the risk of developing schizophrenia.

Toyokawa, Et. Al (2011) suggest many aspects of urban living – ranging from life stressors to the use of drugs, can have an effect on human epigenetics. So the stressors of modern living could cause increased schizophrenia in future generations.

Psych Scene Hub

The Dopamine Hypothesis of Schizophrenia – Advances in Neurobiology and Clinical Application

The dopamine hypothesis stems from early research carried out in the 1960’s and 1970’s when studies involved the use of amphetamine (increases dopamine levels) which increased psychotic symptoms while reserpine which depletes dopamine levels reduced psychotic symptoms.

The original dopamine hypothesis was put forward by Van Rossum in 1967 that stated that there was hyperactivity of dopamine transmission, which resulted in symptoms of schizophrenia and drugs that blocked dopamine reduced psychotic symptoms. [1]

DOPAMINE PRODUCTION AND METABOLISM

Dopamine is synthesised from the amino acid tyrosine. Tyrosine is converted into DOPA by the enzyme tyrosine hydroxylase.

DOPA is converted into dopamine (DA) by the enzyme DOPA decarboxylase (DOPADC).

This dopamine is packed and stored into synaptic vesicles via the vesicular monoamine transporter (VMAT2) and stored until its release into the synapse.

Dopamine Receptors:

When dopamine is released during neurotransmission, it acts on 5 types of postsynaptic receptors (D1-D5).

A negative feedback mechanism exists through the presynaptic D2 receptor which regulates the release of dopamine from the presynaptic neuron.

Dopamine Breakdown

Any excess dopamine is also ‘mopped up’ from the synapse by Dopamine transporter (DAT) and stored in the vesicles via VMAT2.

Dopamine is broken down by monoamine oxidase A (MAO-A), MAO-B and catechol-o-methyltransferase (COMT).

Learning points:

• Tyrosine hydroxylase is the rate-limiting step in the production of dopamine. Its expression is significantly increased in the substantia nigra of schizophrenia patients when compared to normal healthy subjects. [2]
• Carbidopa is a peripheral DOPA-decarboxylase inhibitor co-administered with levodopa. Carbidopa prevents the conversion of levodopa to dopamine in the periphery, thus allowing more levodopa to pass the blood-brain barrier to be converted into dopamine for its therapeutic effect.
• Methamphetamine increases extracellular dopamine by interacting at vesicular monoamine transporter-2 (VMAT2) to inhibit dopamine uptake and promote dopamine release from synaptic vesicles, increasing cytosolic dopamine available for reverse transport by the dopamine transporter (DAT).
• Valbenazine a highly selective VMAT2 inhibitor has been approved by the FDA for the treatment of tardive dyskinesia.
• There is compelling evidence that presynaptic dopamine dysfunction results in increased availability and release of dopamine and this has been shown to be associated with prodromal symptoms of schizophrenia. Furthermore, dopamine synthesis capacity has also been shown to steadily increase with the onset of severe psychotic symptoms. [3] , [Howes & Shatalina, 2022]

• Dopaminergic transmission in the prefrontal cortex is mainly mediated by D1 receptors , and D1 dysfunction has been linked to cognitive impairment and negative symptoms of schizophrenia . [4]

THE 4 DOPAMINE PATHWAYS IN THE BRAIN

1.The Mesolimbic Pathway

• The pathway projects from the ventral tegmental area (VTA) to the nucleus accumbens in the limbic system.
• Hyperactivity of dopamine in the mesolimbic pathway mediates positive psychotic symptoms. The pathway may also mediate aggression.
• The mesolimbic pathway is also the site of the rewards pathway and mediates pleasure and reward. Antipsychotics can block D2 receptors in this pathway reducing pleasure effects. This may be one explanation as to why individuals with schizophrenia have a higher incidence of smoking as nicotine enhances dopamine in the reward pathway (self-medication hypothesis)
• Antagonism of D2 receptors in the mesolimbic pathway treats positive psychotic symptoms.
• There is an occupancy requirement with the minimum threshold at 65% occupancy for treatment to be effective. Observations support this relationship between D2-receptor occupancy and clinical response that 80% of responders have D2-receptor occupancy above this threshold after treatment. [5]

2.The Mesocortical Pathway

• Projects from the VTA to the prefrontal cortex.
• Projections to the dorsolateral prefrontal cortex regulate cognition and executive functioning.
• Projections into the ventromedial prefrontal cortex regulate emotions and affect.
• Decreased dopamine in the mesocortical projection to the dorsolateral prefrontal cortex is postulated to be responsible for negative and depressive symptoms of schizophrenia.
• Nicotine releases dopamine in the mesocortical pathways alleviating negative symptoms (self-medication hypothesis).

3.The Nigrostriatal Pathway

• Projects from the dopaminergic neurons in the substantia nigra to the basal ganglia or striatum.
• The nigrostriatal pathway mediates motor movements.
• Blockade of dopamine D2 receptors in this pathway can lead to dystonia, parkinsonian symptoms and akathisia.
• Hyperactivity of dopamine in the nigrostriatal pathway is the postulated mechanism in hyperkinetic movement disorders such as chorea, tics and dyskinesias.
• Long-standing D2 blockade in the nigrostriatal pathway can lead to tardive dyskinesia. 

4.The Tuberoinfundibular (TI) Pathway

• Projects from the hypothalamus to the anterior pituitary.
• The TI pathway inhibits prolactin release.
• Blockade of D2 receptors in this pathway can lead to hyperprolactinemia which clinically manifests as amenorrhoea, galactorrhoea and sexual dysfunction.
• Long-term hyperprolactinemia can be associated with osteoporosis.

Conceptualisation of Schizophrenia

Based on the above understanding, schizophrenia is best conceptualised as a complex entity which involves multiple pathways.

In clinical practice, there can be a disproportionate focus on positive psychotic symptoms.

It is however, important to recognise that affective (e.g depressive), negative and cognitive symptoms are a core part of schizophrenia and should be taken into account in treatment.

The aim of treatment, thus, is to modulate treatment creating a balance between effectiveness and reduction of side effects.

The balance is achieved by optimal dopamine blockade in the mesolimbic pathway while preserving (or enhancing) dopamine transmission in the other pathways.

DOPAMINE AND SCHIZOPHRENIA

The dopamine hypothesis of schizophrenia has moved from the dopamine receptor hypothesis (increased dopamine transmission at the postsynaptic receptors) to a focus on presynaptic striatal hyperdopaminergia.

According to Howes and Kapur-

This hypothesis accounts for the multiple environmental and genetic risk factors for schizophrenia and proposes that these interact to funnel through one final common pathway of presynaptic striatal hyperdopaminergia. In addition to funneling through dopamine dysregulation, the multiple environmental and genetic risk factors influence diagnosis by affecting other aspects of brain function that underlie negative and cognitive symptoms. Schizophrenia is thus dopamine dysregulation in the context of a compromised brain. [6]

Read more on the molecular imaging of dopamine abnormalities in schizophrenia. 

Clinical Implications

The hypothesis that the final common pathway is presynaptic dopamine dysregulation has some important clinical implications. Firstly, it implies that current antipsychotic drugs are not treating the primary abnormality and are acting downstream. While antipsychotic drugs block the effect of inappropriate dopamine release, they may paradoxically worsen the primary abnormality by blocking presynaptic D2 autoreceptors, resulting in a compensatory increase in dopamine synthesis. This may explain why patients relapse rapidly on stopping their medication, and if the drugs may even worsen the primary abnormality, it also accounts for more severe relapse after discontinuing treatment. This suggests that drug development needs to focus on modulating presynaptic striatal dopamine function, either directly or through upstream effects. [6]

Concept of Salience

Usually, dopamine’s role is to mediate motivational salience and thereby gives a person the ability to determine what stimulus grabs their attention and drives the subsequent behaviour.

The salience network consists of the Anterior Cingulate Cortex (ACC), insula and the amygdala.

Schizophrenia is associated with an aberrant attribution of salience due to dysregulated striatal dopamine transmission.

Dysregulation of the dopamine system ultimately leads to irrelevant stimuli becoming more prominent which provides a basis for psychotic phenomena such as ideas of reference, where everyday occurrences may be layered with a with a heightened sense of bizarre significance.  Furthermore, this misattribution of salience can lead to paranoid behaviour and persecutory delusions. [7]

A stimulus, even if initially lacking inherent salience, once paired with dopaminergic activity, maintains the ability to evoke dopaminergic activity over time. This suggests that in psychosis, once an environmental stimulus has been highlighted by aberrant dopamine signalling, it may maintain its ability to trigger dopaminergic activity, potentially cementing its position in a delusional framework, even if the system subsequently returns to normal function. [McCutcheon, et al, 2019]

LIMITATIONS OF THE DOPAMINE HYPOTHESIS OF SCHIZOPHRENIA

Current research shows that one-third of individuals with schizophrenia do not respond to non-clozapine antipsychotics despite high levels of D2-receptor occupancy.

Furthermore, a study using tetrabenazine (used as augmentation) which depletes presynaptic dopamine was not found to be effective in augmenting a clinical response in schizophrenia. [8]

Therefore, for a significant number of patients with schizophrenia, the basis of their symptoms is either unrelated to dopaminergic dysfunction or is associated with something more than just dopamine excess.

Alternatively, this could also mean that for some patients with schizophrenia there might be a non-dopaminergic sub-type of schizophrenia.

The current dopamine hypothesis of schizophrenia does not adequately explain the cognitive and negative symptoms. Current treatments which modulate dopamine transmission have only modest effects in improving these symptoms.

It has taken two decades for the dopamine hypothesis to evolve and reach its current state. More recent evidence shows another neurotransmitter, glutamate playing an essential role in schizophrenia.

The future likely holds a lot more secrets about schizophrenia which should unravel with the advances in understanding the brain.

Learn more:

Simplified Guide to Mechanisms of Action of Oral Antipsychotics

RECOMMENDED BOOKS

Howes O, et al . Midbrain dopamine function in schizophrenia and depression: a post-mortem and positron emission tomographic imaging study. Brain . 2013

Howes OD, Shatalina E. Integrating the Neurodevelopmental and Dopamine Hypotheses of Schizophrenia and the Role of Cortical Excitation-Inhibition Balance. Biol Psychiatry. 2022 Sep 15;92(6):501-513.

Howes, O., McCutcheon, R., & Stone, J. (2015). Glutamate and dopamine in schizophrenia: an update for the 21st century. Journal of psychopharmacology , 29 (2), 97-115.

Kapur S, et al . Relationship between dopamine D(2) occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia. American Journal of Psychiatry . 2000

Howes O, Murray R. Schizophrenia: an integrated sociodevelopmental-cognitive model. Lancet . 2014

McCutcheon, R. A., Abi-Dargham, A., & Howes, O. D. (2019). Schizophrenia, dopamine and the striatum: from biology to symptoms.  Trends in neurosciences ,  42 (3), 205-220

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Does the dopamine hypothesis explain schizophrenia?

Chi-Ieong David Lau is a Consultant Neurologist whose research interests focus on the cognitive neuroscience underpinning neurological diseases. His recent work includes the investigation of the visual system in migraine, as well as the modulation of slow-wave-sleep-related memory consolidation using a variety of methods, including EEG, neuroimaging, brain stimulation, and genetics. He completed his medical degree and neurology training in Taiwan and postgraduate studies at the University College London and the University of Oxford, supported by the British Chevening Scholarship.

Han-Cheng Wang is a Consultant Neurologist at Shin Kong Wu Ho-Su Memorial Hospital, with specialist clinics for Parkinson’s disease and movement disorders. He is Assistant Professor of Neurology at the College of Medicine, National Taiwan University. He is the former President and present Standing Member of the Executive Board of Taiwan Movement Disorder Society. His research interests include understanding basic neurophysiology underlying human movements and movement disorders. He is interested in linking clinical features with functional connectivity of the brain, reflected in his recent works correlating regional cerebral blood flow (CBF) changes and tract-specific abnormalities with severity of Parkinsonism.

Jung-Lung Hsu is a Clinical Neurologist. He is interested in behavioral/cognitive neuroscience. His main study is focused on brain structural change and human behavior. He is also participating in the event-related potential (ERP) study (P50 and MMN) of schizophrenia patients.

Mu-En Liu’s research interests include biological psychiatry and geriatric psychiatry. Some of the study topics are novel in the genetic study of cognitive ageing. Recently, he examined genetic effects on age-related morphologic changes in the brain. His researches may clarify the underlying molecular mechanisms of brain aging.

The dopamine hypothesis has been the cornerstone in the research and clinical practice of schizophrenia. With the initial emphasis on the role of excessive dopamine, the hypothesis has evolved to a concept of combining prefrontal hypodopaminergia and striatal hyperdopaminergia, and subsequently to the present aberrant salience hypothesis. This article provides a brief overview of the development and evidence of the dopamine hypothesis. It will argue that the current model of aberrant salience explains psychosis in schizophrenia and provides a plausible linkage between the pharmacological and cognitive aspects of the disease. Despite the privileged role of dopamine hypothesis in psychosis, its pathophysiological rather than etiological basis, its limitations in defining symptoms other than psychosis, as well as the evidence of other neurotransmitters such as glutamate and adenosine, prompt us to a wider perspective of the disease. Finally, dopamine does explain the pathophysiology of schizophrenia, but not necessarily the cause per se. Rather, dopamine acts as the common final pathway of a wide variety of predisposing factors, either environmental, genetic, or both, that lead to the disease. Other neurotransmitters, such as glutamate and adenosine, may also collaborate with dopamine to give rise to the entire picture of schizophrenia.

About the authors

The authors would like to thank Miss Frankie Wing See Tam for her valuable comments on the manuscript.

Conflicts of interest: The authors have no conflicts of interest relevant to this article.

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The Relationship Between Schizophrenia and Dopamine

Alla Bielikova / Getty Images

• Dopamine and Schizophrenia Symptoms
• Implications for Treatment

What Does This Mean for Patients?

• Causes of Schizophrenia
• High vs. Low Dopamine
• Implications

Serotonin and Schizophrenia

Experts do not fully understand what causes schizophrenia, but evidence suggests that dopamine abnormalities may play a role. High and low levels of dopamine in certain regions of the brain can also affect different symptoms of schizophrenia.

Schizophrenia is a debilitating mental disorder with a multitude of symptoms. These can range from disorganized speech and behavior to delusions and hallucinations. Some cases are far more disabling than others, but in most cases, people with this disorder require lifelong treatment and care.

Current research suggests that schizophrenia is a neurodevelopmental disorder with an important dopamine component. Four decades of research have focused on the role of dopamine in schizophrenia, and it seems clear that excesses or deficiencies in dopamine can lead to schizophrenic symptoms.

At a Glance

While other factors also play a role in the development of schizophrenia, dopamine imbalances have been identified as a key factor affecting symptoms. Too much dopamine in key areas of the brain results in delusions and hallucinations (positive symptoms) or cognitive deficits and reduced social/emotional activity (negative symptoms). Understanding the factors that contribute to dopamine symptoms can help doctors treat the condition more effectively.

What Is the Dopamine Hypothesis of Schizophrenia?

The dopamine hypothesis of schizophrenia was one of the first neurobiological theories for this disease.

Dopamine Hypothesis

This theory suggests that an imbalance of dopamine is responsible for schizophrenic symptoms. In other words, dopamine plays a role in controlling our sense of reality, and too much or too little can cause delusions and hallucinations.

The evidence for this theory comes from many sources, including post-mortem studies that have imbalances of dopamine as well as its metabolites in schizophrenic patients. In addition, drugs that block the receptors for dopamine can help control schizophrenic symptoms.

How Does Dopamine Cause Schizophrenic Symptoms?

There are two types of schizophrenia symptoms that an excess of dopamine may cause: positive and negative . Positive symptoms include delusions and hallucinations. Negative symptoms include a decrease in social activity, emotional range, and cognitive function.

Positive Symptoms

Positive symptoms are those that appear to come from outside the person. These can include delusions, hallucinations, or thought disorders.

Dopamine contributes to the development of positive symptoms through its effects on subtype-3A dopamine receptors (D3) of cortical neurons. The subtype-3A receptor is found in the prefrontal cortex, which controls planning, thinking, and other cortical areas.

When these receptors are activated by dopamine, they overstimulate neurons. This can lead to all three types of positive symptoms. Evidence for this idea comes from studies that show that patients with schizophrenia have significantly lower levels of the D3 receptor than healthy people.

Negative Symptoms

While positive symptoms appear to come from outside, negative symptoms appear to be internal. These include decreased social activity and emotional range, as well as cognitive deficits like poor problem-solving or memory deficit.

The mechanisms contributing to negative symptoms are linked to dopamine levels in the limbic system . Dopamine excess leads to an increase in the activity of dopamine receptors, creating overstimulation similar to that seen in positive symptoms.

Some researchers suggest that this overactivity decreases neuronal inhibition , leading to decreased social behavior and cognitive deficits.

Treatment Implications of the Dopamine Hypothesis

The dopamine hypothesis has important treatment implications. The vast majority of current antipsychotic medications target dopamine, and this makes sense, given that these drugs were discovered through serendipitous observations of their effect on schizophrenia.

The most important dopamine-affecting medications are the typical antipsychotics, which increase post-synaptic receptor stimulation by blocking dopamine receptors.

Unfortunately, these medications produce a number of debilitating side effects, most notably extrapyramidal symptoms (EPS) like tardive dyskinesia . Newer second-generation antipsychotics have fewer side effects, but none are perfect.

Treatment with dopamine agonists is a third possibility suggested by the dopamine hypothesis. Dopamine agonists stimulate post-synaptic dopamine receptors directly, and as such, they can be used to treat schizophrenia without producing EPS.

Being diagnosed with schizophrenia can be extremely hard on patients and their families. It's important that doctors and researchers continually investigate new treatments that could improve the lives of people living with this disorder.

However, it's also important to remember that schizophrenia is a complex disorder, and there are many ways the disease can manifest. Dopamine hyperactivity may not be the primary cause of schizophrenia in all patients. Furthermore, even if dopamine hyperactivity is the primary cause it still doesn't explain why some patients respond more strongly than others to the same treatment.

The best way for patients and their loved ones to navigate these issues is by staying informed and asking questions about any new or experimental treatments. They should also work with doctors to develop a personalized treatment plan that's appropriate for their own needs.

Does Too Much Dopamine Cause Schizophrenia?

Increased activity of the mesolimbic pathway is related to positive symptoms of schizophrenia (delusions, hallucinations, etc.). This means that increasing the activity of dopamine receptors in this brain system could theoretically reduce delusions and hallucinations.

A closely related idea is that by blocking post-synaptic dopamine receptors, scientists can reduce the psychotic symptoms of schizophrenia.

As mentioned previously, this is what most modern medications do: they block post-synaptic dopamine receptors in order to reduce psychotic symptoms. Unfortunately, when scientists block all available dopamine receptors they also produce a number of debilitating side effects such as extrapyramidal symptoms (EPS) and tardive dyskinesia.

Is Dopamine High or Low in Schizophrenia?

The most common theory about the cause of schizophrenia is that there are too many dopamine receptors in certain parts of the brain, specifically the mesolimbic pathway. This causes an increase in mesolimbic activity which results in delusions, hallucinations, and other psychotic symptoms.

Other research suggests that schizophrenia might be caused by a lack of dopamine activity in other parts of the brain. For example, scientists have discovered that the hippocampus is overactive in schizophrenia.

Schizophrenia might also be characterized by low dopamine in the prefrontal cortex, but again the evidence is inconclusive. Some studies have found that schizophrenics have elevated levels of dopamine in this region, while others suggest that there are too few dopamine receptors.

Implications of the Dopamine Hypothesis

It's important to note that schizophrenia is a complex disorder. Even if dopamine hyperactivity is the primary cause, certain types of schizophrenia might be characterized by increased activity in certain brain areas while others are characterized by reduced activity in certain brain areas.

Furthermore, it's also possible that different patients will respond to treatment differently based on how their disease manifests.

It's important for healthcare providers and researchers to continue investigating how schizophrenia works in the brain. This will help them develop better treatments for this complex disorder.

Research also implicates serotonin as a regulator of dopamine release. Antipsychotic medications, including olanzapine and clozapine , reduce serotonin activity and increase dopamine activity.

For example, olanzapine-induced reductions in serotonin metabolism were associated with significant improvements in negative and positive symptoms, but not cognitive deficits.

Schizophrenia is a severe mental disorder that can be treated. If you or someone you know was recently diagnosed with schizophrenia, you might be wondering what the future holds. Healthcare professionals can help you manage your symptoms and chart a course for the best possible outcome.

Sometimes, there may be periods of remission that allow you to live a productive life even when coping with schizophrenia. As new treatments are continually being developed, we can look forward to better options for people who experience this disorder in the future.

Murray RM, Lappin J, Di Forti M. Schizophrenia: from developmental deviance to dopamine dysregulation .  Eur Neuropsychopharmacol . 2008;18 Suppl 3:S129-S134. doi:10.1016/j.euroneuro.2008.04.002

Brisch R, Saniotis A, Wolf R, et al. The role of dopamine in schizophrenia from a neurobiological and evolutionary perspective: old fashioned, but still in vogue [published correction appears in Front Psychiatry. 2014;5:110. Braun, Anna Katharina [corrected to Braun, Katharina]; Kumaritlake, Jaliya [corrected to Kumaratilake, Jaliya]].  Front Psychiatry . 2014;5:47. Published 2014 May 19. doi:10.3389/fpsyt.2014.00047

Purves-Tyson TD, Owens SJ, Rothmond DA, et al. Putative presynaptic dopamine dysregulation in schizophrenia is supported by molecular evidence from post-mortem human midbrain .  Transl Psychiatry . 2017;7(1):e1003. Published 2017 Jan 17. doi:10.1038/tp.2016.257

Ceraso A, Lin JJ, Schneider-Thoma J, et al. Maintenance treatment with antipsychotic drugs for schizophrenia .  Cochrane Database Syst Rev . 2020;8:CD008016. doi:10.1002/14651858.CD008016.pub3

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Maia TV, Frank MJ. An Integrative Perspective on the Role of Dopamine in Schizophrenia .  Biol Psychiatry . 2017;81(1):52-66. doi:10.1016/j.biopsych.2016.05.021

Weiner I. The "two-headed" latent inhibition model of schizophrenia: modeling positive and negative symptoms and their treatment .  Psychopharmacology (Berl) . 2003;169(3-4):257-297. doi:10.1007/s00213-002-1313-x

Stępnicki P, Kondej M, Kaczor AA. Current concepts and treatments of schizophrenia .  Molecules . 2018;23(8):2087. doi:10.3390/molecules23082087

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By Arlin Cuncic, MA Arlin Cuncic, MA, is the author of The Anxiety Workbook and founder of the website About Social Anxiety. She has a Master's degree in clinical psychology.

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Article Contents

Introduction, the dopamine hypothesis: version i, the dopamine hypothesis: version ii, new evidence and the rationale for version iii, advances in neurochemical imaging of schizophrenia, advances in understanding the genetic etiology of schizophrenia, environmental risk factors for schizophrenia, multiple routes to dopamine dysfunction: interacting environmental and genetic factors, findings from the prodrome and “extended phenotype” of schizophrenia, schizophrenia or psychosis, specificity of presynaptic striatal dopamine elevation to schizophrenia or psychosis, linking dopamine abnormalities to clinical expression of schizophrenia, the dopamine hypothesis of schizophrenia: version iii, implications of the dopamine hypothesis of schizophrenia: version iii, what about the other dimensions of schizophrenia in version iii, what would lead to a rejection of the hypothesis, conclusions.

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The Dopamine Hypothesis of Schizophrenia: Version III—The Final Common Pathway

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Oliver D. Howes, Shitij Kapur, The Dopamine Hypothesis of Schizophrenia: Version III—The Final Common Pathway, Schizophrenia Bulletin , Volume 35, Issue 3, May 2009, Pages 549–562, https://doi.org/10.1093/schbul/sbp006

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The dopamine hypothesis of schizophrenia has been one of the most enduring ideas in psychiatry. Initially, the emphasis was on a role of hyperdopaminergia in the etiology of schizophrenia (version I), but it was subsequently reconceptualized to specify subcortical hyperdopaminergia with prefrontal hypodopaminergia (version II). However, these hypotheses focused too narrowly on dopamine itself, conflated psychosis and schizophrenia, and predated advances in the genetics, molecular biology, and imaging research in schizophrenia. Since version II, there have been over 6700 articles about dopamine and schizophrenia. We selectively review these data to provide an overview of the 5 critical streams of new evidence: neurochemical imaging studies, genetic evidence, findings on environmental risk factors, research into the extended phenotype, and animal studies. We synthesize this evidence into a new dopamine hypothesis of schizophrenia—version III: the final common pathway. This hypothesis seeks to be comprehensive in providing a framework that links risk factors, including pregnancy and obstetric complications, stress and trauma, drug use, and genes, to increased presynaptic striatal dopaminergic function. It explains how a complex array of pathological, positron emission tomography, magnetic resonance imaging, and other findings, such as frontotemporal structural and functional abnormalities and cognitive impairments, may converge neurochemically to cause psychosis through aberrant salience and lead to a diagnosis of schizophrenia. The hypothesis has one major implication for treatment approaches. Current treatments are acting downstream of the critical neurotransmitter abnormality. Future drug development and research into etiopathogenesis should focus on identifying and manipulating the upstream factors that converge on the dopaminergic funnel point.

The hypothesis that dopamine and dopaminergic mechanisms are central to schizophrenia, and particularly psychosis, has been one of the most enduring ideas about the illness. Despite a relatively inauspicious start—dopamine was initially thought to be a precursor molecule of little functional significance—the idea has evolved and accommodated new evidence to provide an increasingly sophisticated account of the involvement of dopamine in schizophrenia. This review summarizes the evolution of the dopamine hypothesis, which we characterize as having 2 main prior incarnations (version I, the original incarnation, and version II, which was articulated in 1991 and has been the guiding framework since). The main effort in this article is to synthesize the evidence since version II and articulate what we call “The Dopamine Hypothesis of Schizophrenia: Version III,” which represents the most parsimonious account of the current state of knowledge. We call it version III—because we expect it to be revised. However, we highlight features of version III that we believe are sufficiently well established that they are likely to be constant in future revisions, as well as aspects that are still in evolution. Finally, we review the explanatory power of the hypothesis—indicating the known aspects of schizophrenia that it can and cannot explain.

The first version of the dopamine hypothesis could be entitled the dopamine receptor hypothesis. It emerged from the discovery of antipsychotic drugs 1 and the seminal work of Carlsson and Lindqvit who identified that these drugs increased the metabolism of dopamine when administered to animals. 2 Further evidence came from observations that reserpine, which is effective for treating psychosis, was found to block the reuptake of dopamine and other monoamines, leading to their dissipation. 3 Studies showing that amphetamine, which increases synaptic monoamine levels, can induce psychotic symptoms (reviewed in Lieberman et al 4 ) provided additional evidence. It was not until the 1970s, however, that the dopamine hypothesis was finally crystallized with the finding that the clinical effectiveness of antipsychotic drugs was directly related to their affinity for dopamine receptors. 5–7 The focus at the time was on excess transmission at dopamine receptors and blockade of these receptors to treat the psychosis (eg, Matthysse 8 and Snyder 9 ). While version I accounted for the data available then, it was seen as a hypothesis of schizophrenia as a whole without a clear articulation of its relationship to any particular dimension (eg, positive vs negative symptoms) and no link was made to genetics and neurodevelopmental deficits (understandably as little was then known about them), and there was little clear indication of where the abnormality was in the living brain—this would require the later application of in vivo imaging techniques. Additionally, dopamine was thought of in isolation, with little consideration of how it might relate to known risk factors for schizophrenia, and finally there was no framework for linking the dopaminergic abnormality to the expression of symptoms.

In 1991, Davis et al 10 published a landmark article describing what they called “a modified dopamine hypothesis of schizophrenia” that reconceptualized the dopamine hypothesis in the light of the findings available at the time. The main advance was the addition of regional specificity into the hypothesis to account for the available postmortem and metabolite findings, imaging data, and new insights from animal studies into cortical-subcortical interactions. It was clear by this stage that dopamine metabolites were not universally elevated in the cerebrospinal fluid (CSF) or serum of patients with schizophrenia. Also the focus on D2 receptors was brought into question by findings showing that clozapine had superior efficacy for patients who were refractory to other antipsychotic drugs despite having rather low affinity for and occupancy at D2 receptors. Furthermore, the postmortem studies of D2 receptors in schizophrenia could not exclude the confounds of previous antipsychotic treatment, and the early positron emission tomography (PET) studies of D2/3 receptors in drug-naive patients showed conflicting results.

Taken together, these findings were incompatible with the simple excess dopaminergic neurotransmission proposal of version I. Furthermore, there was the paradox that dopamine metabolite measures were reduced in some patients with schizophrenia while still correlating with symptom severity and response to antipsychotic drugs. Davis et al 10 drew on these inconsistencies and the emerging evidence that dopamine receptors show different brain distributions—characterized as D1 predominantly cortical and D2 predominantly subcortical—to provide a basis for suggesting that the effects of abnormalities in dopamine function could vary by brain region. However, it was PET studies showing reduced cerebral blood flow in frontal cortex that provided the best evidence of regional brain dysfunction in schizophrenia. “Hypofrontality” in these studies was directly correlated with low CSF dopamine metabolite levels. Because CSF dopamine metabolite levels reflect cortical dopamine metabolism, they argued that the relationship between hypofrontality and low CSF dopamine metabolite levels indicates low frontal dopamine levels. Thus, the major innovation in version II was the move from a one-sided dopamine hypothesis explaining all facets of schizophrenia to a regionally specific prefrontal hypodopaminergia and a subcortical hyperdopaminergia. While the evidence for this in humans was indirect, animal studies provided direct evidence of a link between hypo- and hyperdopaminergia. Lesions of dopamine neurons in the prefrontal cortex result in increased levels of dopamine and its metabolites and D2 receptor density in the striatum, 11 while the application of dopamine agonists to prefrontal areas reduced dopamine metabolite levels in the striatum. 12 This provided a mechanism to propose that schizophrenia is characterized by frontal hypodopaminergia resulting in striatal hyperdopaminergia. Furthermore, Davis et al 10 hypothesized that negative symptoms of schizophrenia resulted from frontal hypodopaminergia, based on the similarities between the behavior exhibited by animals and humans with frontal lobe lesions and the negative symptoms of schizophrenia. Positive symptoms were hypothesized to result from striatal hyperdopaminergia, based on the findings that higher dopamine metabolite levels are related to greater positive symptoms and response to antipsychotic drug treatment.

Although a substantial advance, there are a number of weaknesses in “version II” of the dopamine hypothesis, many of which the authors acknowledged at the time. Much of the evidence for the hypothesis relied on inferences from animal studies or other clinical conditions. There was no direct evidence for low dopamine levels in the frontal cortex and limited direct evidence for elevated striatal dopaminergic function. It was unclear how the dopaminergic abnormalities were linked to the clinical phenomena—there was no framework describing how striatal hyperdopaminergia translates into delusions or how frontal hypodopaminergia results into blunted affect, for example. Furthermore, it has subsequently become clear that the cortical abnormalities are more complicated that just the hypofrontality proposed at that time (eg, see reviews by Davidson and Heinrichs 13 and McGuire et al 14 ) and little clear evidence of frontal hypodopaminergia in schizophrenia has emerged (see below). But, more importantly, version II predated the studies into the neurodevelopment and prodromal aspects of schizophrenia, did not describe the etiological origins of the dopaminergic abnormality, and, beyond specifying “hyperdopaminergia” or “hypodopaminergia,” did not pinpoint which element of dopaminergic transmission was abnormal.

Much has changed since version II. There have been more than 6700 articles and 181 000 citations to the topic of “dopamine and schizophrenia” since 1991. It is not possible to provide a comprehensive review of all the new findings since then, much less try to weave them into a coherent hypothesis. So, the focus of our effort is to identify the 5 most critical streams of new evidence, briefly summarize what we see as the key findings from these, and use them to develop the most parsimonious understanding of the role of dopamine in schizophrenia—version III.

Presynaptic Dopamine Function and Synaptic Dopamine

Although it is not possible to measure dopamine levels directly in humans, techniques have been developed that provide indirect indices of dopamine synthesis and release and putative synaptic dopamine levels. Presynaptic striatal dopaminergic function can be measured using radiolabelled L -dopa, which is converted to dopamine and trapped in striatal dopamine nerve terminals ready for release. This provides an index of the synthesis and storage of dopamine in the presynaptic terminals of striatal dopaminergic neurons (see review by Moore et al 15 ). Seven out of 9 studies in patients with schizophrenia using this technique have reported elevated presynaptic striatal dopamine synthesis capacity in schizophrenia, 16–22 with effect sizes in these studies ranging from 0.63 to 1.89. 23 The other 2 studies, both in chronic patients, reported either a small but not significant elevation 24 or a small reduction in levels. 25 All the studies that investigated patients who were acutely psychotic at the time of PET scanning found elevated presynaptic striatal dopamine availability, 18–21 with effect sizes from 0.63 to 1.25. 23 This, then, is the single most widely replicated brain dopaminergic abnormality in schizophrenia, and the evidence indicates the effect size is moderate to large.

The next step in dopamine transmission is the release of dopamine. Striatal synaptic dopamine release can be assessed following a challenge that releases dopamine from the neuron using PET and single photon emission computerized tomography (SPECT). The released dopamine competes with the radioligand and leads to a reduction in radiotracer binding and is considered to be an indirect index of released dopamine. 26 , 27 All the studies using this approach have found evidence of roughly doubled radiotracer displacement in patients with schizophrenia compared with controls—an elevation that is again equivalent to a moderate to large effect size. 28–32 Finally, if dopamine synthesis is increased and is more sensitive to release in the face of challenges, one would expect heightened levels of endogenous synaptic dopamine when patients are psychotic. Evidence in line with this comes from a SPECT study using a dopamine depletion technique that found that baseline occupancy of D2 receptors by dopamine is also increased in schizophrenia. 33

Dopamine Receptors

PET and SPECT studies have used various radiotracers to image dopamine D2/3 receptors in schizophrenia. As Davis et al 10 noted, the findings of the initial studies were inconsistent, with some reporting increased D2/3 receptor binding in schizophrenia 34–36 and others no difference from controls. 37 , 38 There have now been at least 19 studies investigating striatal D2/3 receptors in patients with schizophrenia and 3 meta-analyses. 30 , 39 , 40 These meta-analyses conclude that there is at most a modest (10%–20%) elevation in striatal D2/3 receptor density in schizophrenia independent of the effects of antipsychotic drugs. This appears to be specific to D2/3 receptors—striatal D1 receptor densities are unaltered, 30 , 39 , 41 , 42 and this elevation may be regionally specific because these increases are not seen in the extrastriatal regions. If anything, there is a decrease in D2/D3 receptors in extrastriatal areas such as the thalamus and anterior cingulate. 43–46 The D2 receptor exists in 2 states, and it remains to be determined if the balance between these 2 states is altered in schizophrenia. 47 Also, because the current tracers bind to a mix of D2 and D3 receptors, it is difficult to be precise whether changes are in the D3 or the D2 subtype of the receptors—though preliminary data with a recently developed tracer, [ 11 C]-(+)-4-propyl-9-hydroxynaphthoxazine, show that there is no abnormality in high states or in D3 receptors in schizophrenia. 48

Dopaminergic transmission in the prefrontal cortex is mainly mediated by D1 receptors, and D1 dysfunction has been linked to cognitive impairment and negative symptom in schizophrenia (see reviews by Goldman-Rakic et al 49 and Tamminga 50 among others). Three studies have investigated D1 receptor levels in drug-free patients with schizophrenia and found associations with cognitive impairment and negative symptoms. One reported reduced D1 receptor density 41 another no difference from controls, 42 and a further study using a different radiotracer reported increased D1 levels. 51 This variation may be explained by different properties of the radiotracers: the effect of dopamine depletion on binding by the tracer used in the first 2 studies may obscure D1 receptor density elevation that is detectable by the tracer used in the last study. 52 The increased binding shown by the tracer used by Abi-Dargham and colleagues, which was directly correlated with cognitive impairment, is thus consistent with chronic low levels of dopamine in the prefrontal cortex underlying cognitive dysfunction in schizophrenia, assuming that there has been a compensatory D1 receptor density upregulation. 51 Further studies in patients are required to clarify this, particularly because both tracers may also bind to serotonin receptors. 53

Treatment and Dopamine Receptors

Over 120 neurochemical imaging studies have investigated the in vivo effects of antipsychotic treatments on dopamine receptors in schizophrenia (see, eg, review by Frankle and Laruelle 54 ). These show that at clinical doses all currently licensed antipsychotic drugs block striatal D2 receptors. Furthermore, a threshold striatal D2 blockade is required for antipsychotic efficacy, but this is not sufficient—some patients show little improvement despite high D2 occupancy. 55–57 A major stumbling block for the dopamine hypothesis used to be the notion that antipsychotic response was delayed for 2–3 weeks after the start of treatment (see review by Grace et al 58 ). However, there is now convincing evidence that there is no delayed response: the onset of antipsychotic action is early, 59 , 60 this response is related to striatal D2 receptor occupancy, 61 and D2 occupancy at as early as 48 hours predicts the nature of response that follows over the next 2 weeks. 62 Thus, the original tenet of version I still stands—dopamine D2 receptors continue to dominate and remain necessary for antipsychotic treatment and the imaging data has further strengthened the quantitative and temporal aspects of this relationship.

In summary, the molecular imaging studies show that presynaptic striatal dopaminergic function is elevated in patients with schizophrenia and correlates most closely with the symptom dimension of psychosis and blockade of this heightened transmission, either by decreasing dopamine levels or blocking dopamine transmission, leads to a resolution of symptoms for most patients.

The dopamine hypothesis ‘version II’ was published before the Human Genome Project and the huge advances in genetic research in schizophrenia. After over 1200 studies, it seems clear that no one gene “encodes” for schizophrenia. 63 Rather, in common with many other complex diseases, there are a number of genes each of small effect size associated with schizophrenia. 63 The gene database on the Schizophrenia Research Forum ( http://www.schizophreniaforum.org ) provides a systematic and regularly updated meta-analysis of genetic association studies. As of autumn 2008, 4 of the top 10 gene variants most strongly associated with schizophrenia are directly involved in dopaminergic pathways. The strongest association is with a gene variant affecting the vesicular monoamine transporter protein ( rs2270641, odds ratio 1.63). This protein acts to accumulate dopamine and other monoamines into vesicles, which fits with the PET studies that show elevated radiolabeled dopamine accumulation into striatal vesicles in schizophrenia. Additionally, other gene variants in the list of the strongest associations, such as in the genes for methylenetetrahydrofolate reductase and V-akt murine thymoma viral oncogene homolog 1, indirectly affect the dopaminergic system among other effects. 64 Many of the other gene variants in the top list are involved in brain development, such as the gene for dysbindin, or influence more ubiquitous brain transmitters such as glutamate or γ-aminobutyric acid (GABA). 63 , 64 While recent findings have breathed great interest in the copy number variations in schizophrenia—the early evidence there also suggests that they are rare, tend to be unique to families, and are unlikely to account for more than a few percent of schizophrenia. 63 , 65–67 It would be premature to try and synthesize these genes into a pathway leading to dopamine abnormality because the precise number, nature, function, and association of these genes to schizophrenia is evolving. The most parsimonious statement that can be made today is that while a number of genetic associations have been identified, none of them accounts for the majority of schizophrenia and most of them are likely to be susceptibilities. Of the ones that have been identified, some have already been tied to altered dopamine transmission. 68 However, the functional relevance of most of them to dopamine function is not known. 68 This view of schizophrenia genetics then reemphasizes a critical role for other interacting factors—particularly the environmental risk factors for schizophrenia.

A large number of disparate environmental factors clearly contribute to the risk for schizophrenia, yet many hypotheses of schizophrenia, including previous versions of the dopamine hypothesis, make no allowance for them. Markers of social adversity such as migration, unemployment, urban upbringing, lack of close friends, and childhood abuse are all associated with a well-established increased risk for schizophrenia that cannot readily be explained by genetic factors alone. 69 These factors either directly index social isolation/subordination or are linked to these experiences. 70 Studies in animals of social isolations 71–73 and subordination 73 , 74 find that these factors lead to dopaminergic overactivity.

Other environmental factors, such as pregnancy/obstetric complications, act in early life to increase the subsequent risk of schizophrenia (reviewed by Cannon et al, 75 Geddes and Lawrie, 76 and Kunugi et al 77 ). There is now substantial evidence from animal models that pre- and perinatal factors can lead to long-term overactivity in mesostriatal dopaminergic function (reviewed by Boksa and El-Khodor 78 and Boksa 79 ). For example, neonatal lesions affecting the hippocampus 80 , 81 or frontal cortex 82 increase dopamine-mediated behavioral responses in rats, as does prenatal stress, whether induced by corticosterone administration 83 or maternal handling. 84 Neonatal exposure to toxins also leads to increased dopamine-mediated behavioral responses 85 and elevated striatal dopamine release. 86 Prenatal and neonatal stress, such as maternal separation, also increases striatal dopamine metabolism 83 and release. 87 , 88 The latter findings parallel the increased presynaptic dopaminergic function found in schizophrenia.

A number of psychoactive substances also increase the risk of schizophrenia. The relationship between stimulants, psychosis, and their effects on dopaminergic function has already been considered (eg, Lieberman et al, 4 Angrist and Gershon, 89 and Yui et al 90 ). However, recent PET imaging work has shown that even a few doses of a stimulant may sensitize the striatal dopamine system and can lead to enduring increases in dopamine release to amphetamine even after many months of abstinence. 91 Since earlier versions of the dopamine hypothesis, cannabis use has emerged as a risk factor for schizophrenia. 92 , 93 The main psychoactive component of cannabis primarily acts at cannabinoid receptors, 94 and this as well as other cannabinoid agonists have been shown in animals to increase striatal dopamine release. 95 , 96 Initial findings indicate this is the case in man as well, 97 a result supported by observations that dopamine metabolite levels are increased in patients admitted during a first episode of psychosis associated with cannabis use. 98 Psychoactive drugs acting on other systems may also indirectly act on the dopaminergic system by potentiating dopamine release caused by other effects. This has been shown for the N -methyl- D -aspartic acid (NMDA) blocker ketamine, which has been found to increase amphetamine-induced dopamine release in healthy humans to the levels seen in schizophrenia. 99 These new data therefore indicate that even psychoactive drugs that do not directly act on the dopamine system can impact on dopamine release through indirect effects.

Genes and environmental factors do not exist in isolation. Many add to each other, and some show synergistic effects on the risk of schizophrenia or brain abnormalities associated with schizophrenia (see, eg, Cannon et al 100 and Nicodemus et al 101 and reviews by Mittal et al 102 and van Os et al 103 ). Furthermore, animal studies indicate that at least some of these factors interact in their effects on the dopamine system: social isolation rearing potentiates the later effects of stimulants 104 , 105 or of stress 106 on the dopamine system. 105 Similar effects have also been found in humans, where striatal dopamine release in response to stress was increased in people who reported low maternal care during their early childhood. 107 Additionally, there are interactions with other neurotransmitter systems: dopamine release is not seen under the influence of ketamine alone 108 but enhances the action of amphetamine, suggesting the effects of NMDA blockade, or by extension other putative causes of glutamatergic dysfunction, such as neonatal insults, are modulatory. GABA interneurons are also involved in the regulation of subcortical dopamine function and have been implicated in schizophrenia. 109

Interactions between gene variants, including those influencing dopaminergic function, and environmental risk factors are another possible route to dopaminergic dysfunction. This is illustrated by findings that variants of the catechol- O -methyltransferase gene (involved in dopamine catabolism) interact with early cannabis exposure to increase the subsequent risk of psychosis 110 and, in other studies, to increase stress reactivity and paranoid reactions to stress (see review by van et al 70 ). Family history of psychosis also interacts with environmental factors such as urbanicity to increase the risk of schizophrenia. 111 , 112 Additionally, genetic risk for schizophrenia appears to interact with obstetric complications: some “schizophrenia” genetic factors make the individual more susceptible to the effects of obstetric complications, such as frontal and temporal structural abnormalities (see review by Mittal et al 102 ). As reviewed above, animal studies indicate that frontal and temporal dysfunction can lead to increased striatal dopamine release and suggest that this is another route to dopamine dysregulation.

While further work is clearly needed to investigate the nature and extent of all these possible interactions, the evidence indicates that many disparate, direct and indirect environmental and genetic, factors may lead to dopamine dysfunction and that some occur independently while others interact. The striking empirical fact is this: the relative risks for developing schizophrenia that are accorded to migration (about 2.9 113 ), obstetric complications (about 2.0, see meta-analyses 75 , 76 ), and frequent cannabis or amphetamine use (2.09 for cannabis 93 and about 10 for amphetamine use 114 ) are considerably higher than those for any single gene variant. Thus, as the dopamine hypothesis evolves, the scientific challenge will be not just to find predisposing genes but to articulate how genes and environment interact to lead to dopamine dysfunction.

Another area of significant neurobiological research over recent years has focused on the early signs, or “prodrome,” of the illness and the subtler manifestations of symptoms within family members and the population at large. These groups are at increased risk of schizophrenia but have not yet developed the illness. Evidence from studying these groups therefore has the potential to provide information about the causal chain of events leading to the development of schizophrenia. Individuals meeting clinical criteria for a high risk of psychosis, eg, have an approximate 400-fold increased risk of developing of psychotic illnesses, predominantly schizophrenia, within the following few years. 115 , 116 They show elevated striatal [ 18 F]-dopa accumulation, which is positively associated with greater symptom severity and approaches the levels seen in patients with schizophrenia. 20 Elevated presynaptic striatal dopaminergic function is also seen in other groups with an increased risk of developing psychosis, such as schizotypy, 117 , 118 and the relatives of people with schizophrenia. 119 The latter also show a greater change in dopamine metabolite levels in response to a given stressor than healthy controls 120 and an association between greater change in dopamine metabolite levels with higher levels of psychotic-like symptoms following stress. 121 These dopaminergic abnormalities appear intermediate to those seen in patients with schizophrenia, 20 , 117 , 120 although this needs to be tested in adequately powered studies. Overall, these findings indicate that dopaminergic abnormalities are not just seen in people who are frankly psychotic but are also seen in people with risk factors for psychosis, who often have symptoms, albeit at a less severe level. Furthermore, stress in these individuals has been linked to both an increase in these symptoms and an increase in dopaminergic indices (see review by van et al 70 ). This suggests that the dopaminergic abnormalities might underlie “psychosis proneness” and shows how the environment might further impact on this to lead to frank psychosis.

A further development since version II of the dopamine hypothesis is the evidence regarding structural differences prior to the onset of schizophrenia. Individuals with prodromal signs also show brain structural deficits, quite like those in patients, although to a lesser degree (see review by Wood et al 122 ), as do the relatives of people with schizophrenia and people with schizotypal features 123 (see review by Dickey et al 124 ). These brain abnormalities are in frontotemporal regions—the same areas where lesions in animals result in striatal dopaminergic abnormalities. 80 , 82 , 125 There is also evidence of longitudinal brain structural changes in schizophrenia (eg, DeLisi 126 and van Haren et al 127 ) and people at risk of schizophrenia. 122 , 128 However, the contribution of factors such as medication 129 , 130 and cannabis use 131 to the longitudinal brain changes has yet to be fully resolved—as such these changes are not addressed in the proposed dopamine hypothesis: version III. It is not just brain structure that is altered in these individuals at risk of schizophrenia—there are functional differences as well that are generally in similar brain regions to those seen in schizophrenia (see reviews by Fusar-Poli et al 132 and Lawrie et al 133 ) and a similar pattern of neurocognitive impairments to those seen in schizophrenia, although again to a lesser degree (see review and subsequent studies by Brewer et al, 134 Eastvold et al, 135 and Simon et al 136 ).

Parsimoniously, one can conclude that striatal dopaminergic elevation is present in a compromised brain in schizophrenia and that the same appears true in the “extended phenotype.” Furthermore, there is some evidence that the 2 are connected in the prodrome as well as in schizophrenia: greater striatal dopaminergic elevation in “prodromal individuals” is directly associated with poorer neurocognitive function and altered activation in frontal cortical areas during the task. 20 There are also indications that there may be a gradation in the degree of dopaminergic elevation, although direct comparisons are required to substantiate this. Finally, recent studies in schizophrenia and its prodrome have begun to further localize the presynaptic dopamine elevation in the striatum to the parts functionally linked to associative cortical areas. 20 , 137

The diagnosis of schizophrenia encapsulates patients with markedly different clinical features and courses (see reviews by Dutta et al 138 and Peralta and Cuesta 139 ). Classification systems have attempted to deal with this categorically by proposing subtypes and intermediate syndromes. 138 , 139 On the other hand, factor analyses have identified a number of symptom dimensions: positive, negative, disorganized, affective, and cognitive, eg, Dutta et al 138 and Peralta and Cuesta. 139 The dominance and mix of the dimensions may fluctuate during the natural history of the illness. 138 , 139 Additionally, many patients meet Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) ( DSM-IV ) criteria for other psychiatric disorders as well. 140 Despite this variability, it remains the fact that the vast majority of patients with schizophrenia come to clinical attention due to their psychosis. However, psychosis itself is not unique to schizophrenia. About 8% of the general population also report psychotic experiences, and in some 4% or so this is associated with impairment and distress (see review by van Os et al 141 ). Thus, the distinction between clinical and subclinical psychosis may reflect interacting personal and sociocultural factors as much as it does biology. 141

The paragraph above underlines that it would be highly implausible that any one biological factor could deterministically “explain” a diagnosis of schizophrenia. A much more likely scenario is that a biological dysfunction may contribute to one of the major dimensions of the illness. The evidence certainly suggests that striatal dopamine function appears most elevated in people who are acutely psychotic whether in the context of schizophrenia or psychosis seen in another condition. The dopamine dysfunction is present even in subjects reflecting the extended phenotype—family members, people with schizotypy, and symptomatic individuals at high risk of psychosis. 20 , 117 , 119 Thus, the current evidence is consistent with dopamine hyperfunction being most closely linked to the dimension of psychosis. Insofar because psychosis is a hallmark of schizophrenia, dopamine abnormality is routinely seen in schizophrenia. However, we would predict that if nonpsychotic forms of schizophrenia were studied (and such a category is allowable under the DSM-IV ), they would not show similar dopamine abnormalities—thus dissociating psychosis from schizophrenia.

Striatal dopamine elevation is not seen in mania, depression, or other psychiatric disorders without psychosis 142–147 and not related to measures of anxiety or depression in people with psychotic symptoms. 20 , 148 Thus, it is not a nonspecific indicator of psychiatric morbidity. However, striatal dopamine elevation is seen in psychosis associated with psychosis in at least one disorder other than schizophrenia. 22 Furthermore, dopamine blockade with antipsychotic drugs does not respect diagnostic boundaries either—it is effective for psychosis related to mania, depression, or Parkinson disease 149 , 150 as well as for psychosis in schizophrenia. While further studies and direct comparisons are required, dopamine elevation appears specifically related more generally to psychosis proneness and not just to psychosis in schizophrenia.

If a neurochemical hypothesis (based on dopamine or any other neurotransmitter) is to explain a psychiatric illness defined by its clinical expression, it has to link the 2. A major shortcoming of the first 2 versions of the dopamine hypothesis was the total silence on the issues of how dopaminergic abnormalities led to the clinical expression of the disease. Since version II of the dopamine hypothesis, developments in neuroscience have provided increasing evidence of dopamine's role in motivational incentive salience. The experiments and syntheses of data by Berridge and Robinson, 151 Robbins and Everitt, 152 , 153 and Schultz and others 154–158 have implicated a distinct role for subcortical dopamine systems in incentive or motivational salience and reward prediction, respectively. These conceptualizations provided a framework to link neurochemical dysfunction to clinical expression using concepts of salience and reward. According to one such extension of the dopamine hypothesis, 159 , 160 the abnormal firing of dopamine neurons and the abnormal release of dopamine leads to an aberrant assignment of salience to innocuous stimuli. It is argued that psychotic symptoms, especially delusions and hallucinations, emerge over time as the individual's own explanation of the experience of aberrant salience. Psychosis is, therefore, aberrant salience driven by dopamine and filtered through the individual's existing cognitive and sociocultural schemas—thus allowing the same chemical (dopamine) to have different clinical manifestations in different cultures and different individuals. 159 , 160 Incentive salience models also provide a plausible explanation for negative symptoms: dopamine dysregulation may increase the noise in the system, “drowning out” dopaminergic signals linked to stimuli indicating reward, eg, Roiser et al 161 and Seamans and Yang. 162 The net result would be reduced motivational drive that would lead over time to negative symptoms, such as social withdrawal, and neglect of interests. As an explanation, this has face validity, and there is some evidence that schizophrenia is associated with reduced ventral striatal activation to reward, and greater reduction is related to higher levels of negative symptoms. 163 However, this proposal and the hypothesis linking low frontal dopamine levels to the cognitive impairments in schizophrenia both need to be tested by further in vivo studies of neurochemical function in patients.

We propose a revised “third version” of the dopamine hypothesis to account for the new evidence, drawing on the work of many previous reviews (eg, Laruelle and Abi-Dargham, 32 van et al, 70 Cannon et al, 164 and Howes et al 165 ). The hypothesis has 4 distinctive components.

Firstly, we hypothesize that multiple “hits” interact to result in dopamine dysregulation—the final common pathway to psychosis in schizophrenia. This is illustrated schematically in figure 1 . Second, the locus of dopamine dysregulation moves from being primarily at the D2 receptor level to being at the presynaptic dopaminergic control level. Third, dopamine dysregulation is linked to “psychosis” rather than schizophrenia, and perhaps in the fullness of time it will be about “psychosis proneness.” The exact diagnosis, however, reflects the nature of the hits coupled with sociocultural factors and not the dopamine dysfunction per se. And finally, the dopamine dysregulation is hypothesized to alter the appraisal of stimuli, perhaps through a process of aberrant salience.

Multiple hits interact to result in striatal dopamine dysregulation to alter the appraisal of stimuli and resulting in psychosis, whilst current antipsychotic drugs act downstream of the primary dopaminergic dysregulation.

The hypothesis that the final common pathway is presynaptic dopamine dysregulation has some important clinical implications. Firstly, it implies that current antipsychotic drugs are not treating the primary abnormality and are acting downstream. While antipsychotic drugs block the effect of inappropriate dopamine release, they may paradoxically worsen the primary abnormality by blocking presynaptic D2 autoreceptors, resulting in a compensatory increase in dopamine synthesis. There is some evidence from healthy volunteers that acute antipsychotic treatment does increase presynaptic dopamine synthesis capacity, 166 and while successful subacute treatment can reduce this, 167 it is nevertheless elevated in patients who have received antipsychotic treatment for many years. 17 This may explain why patients relapse rapidly on stopping their medication, and if the drugs may even worsen the primary abnormality, it also accounts for more severe relapse after discontinuing treatment. This suggests that drug development needs to focus on modulating presynaptic striatal dopamine function, either directly or through upstream effects.

An attractive feature of version II was that it proposed a dysfunction in the dopamine system as a complete explanation for schizophrenia: a prefrontal hypodopaminergia leading to a subcortical hyperdopaminergia. We depart from this parsimony in version III mainly because in the last 2 decades there has been little convincing evidence for this sequence of dopamine dysfunction. On the other hand, the last 2 decades have provided substantially more evidence about the multiple routes (genetic, neurodevelopmental, environmental, social) that lead to the striatal hyperdopaminergia, as discussed earlier. Furthermore, the appreciation of the dimensional nature of symptoms of schizophrenia also speaks for partial independence of the different features (cognitive, negative) from psychosis. 139 There is of course correlational evidence that striatal dopamine abnormalities are associated with poor performance on cognitive tasks 17 , 20 , 168 and suggestion that higher striatal dopamine synthesis capacity is linked to functional abnormalities in the cortical regions engaged by these tasks. 168 , 169 However, it should be noted that recent data suggest that these frontal/cognitive changes need not necessarily be primary but instead may arise as a consequence of striatal dysfunction. 170 Thus, in contrast to version II, which proposed a single pathway, we propose that changes in multiple transmitter/neural systems underlie the cognitive dysfunction and negative symptoms of schizophrenia, and in many cases these dysfunctions precede the onset of psychosis. It is when these pathways, in convergence with other biological or environmental influences, lead to striatal dopamine hyperfunction that psychosis becomes evident and the label of schizophrenia is assigned. Thus, rather than being a hypothesis of schizophrenia—version III is more accurately a “dopamine hypothesis of psychosis-in-schizophrenia.” It remains to be tested whether this is specific to psychosis of schizophrenia or is seen with psychosis in other disorders too.

Because so much is unknown, it is given that the hypothesis will be revised as more data become available. The more intriguing question is whether one can envisage evidence that would lead to a wholesale rejection of the hypothesis. The 2 central claims of version III are the primacy of the presynaptic abnormality and the claim that dopamine is the “final common pathway.” Two different kinds of evidence could lead to a complete rejection of the hypothesis. PET studies directly implicating presynaptic dopamine dysfunction are a major foundation of this new version of the hypothesis. PET data require to be modeled to provide estimates of L -dopa uptake or synaptic dopamine levels—and the results are inferred rather than direct measurements. Thus, if it turns out that the body of evidence based on PET imaging is a confound or an artifact of modeling and technical approaches, this would be a serious blow for version III, though the data behind versions I and II would still stand strong. While possible, we think this to be highly unlikely. What is perhaps more likely is that a new drug is found that treats psychosis without a direct effect on the dopamine system. In other words, the dopamine abnormalities continue unimpeded, and psychosis improves despite them. A good example of such a new drug might be LY2140023, an mGlu 2/3 agonist. 171 If this were to be an effective antipsychotic and it could be shown that the new pathways do not show any interaction with the dopamine system, then the fundamental claim of version III, that it is the final common pathway, would be demolished. A similar situation would arise if a pathophysiological mechanism that does not impact on the dopamine system is found to be universal to schizophrenia. Much more likely is the possibility that the hypothesis will be revised but with a stronger version IV. The next decade will provide more information on the role of dopamine, particularly how genetic and environmental factors combine to influence the common pathway, and better drugs will be developed that directly influence presynaptic dopaminergic function—both logical successors to the idea of a final common pathway.

A considerable body of new evidence has amassed in the last 2 decades that is not compatible with reconceptualization of Davis and colleagues of the dopamine hypothesis of schizophrenia. To account for these developments, we have elaborated the dopamine hypothesis of schizophrenia: version III—the final common pathway. This hypothesis accounts for the multiple environmental and genetic risk factors for schizophrenia and proposes that these interact to funnel through one final common pathway of presynaptic striatal hyperdopaminergia. Furthermore, it provides a framework linking the abnormal neurochemistry to symptoms and explains both why many disparate risk factors and functional and structural abnormalities are associated with schizophrenia but are not specific to schizophrenia. It provides an explanation for overlapping findings in people with risk factors for schizophrenia and explains eventual diagnosis not in neurochemical terms but as the result of individual factors interacting with the sociocultural milieu. In addition to funneling through dopamine dysregulation, the multiple environmental and genetic risk factors influence diagnosis by affecting other aspects of brain function that underlie negative and cognitive symptoms. Schizophrenia is thus dopamine dysregulation in the context of a compromised brain. It follows from this that future drug development should focus on the systems acting on the funnel points leading to the final common pathway.

Howes has received investigator-led charitable research funds or speaking engagements from AstraZeneca, Eli Lilly, and Janssen. Kapur has received grant support or has been a consultant/scientific advisor or had speaking engagements with AstraZeneca, Bristol Meyers Squibb, Eli Lilly, EMD—Darmstadt, Glaxo Smith Kline, Janssen (Johnson and Johnson), Neuromolecular Inc, Pfizer, Otsuka, Organon, Sanofi-Synthelabo, Servier, and Solvay Wyeth.

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Do we still believe in the dopamine hypothesis? New data bring new evidence

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• 1 Department of Psychiatry, Columbia University, 1051 Riverside Drive, New York, NY 10032, USA. [email protected]
• PMID: 14972078
• DOI: 10.1017/S1461145704004110

Schizophrenia is characterized by positive symptoms, negative symptoms and cognitive impairment. The dopamine hypothesis of schizophrenia postulates that an excess of dopamine subcortically is associated with the positive symptoms. At the same time, the negative and cognitive symptoms of schizophrenia are thought to arise from a deficit of dopamine in the cortex. Evidence for the co-existence of subcortical dopamine excess and cortical dopamine deficit in the schizophrenic brain is presented. Neuroreceptor-imaging techniques, such as SPECT and PET, have been used to provide that evidence. After amphetamine challenge (to stimulate dopamine release), dopamine transmission was substantially increased in the brains of schizophrenic subjects compared with healthy controls. In addition, amphetamine challenge was associated with an increase in positive symptoms of schizophrenia. Furthermore, acute dopamine depletion studies indicated that there was an increased occupancy of D2 receptors by dopamine at baseline in schizophrenia in comparison with healthy controls. This is consistent with the notion of hyperstimulation of D2 receptors in schizophrenia. In the cortex, dopamine type-1 (D1) receptors were found to be up-regulated in patients with schizophrenia compared to controls; in the dorsolateral prefrontal cortex, a brain region involved in working memory, this increase correlated with a poor performance on the n-back task. The up-regulation of D1 receptors may represent a compensatory effect of the dopamine deficit in the cortex. These findings provide evidence for a corticalsubcortical imbalance in the schizophrenic brain.

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• The Dopamine Hypothesis

Often called the ‘feel-good’ hormone, dopamine is in charge of making you feel happy, satisfied, and motivated. When you feel good because you have accomplished something, your brain experiences a dopamine spike. What occurs, though, when there is an imbalance? Could this imbalance play a role in the development of schizophrenia ? This is where the dopamine hypothesis of schizophrenia enters the picture, examining how the imbalance of dopamine levels and the abundance of dopamine receptors contributes to schizophrenia.

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• Cell Biology

What is dopamine?

What is a synapse?

Issues with dopamine production in the ________ nigra contributes to symptoms of schizophrenia.

What did Farde et al. (1990) find in their study into the dopamine hypothesis?

The dopamine hypothesis is a deterministic theory. Why is this a limitation?

How does Parkinson's treatment, L-Dopa, support the dopamine hypothesis?

Are antipsychotics able to cure schizophrenia for good?

True or False: The dopamine hypothesis was later revised as research revealed schizophrenic patients may also have too many dopamine receptors, which can also contribute to the disorder.

Excess dopamine in the mesolimbic pathway (ventral tegmental area and nucleus accumbens) contributes to ________ symptoms of schizophrenia.

True or False: Damage to dopaminergic neurons in the substantia nigra is correlated with the development of Parkinson's.  

When did Van Rossum propose the dopamine hypothesis?

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• We will discuss the dopamine hypothesis of schizophrenia .
• First, we will provide a dopamine hypothesis psychology definition.
• Then, we explore the various aspects of the biological explanations of the schizophrenia dopamine hypothesis. including the dopamine hypothesis of psychosis.
• Finally, we will examine the d opamine hypothesis's strengths and weaknesses through an evaluation of the dopamine hypothesis.

The D opamine Hypothesis of Schizophrenia: Definition

The dopamine hypothesis, first proposed by Van Rossum in 1967, is the theory that too much dopamine in the subcortical and limbic regions of the brain may cause positive schizophrenic symptoms . According to the dopamine hypothesis, negative symptoms are associated with less dopamine in the prefrontal cortex .

The dopamine hypothesis was later revised as research revealed schizophrenic patients might also have too many dopamine receptors.

Dopamine is a neurotransmitter that helps the brain send messages to specific body parts. Neurotransmitters are chemical messengers within the brain .

Neurotransmitters bind to receptors in nerve cells after they cross a small gap between them called the synapse. Dopamine is a neurotransmitter involved in our brain’s pleasure and reward systems. The receptors of dopamine are implicated in the dopamine hypothesis of schizophrenia, in that some researchers theorise too many receptors contribute to the overactivity of dopamine in the brain and any subsequent schizophrenic developments.

Biological Explanations of Schizophrenia: Dopamine Hypothesis

The dopamine hypothesis is a biological explanation of schizophrenia, so how does it work? What parts of the brain are involved in the dopamine hypothesis?

• Dopamine is produced in different areas of the brain, and for schizophrenia, we are concerned with the substantia nigra and the ventral tegmental area .

The dopamine produced in the substantia nigra helps us trigger physical movements, including the parts of the face and mouth needed for speech. Problems with this may be responsible for some symptoms of schizophrenia , such as alogia (lack of speech) and psychomotor disturbances.

Damage to dopaminergic neurons in the substantia nigra is correlated with the development of Parkinson's.

Dopamine produced in the ventral tegmental area is released when we expect or receive a reward. This helps both animals and humans modify their behaviour to be more likely to result in a reward or positive experience. An excess of dopamine can lead to hallucinations and delusional or confused thinking, all of which are symptoms of schizophrenia .

Studies of amphetamines given to people without a history of schizophrenia showed that the effect of high levels of dopamine the drug had induced led to symptoms very similar to those of paranoid schizophrenia.

Later revisions of the hypothesis stated that possibly an excess of dopamine in the mesolimbic areas of the brain contributes to positive symptoms, and a low level of dopamine in the brain’s prefrontal cortex contributes to negative symptoms.

Dopamine Hypothesis of Psychosis: Development of the Dopamine Hypothesis

In the 1960s and 1970s, research was conducted into the use of amphetamine drugs and their effect on dopamine levels within the brain. The researchers found that psychotic symptoms increased when these drugs were consumed, sparking the idea that dopamine may help us understand how psychotic symptoms in schizophrenia patients may come to be.

The Dopamine Hypothesis: Strengths and Weaknesses

The dopamine hypothesis has been around for close to 60 years, and has gone through a series of developments alongside facing scrutiny in research. Let's evaluate the dopamine hypothesis of schizophrenia and examine its strengths and weaknesses.

Weaknesses of the Dopamine Hypothesis

The dopamine hypothesis, like any other, has its weaknesses.

• Cause and Effect: One problem with this explanation is that it is not certain whether a dopamine imbalance causes schizophrenia or whether schizophrenia causes a dopamine imbalance. Since the causal nature of the argument is unclear, it is crucial to be careful in determining cause and effect in the development of schizophrenia.
• Farde et al. (1990): Farde et al. (1990) found no difference between the dopamine receptor (D2) levels of schizophrenia patients and control patients. Farde et al.'s (1990) finding suggests that the dopamine hypothesis may not apply to all patients with schizophrenia.
• Determinism: The dopamine hypothesis can be considered deterministic (the belief that factors beyond our control determine human behaviour) because it assumes that the development of schizophrenia depends on the amount of dopamine or dopamine receptors in our brains, which does not correspond to psychological explanations of schizophrenia. It ignores how the environment affects the development of the disorder.Deterministic theories have their limitations, as they are not compatible with societal notions of responsibility, free will and self-control, on which many of our legal and moral norms are based.

Strengths of the Dopamine Hypothesis

On the other hand, some studies are sympathetic to the role dopamine plays in the development of schizophrenia.

• Parkinson's Disease and Levodopa (L-Dopa): Some patients are given levodopa when treating Parkinson’s disease, a drug that increases dopamine levels in the brain. These patients are reported to experience psychotic side effects similar to schizophrenia symptoms, such as hallucinations and dyskinesia. The dopamine aspect supports the role that dopamine plays in the development of schizophrenic symptoms.
• Abi-Dargham et al. (2000): Abi-Dargham et al. (2000) investigated whether there was a true increased level of dopamine and dopamine 2 (D2) receptors within the brain for schizophrenic people compared to controls, accounting for the effects of patients taking antipsychotics and artificially elevating their levels. They found that their results indicated, that for the levels to match up, schizophrenic patients must have an increased level of both dopamine and dopamine receptors compared to controls.

Practical Applications of the Dopamine Hypothesis

Now that we have gained some insight into the dopamine hypothesis’s theoretical aspects, let us look at how it is applied in practice.

Typical Antipsychotic Drugs: First Generation

The dopamine hypothesis has contributed to the development of antipsychotics for schizophrenia and several other disorders in which sufferers experience psychosis.

Typical antipsychotic drugs work by blocking D2 receptors in the brain, limiting dopamine activity. Blocking dopamine receptors can help reduce positive symptoms such as hallucinations

Typical antipsychotics tend to block dopamine in all areas of the brain, not just those that cause schizophrenic symptoms, which can lead to harmful side effects.

Examples of typical antipsychotics include chlorpromazine and haloperidol .

Atypical Antipsychotic Drugs: Second Generation

Atypical antipsychotic s are newer drugs that usually do not have as severe side effects as typical antipsychotics.

Atypical antipsychotics only inhibit dopamine receptors in the limbic system rather than throughout the brain.

They help control the symptoms of schizophrenia without interfering with other systems and potentially causing the same side effects as the previous generation of medications.Atypical antipsychotics bind to dopamine receptors and act on glutamate (an excitatory neurotransmitter) and serotonin. This means that these drugs can help with positive symptoms and reduce negative symptoms such as low mood and impaired cognitive function.

Because of their effect on serotonin, these antipsychotics can also help treat some comorbidities associated with schizophrenia, such as anxiety and depression .

Evaluating Practical Applications of the Dopamine Hypothesis

Considering the practical applications of the dopamine hypothesis affect patients, it's important we evaluate it thoroughly before moving forwards.

Drug treatments such as antipsychotics, developed based on the dopamine hypothesis, help patients manage their daily lives and quality of life. These drugs are relatively easy to make and administer and can positively impact healthcare providers and the economy. This is because they help people with schizophrenia to leave treatment and return to their daily lives, such as their jobs, allowing more people to be treated.

While these drugs help with schizophrenic symptoms, it is essential to point out that they cannot cure schizophrenia. This means that we need more research to find a long-term solution to the disease.

There are some ethical questions about these drugs. In some hospitals, antipsychotic medications may be used to benefit staff rather than patients to make it easier to work with patients.

Antipsychotic medications can have serious side effects, such as tardive dyskinesia, a condition that involves involuntary facial ‘tics’ such as rapid blinking, chewing movements, or rolling of the tongue. Sometimes the side effects can be worse than the initial symptoms of schizophrenia.

The Dopamine Hypothesis - Key takeaways

• The dopamine hypothesis, first proposed by Van Rossum in 1967, is the theory that high dopamine levels may cause schizophrenic symptoms.
• In the 1960s and 70s, researchers studied amphetamines and their effect on dopamine levels in the brain. Researchers found that psychotic symptoms increased when these drugs were used. This finding gave us the idea that this could help us understand the cause of psychotic symptoms in schizophrenia patients.
• Problems with dopamine production and imbalances in dopamine in the substantia nigra and ventral tegmental area may be responsible for the symptoms of schizophrenia, such as alogia, hallucinations, and psychomotor disturbances.
• It is difficult to establish cause and effect in the dopamine hypothesis, however, many studies support the evidence that imbalances in the brain concerning dopamine are related to psychotic and negative symptoms. More research is needed to identify what causes schizophrenia.

Flashcards in The Dopamine Hypothesis 13

 A neurotransmitter associated with the rewards system of our brains.

A small gap between neurons across which messages are fired through neurotransmitters.

substantia.

No difference in dopamine (D2) receptor levels between schizophrenic and non-schizophrenic participants.

Deterministic theories have their limitations, as they are not compatible with societal notions of responsibility and self-control, on which many of our legal and moral norms are based.

Some patients are given levodopa (L-Dopa) when treating Parkinson’s disease, a drug that increases dopamine levels in the brain. These patients are reported to experience psychotic side effects similar to schizophrenia symptoms. This supports the role that dopamine plays in the development of schizophrenic symptoms.

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Frequently Asked Questions about The Dopamine Hypothesis

What is the dopamine hypothesis of schizophrenia in psychology?

The dopamine hypothesis, first proposed by Van Rossum in 1967, is the theory that high or low levels of dopamine may cause schizophrenic symptoms.

What is the role of dopamine in schizophrenia?

The dopamine hypothesis suggests dopamine level imbalances and too many dopamine receptors play a role in the development of symptoms of schizophrenia. However, the dopamine hypothesis does not fully explain how the disorder develops. Newer antipsychotics that are generally more effective than previous drug treatments target more neurotransmitters than just dopamine, suggesting that it may not exclusively be dopamine that causes schizophrenia.

What is the original dopamine hypothesis of schizophrenia?

The original dopamine hypothesis states that too much dopamine within an individual's brain causes the onset of schizophrenic symptoms, such as hallucinations.

Do people with schizophrenia have low levels of dopamine?

Schizophrenic people may have low levels of dopamine. The dopamine hypothesis suggests both low and high levels of dopamine in certain areas of the brain may be responsible for schizophrenic symptoms. Low levels of dopamine, for instance, may result in negative symptoms. 

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• > The Dopamine Hypothesis Survives, but There Must Be...

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The dopamine hypothesis survives, but there must be a way ahead.

Published online by Cambridge University Press:  02 January 2018

Karl Popper has taught us that no hypothesis can be regarded as proved-merely as having survived the most stringent tests which have so far been devised. Dinan makes a further attempt to overthrow the dopamine hypothesis of the mechanism of the antipsychotic effect, and provides an alternative suggestion. As one time critic and later advocate of the theory, I think he underestimates its explanatory power and capacity for survival. I doubt that his alternative yet poses a serious challenge. I propose below a second (and perhaps more idiosyncratic) alternative. I do not claim it yet has the explanatory power of the dopamine theory, but I think it generates some new approaches.

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• Volume 151, Issue 4
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• DOI: https://doi.org/10.1192/bjp.151.4.460

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• Published: 16 July 2024

Humans adaptively deploy forward and backward prediction

• Paul B. Sharp   ORCID: orcid.org/0000-0003-4949-1501 1 , 2 , 3 &
• Eran Eldar 1 , 2  

Nature Human Behaviour ( 2024 ) Cite this article

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The formation of predictions is essential to our ability to build models of the world and use them for intelligent decision-making. Here we challenge the dominant assumption that humans form only forward predictions, which specify what future events are likely to follow a given present event. We demonstrate that in some environments, it is more efficient to use backward prediction, which specifies what present events are likely to precede a given future event. This is particularly the case in diverging environments, where possible future events outnumber possible present events. Correspondingly, in six preregistered experiments ( n  = 1,299) involving both simple decision-making and more challenging planning tasks, we find that humans engage in backward prediction in divergent environments and use forward prediction in convergent environments. We thus establish that humans adaptively deploy forward and backward prediction in the service of efficient decision-making.

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All emojis were modified from designs by OpenMoji under CC BY-SA 4.0 . P.B.S. was funded on a Fulbright Association US Scholar grant (no. PS00318453). This work has been made possible by NIH grants no. R01MH124092 and no. R01MH125564, ISF grant no. 1094/20 and US–Israel BSF grant no. 2019801. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

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• Biomedicines

Dopamine in Health and Disease: Much More Than a Neurotransmitter

Rafael franco.

1 Neurodegenerative Diseases, CiberNed. Network Research Center, Spanish National Health Institute Carlos III, Valderrebollo 5, 28031 Madrid, Spain; [email protected]

2 Department of Biochemistry and Molecular Biomedicine, University of Barcelona, 08028 Barcelona, Spain

Irene Reyes-Resina

Gemma navarro.

3 Department of Biochemistry and Physiology, Faculty of Pharmacy and Food Science, University of Barcelona, 08028 Barcelona, Spain

Dopamine is derived from an amino acid, phenylalanine, which must be obtained through the diet. Dopamine, known primarily to be a neurotransmitter involved in almost any higher executive action, acts through five types of G-protein-coupled receptors. Dopamine has been studied extensively for its neuronal handling, synaptic actions, and in relation to Parkinson’s disease. However, dopamine receptors can be found extra-synaptically and, in addition, they are not only expressed in neurons, but in many types of mammalian cells, inside and outside the central nervous system (CNS). Recent studies show a dopamine link between the gut and the CNS; the mechanisms are unknown, but they probably require cells to act as mediators and the involvement of the immune system. In fact, dopamine receptors are expressed in almost any cell of the immune system where dopamine regulates various processes, such as antigen presentation, T-cell activation, and inflammation. This likely immune cell-mediated linkage opens up a new perspective for the use of dopamine-related drugs, i.e., agonist–antagonist–allosteric modulators of dopamine receptors, in a variety of diseases.

1. Introduction

Mammalian endogenous monoamines are very interesting compounds. They act as neurotransmitters and as regulatory molecules that participate in keeping homeostasis, but that may become part of the problem in some diseases. An example is adrenaline/noradrenaline, which are neurotransmitters of sympathetic neurons but which, in addition, are secreted by the adrenal gland to maintain homeostasis. In tumors of the adrenal gland, overproduction of these monoamines leads to many of the serious symptoms of the patients. Dopamine (DA) is more known as a neurotransmitter, although it also acts as a compound that helps in maintaining homeostasis. However, a difference with adrenaline/noradrenaline is that DA seems to act more in the paracrine mode than in an endocrine-type fashion.

Monoamines (adrenaline, noradrenaline, DA, etc.) were first detected in the brain. The first detection of a compound that was likely DA was in 1951 in the brain of different animals (humans included) [ 1 ]. Similar studies but addressing regional distribution failed to detect DA in areas of low noradrenaline content (e.g., the caudate putamen) [ 2 ]. A few years later, the compound, which was neither noradrenaline nor adrenaline, was isolated and identified as DA by paper chromatography [ 3 , 4 ]. At that moment, the main question was the physiological role of DA. A very important piece of information came from the discovery that L-DOPA, which is the precursor of DA ( Figure 1 ), was facilitating waking up after hexobarbital anesthesia; the authors of the study postulated that DA was the active compound whose precursor was L-DOPA [ 5 ]. Research in the late 1950s was key in demonstrating that DA had specific functions in and out of the brain, and that L-DOPA was a precursor that upon administration to animals could be converted into DA [ 6 , 7 ].

Dopamine synthesis and degradation pathways. ASC, ascorbic acid; COMT, catechol-o-methyltransferase; DA βH, dopamine β-hydroxylase; DOPAC, 3,4-dihydroxyphenylacetic acid; DOPA DEC, L-DOPA decarboxylase; L-DOPA, levo-dopa; L-Phe, L-phenylalanine; L-Tyr, L-tyrosine; MAO, monoamine oxidase; PH, phenylalanine hydroxylase; TH, tyrosine hydroxylase.

A key discovery was the link between dopamine deficiency and Parkinson’s disease (PD). Several laboratories participated, some to discover that the cause of PD was in the brain structures related to the striatum, and others showed that it was a lack of dopamine in the substantia nigra which, in turn, led to the depletion of DA in the striatum. Soon after these early discoveries, L-DOPA was proposed as a medication to combat the symptoms of PD (see Ref. [ 8 ] for a detailed account of the discovery of DA and of DA deficiency in the Parkinsonian brain) [ 9 , 10 ]. Studies with animal models of PD have suggested that the motor disturbances are due to a disbalance in the so-called direct and indirect striatal pathways, in which neurons projecting to the globus pallidus and substantia nigra pars reticulata have two different types of dopamine receptors (D 1 or D 2 ; five DA receptor types have been discovered; see below). This view has been recently challenged by immunochemical-based assays in non-human primates showing that striatal neurons may express the two receptor types [ 11 ], and by single-axon tracing studies (also in non-human primates), indicating evidence against a dual striatofugal system [ 12 ].

Dopamine is now arising as one of the most relevant neurotransmitters, as it seemingly participates directly or indirectly in almost any physiological function occurring in the central nervous system (CNS). This review presents information about dopamine that has mainly been obtained from enzymatic studies, and about the link with PD, without forgetting the actions that DA exerts in the periphery. The review also highlights the cell-based communication that links the gut and the CNS.

2. Dopamine, Dopamine Receptors and Catechol-Related Enzymes

DA, or 4-(2-aminoethyl)-1,2-benzenediol, is one of the main neurotransmitters in the mammalian nervous system. In the central nervous system, it is produced and released by the so-called dopaminergic neurons, which are found in different brain areas but are especially abundant in the substantia nigra. Dopaminergic neurons of the substantia nigra pars compacta project to the striatum, where specific receptors are activated and the signal is transmitted by projection neurons and further circuitry to the pallidus, the thalamus, and the substantia nigra pars reticulata. DA participates in almost any centrally controlled event, from motor control to cognition.

Overall, DA acts via two well-described mechanisms, namely, wiring and volume transmission. Wiring transmission participates in releasing DA to the synaptic cleft, where it acts on postsynaptic DA receptors. Volume transmission occurs when extracellular DA arrives to neurons other than those postsynaptically located; i.e., by diffusion, DA reaches receptors in other neurons (or glial cells) that are not in direct contact with the cell that has released the neurotransmitter [ 13 , 14 , 15 , 16 ]. This means that the brain contains a certain degree of dopaminergic tone resulting from the DA that, released to the extracellular medium, activates extrasynaptic receptors in different cells across the brain.

So far, five DA receptors have been described (D 1 , D 2 , D 3 , D4 and D 5 ), which belong to the superfamily of G protein-coupled receptors (GPCRs). For many years it was assumed that DA’s role in the brain consisted of producing variations in intraneuronal cAMP levels, and in the activation/inactivation of protein kinase, which in turn regulates the activity of a protein that is considered key in dopaminergic neurotransmission, DA- and cAMP-regulated phosphoprotein of 32 kDa molecular weight (DARPP32). The cognate protein of D 1 and D 5 receptors is Gs, whose engagement activates adenylate cyclase, thus leading to increases in cytosolic cAMP levels. Instead, the cognate protein of the D 2 , D 3 and D 5 receptors is Gi, whose engagement inactivates adenylate cyclase, thus leading to decreases in cytosolic cAMP levels [ 17 ]. Gs or Gi coupling may occur in cells other than neurons because DA receptors are found in many cell types (even in the periphery), thus substantiating the interpretation that DA is more than a neurotransmitter. As shown below, there are splice variants of dopamine receptors; some of them are “natural”, i.e., occurring in all individuals, and some vary from individual to individual and may be associated with impulsive behaviors or with the risk of addiction. Splice variants are mainly described for the D 2 and the D 4 receptors; importantly, other gene polymorphisms described for all five receptors, including single nucleotide polymorphism, may be associated with a variety of addictions (drugs, alcohol, etc.) and obesity [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ]; other non-dopamine-receptor-related factors also influence addictive behaviors.

3. Features of DA Receptors That Are Important in Dopaminergic Transmission in Both Health and Disease

For decades it was assumed that the DA link to calcium-mediated actions was indirect. However, the laboratory of Susan George provided evidence that the D 1 –D 2 receptor assemblies couple to Gq/11 instead of coupling to Gs or Gi [ 26 , 27 ]. Gq coupling allows calcium mobilization, this being a direct link between DA and actions mediated by the ion. The controversy as to whether D 1 –D 2 receptor interactions do not occur in primates was solved by the demonstration that there are a significant percentage of neurons expressing D 1 –D 2 receptor complexes in the Macaca fascicularis monkey model [ 11 ]. A physiological role of D 1 –D 2 receptor heteromers was demonstrated in the healthy brain, and a pathophysiological one in models of addiction [ 11 , 28 , 29 , 30 ]. In addition, the same laboratory has reported that expression differences depending on the sex affect anxiety- and depression-like neuropsychiatric diseases [ 31 ].

The variety of effects in the healthy brain and the therapeutic potential of targeting DA receptors in diseases of the nervous system is sustained by the myriad possibilities derived from the occurrence of complexes formed by DA receptors, or by DA receptors and other cell surface receptors. DA’s action in a given cell will depend on the DA receptors expressed on the plasma membrane and on the expression of complexes in which these receptors participate. Indeed, each receptor–receptor heteromer conveys a different signaling when activated by DA, i.e., each receptor heteromer has its own physiological role and pharmacological properties [ 32 , 33 , 34 ]. An example that is relevant for Parkinson’s disease is the occurrence of striatal neurons expressing D 1 and adenosine A 1 receptors [ 35 ], or D 2 and adenosine A 2A receptors [ 36 ]. The antagonism between the dopaminergic transmission and purinergic regulation of neurotransmitter release is, in part, due to the occurrence of these heteromers [ 37 , 38 , 39 , 40 ].

Other homotropic heteromers that have been so far reported include D 1 –D 3 [ 41 , 42 ], D 2 –D 3 [ 43 ], D 2 –D 5 [ 28 ] and D 2 –D 4 [ 44 ]. Apart from the A 1 –D 1 and the A 2A –D 2 , other heterotropic receptor heteromers include the D 1 –histamine H 3 [ 45 ], the D 2 –histamine H 3 [ 46 ], the D 4 –adrenergic [ 47 ], etc.; for a complete list of DA receptor-containing complexes, see http://www.gpcr-hetnet.com/ [ 48 ]. As an example of the physiological role of DA-containing heteromers, those involving some adrenergic receptors are involved in the circadian regulation of melatonin production by the pineal gland [ 48 ].

Despite the fact that there are few examples of isoforms in GPCRs, the mRNAs for the D 2 and D 4 receptors may suffer differential splicing, thus giving rise to various isoforms. The most studied is the D 2 short and the D 2 , which differ in the size of the third intracellular loop [ 49 ]. Interestingly, the D 2 short may be expressed presynaptically to regulate neurotransmitter release, thus acting as an autoreceptor [ 50 , 51 ]. The circa 20 variants of the D 4 receptor are due to a hypervariable region of the D 4 gene; they come from 27 haplotypes [ 52 , 53 ] and one of them, the D 4.7 , is associated with attention-deficit hyperactivity disorder [ 54 ]. The structural particularities of the different heteromers, for instance the interacting interfaces, underlie differential signaling [ 55 , 56 , 57 ]. In the case of the D 2 short isoform, it so happens that it may interact with some of the D 4 receptor variants but not with the D 4 . 7 isoform [ 58 ]. Whether this lack of homotropic DA receptor–receptor interaction has an impact on the pathophysiology of attention-deficit hyperactivity disorder is, at present, unknown.

4. Dopamine, L-DOPA and Parkinson’s Disease

Both imbalances in dopamine neurotransmission and alterations of brain circuits where dopamine is a key factor are involved in a variety of neurological and neuropsychiatric diseases, from alcohol/drug addiction to schizophrenia [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 59 , 60 , 61 , 62 ]. In fact, typical antipsychotics act “almost exclusively on the dopamine system” [ 63 ]. A review taking into account all those diseases is out of the scope of the present review, which will focus on the main dopamine-associated disease, namely, Parkinson’s disease (PD).

Details of DA synthesis are found in Figure 1 . In the human, DA synthesis requires an essential amino acid, phenylalanine, which is the precursor of another relevant amino acid, tyrosine, that is the precursor of several bioactive molecules. Two enzymes are required for DA synthesis: L-tyrosine hydroxylase, which is a used as a marker of DA-producing cells/neurons, and L-3,4 dihydroxyphenylalanine (L-DOPA) decarboxylase. In “dopaminergic” cells, DA is the final product that can be re-used or degraded; however, in cells containing dopamine β-hydroxylase, e.g., cells in the adrenal gland, it is converted into noradrenaline. It has been considered that phenylalanine is essential because it would be quite “expensive” to synthesize it in neurons. Evolution has allowed mammals to obtain phenylalanine from nutrients for the easy procurement of tyrosine and its derivatives (DA, thyroxine, adrenaline, tyramine, etc.). This selective advantage has allowed us to save energy and synthetic enzymes. However, the hydroxylation of tyrosine to lead to L-DOPA requires reducing power, meaning that sustained DA production may lead to oxidative stress. To minimize the synthesis of new DA molecules, neurons have specific uptake mechanisms to incorporate interstitial DA and reuse it.

Parkinson’s disease (PD), resulting from the death of dopaminergic neurons of the substantia nigra, is characterized by motor symptoms, including tremors at rest and difficulty in performing movements. Consistent with the key role of DA in reward circuits, PD associates with impulsive control disorders. Some centers report that up to 40% of patients have impulsive tendencies, with hypersexuality being the most common, and men being most at risk (see Ref. [ 64 ] for review).

An efficacious drug still used today was suggested decades ago by the seminal work of Hornykiewicz and colleagues. After discovering that the cause of motor symptoms was a lack of DA in certain areas of the brain and noticing that DA is unable to cross the blood–brain barrier, they thought of using L-DOPA, i.e., its precursor. L-DOPA readily crosses the blood–brain barrier and is converted into DA in the brain. Fluctuations in the blood/brain levels of the drug and the need for a chronic treatment may lead to some side effects, mainly dyskinesia [ 65 , 66 ].

5. Dopamine Derivatives in Neurological and Neuropsychiatric Diseases

The route for DA degradation consists of two enzymatic steps catalyzed by monoamine oxidase and catechol-O-methyl transferase (COMT), which lead to homovanillic acid (IUPAC name: 2-(4-hydroxy-3-methoxyphenyl)acetic acid), a compound identifiable in the urine of healthy individuals ( Figure 1 ). Obviously, the level in the urine decreases in untreated Parkinsonian patients, while it increases in patients receiving L-DOPA therapy. Homovanillic acid in the cerebrospinal fluid (CSF) is a surrogate marker for the catabolism of DA in the central nervous system [ 67 ]. The relevance of DA in the circuits involved in almost any higher function may be deduced from alterations in the levels of homovanillic acid in the CSF of patients with neurological diseases. An example is provided by tests in the CSF of 1388 children who were prescribed a lumbar puncture due to neurological clinical manifestations. The majority of patients had conditions that were not related to inheritable diseases related to DA. Among them, 696 had a clinical history that allowed stratification into the following categories, among others: epilepsy/epileptic encephalopathy ( n = 206), dysmorphic traits/genetic syndromes ( n = 69), motor disturbances ( n = 65), hemorrhagic/ischemic injuries ( n = 45) and mitochondrial disorders ( n = 47). The level of the compound was significantly altered in the group of hemorrhagic or hypoxic/ischemic injuries. In addition, in patients with definitive diagnosis high HVA levels were seldom found, while low levels were mainly detected in infectious diseases of the CNS and in perinatal stroke [ 68 ]. In summary, measuring homovanillic acid in the CSF may be complementary but not essential for the diagnosis of neurological alterations [ 67 , 69 ].

In relatively mild conditions, DA may be spontaneously oxidized using molecular oxygen to produce DA quinones and free radical products. This possibility has attracted attention as the non-enzymatic degradation of DA leads to aminochrome, the precursor of the pigment that gives the particular dark color to the substantia nigra, neuromelanin. Several years ago, the oxidation of DA was linked to an excess of aminochrome and oxidative stress that could alter mitochondrial function and even produce autophagy in dopaminergic neurons (see Ref. [ 70 ] for review). A recent review has also addressed this issue [ 71 ].

The enzymes involved in the production and the degradation of DA ( Figure 1 ) are very important in maintaining appropriate catecholamine levels and homeostatic conditions. Drugs that alter the activity of COMT, monoamine oxidase (MAO) or dopamine β-hydroxylase, may affect dopaminergic neurotransmission and any other DA-mediated physiological effects. However, the inhibition of COMT or MAO-B at adequate dosages may be beneficial for neuroprotection in PD [ 72 , 73 ]. The imbalance of systems that depend on DA may also occur following alterations in the expression of those enzymes, or polymorphisms in their respective genes [ 74 , 75 ].

6. Dopamine in the Gastrointestinal Tract

The notion of a gut–brain link is gaining momentum due to much evidence regarding the relevance of the composition of the gut microbiota to staying healthy and/or affecting the development or course of a disease. The communication starts by the regulation of the microbiota composition and intestinal function by molecules produced by either microbiota or gut cells. However, the long-distance regulations are mediated by cells of the immune system (see Refs. [ 76 , 77 , 78 ] for review). Although it is not completely canonical because the endocrine system involves the blood as a mediator of hormonal action, the concept of “microbial endocrinology” has been coined to delve into the symbiotic mechanisms that are established between our cells and the microbes that accompany us in our body [ 79 ].

As an example of the gut–brain link, there is cumulative evidence of the role of gut microbiota in the development of Parkinson’s disease. Although the underlying mechanisms are not known (see Ref. [ 80 ] for a review), it is reasonable to assume that the DA in the gut is key to a variety of physiological processes that may directly or indirectly impact on neurotransmission and neuronal fate in the CNS.

The amount of DA in the periphery is much higher than that in the CNS. More than 50 years ago, the release of DA by the rabbit ileum, likely coming from sympathetic nerve terminals, was demonstrated [ 81 ]. Apart from being produced by sympathetic neurons, DA in the periphery may be produced by a variety of cells. More than 50 years ago, the “staining characteristics” of so-called “dopamine cells” of the duodenal mucosa of cow or pig were reported [ 82 ]. Previously, a method for identifying monoamines in cells was reported by Falck [ 83 ]. DA in the gastrointestinal tract is surely produced by the phenylalanine coming from food digestion. The extra amino acid that is not processed in the intestinal cells is distributed, mainly through the blood, to all the organs of the mammalian body. In other words, not all phenylalanine coming from food digestion reaches the blood stream. On the one hand, microorganisms in the gut may both synthesize (using phenylalanine) or degrade neurotransmitters, DA included [ 84 ]. On the other hand, cells of the intestine or nerves in the intestine may accumulate and/or release DA. An example would be Paneth cells, whose cytoplasm contains aggregates of DA and 1-3,4-dihydroxyphenylalanine [ 85 ]. These are specialized cells, which are monoamine-secreting epithelial cells of the intestine located in the crypts of Lieberkühn. Paneth cells are involved in controlling the composition of the intestinal flora [ 86 , 87 ] and, remarkably, these cells together with enterocytes are in the front line of defense, thus having an intimate relationship with cells of the immune system [ 88 , 89 ].

A detailed description of all the possibilities of cells involved in phenylalanine and DA processing is out of the scope of the present review. However, it is worth assuming that DA locally produced is impacting cells of the gastrointestinal tract, and cells in Peyer’s patches and mesenteric lymph nodes ( Figure 2 ). Non-neuronal cells surely respond to DA, but further research is needed in order to know how to take advantage of gut DA and DA-rich gastrointestinal cells to combat PD and inflammatory bowel diseases [ 90 ]. Immune cells, which express different DA receptor types, play a key role (see next section). A prominent role of polymorphisms of the DRD2 gene, which codes for the D2 receptor, has been associated with the risk and the course of inflammatory bowel disease and the efficacy of the treatment; the authors of the study suggested that the receptor might be a target for Crohn’s patients refractory to the medication [ 91 ].

Dopamine link between gut and inflammation in the periphery and in the CNS. Cells in the intestine and also gut microbiota cells produce DA, which on one hand influences the composition of the gut microbiota and on the other hand binds to the dopamine receptors located in the surrounding cells, including immune cells. ( A ) In healthy conditions, there is homeostasis of the gut immune system. ( B ) In diseases affecting the gut, e.g., autoimmune diseases such as inflammatory bowel disease, immune cells (DCs, TLs, BLs, etc.) get primed. Macrophages infiltrate from the intestinal lumen trough the damaged epithelium. These primed immune cells produce local inflammation, but also reach the blood and may permeate the blood–brain barrier, reaching the brain and boosting CNS inflammation. BL, B lymphocyte; DC, dendritic cell; DA, dopamine; DR, dopamine receptor; TL, T lymphocyte.

7. Dopamine, Immune Cells, Inflammation, Autoimmunity and Parkinson’s Disease

Being produced by neurons, or not, DA acts in a wide variety of cells that express DA receptors. Generally speaking, DA is not an endocrine hormone, i.e., it does not travel by blood to reach cells in different places in the mammalian body. DA is more a molecule that acts locally; analogous to synaptic action, the compound may act in different set ups where cells are exchanging information. Therefore, for DA to act in the gut and have an impact in the CNS (and other systems), intermediate cells are needed. One of the best examples of the local action of DA occurs at the so-called immunological synapse where dendritic cells interact with lymphocytes. Additionally, DA is present in lymph nodes, and not only in those of the gastrointestinal tract. Although the role of another “neurotransmitter”, glutamate, has been more studied in the immunology research field [ 92 ], DA plays a key role in the germ center, where B and T lymphocytes interact. A subpopulation of T helper cells releases DA that “accelerates productive synapses in germinal centers” [ 93 ].

DA acting on T-cells may contribute to neurodegeneration in PD. On the one hand, the expression of the mRNA transcripts of D 3 receptors is altered in blood lymphocytes from patients [ 94 ]. On the other hand, the deletion of the D 3 receptor gene or the pharmacological blockade using receptor antagonists in rodent models of PD protect against neuroinflammation and dopaminergic denervation [ 95 , 96 ]. It is tempting to speculate that DA occupies a central place in the gastrointestinal manifestations of PD patients, also constituting an important piece in the gut–brain communication puzzle occurring in PD [ 97 , 98 , 99 , 100 ]. Although DA acting on D 3 receptors is noxious in PD models, the deletion of the receptor leads (in animal models) to chronic depression and anxiety [ 101 ].

Via the regulation of cAMP levels and mitogen-activated protein kinase (MAPK) pathway activation, D 3 but also D 5 receptors regulate T lymphocyte activation and contribute to the immune response in a variety of diseases [ 102 ]. For instance, D 3 receptor-mediated actions in CD4 + cells favor Th1/Th17-mediated immunity, thus favoring the inflammatory potential of the lymphocytes [ 103 ]. The activation of D 5 receptors in myeloid antigen-presenting cells facilitates the development of an experimental model of autoimmune disease of the nervous system (encephalitis) [ 104 ]. Overall, DA plays an important role in the immune system, regulating the functionality of dendritic cells and lymphocytes and, in addition, there is evidence of its important role in the development of autoimmune diseases [ 105 , 106 ]. The often-found detrimental action exerted by DA acting on lymphocytes opens up therapeutic opportunities. Thus, the inhibition of DA receptor-mediated actions may be beneficial in autoimmune disorders. In addition, it has been proven in an experimental model that the blockade of D3 receptor-mediated signaling in dendritic cells favors T-cell-mediated anti-tumor activity [ 107 ].

8. Future Perspectives of DA as Neurotransmitter

DA is associated with more diseases than Parkinson’s, and exerts actions that go beyond the substantia nigra and the striatum. Dopamine receptors are in the reward circuits in the brain, and are related, for instance, to plastic changes occurring in drug addiction. As above-mentioned, DA receptors are extrasynaptically located and participate in, among other things, brain remodeling/plasticity. Accordingly, future research must address (i) DA receptor (including heteromers) distribution in different areas of the brain in both health and disease, and (ii) the circuitry associated with executive actions (both in health and disease).

Knowledge of the reasons why gambling behavior is more widespread in Parkinsonian men than in Parkinsonian women is lacking. This is an example of what is needed to know and can be figured out by ad hoc research using animal models or in the human brain (e.g., by in vivo positron emission tomography or by immunochemical methods on post mortem samples). Addressing this topic can not only serve to help better manage the disease, but can also provide clues as to what may be different in the human brain according to gender: are the sex hormones that give this differential trait in the circuits related to PD? This is one of the many interesting questions that arise when considering DA as a neurotransmitter of the CNS in its broad sense: both in wiring and in volume neurotransmission.

9. Future Perspectives of DA as Regulatory Molecule

The quite recently discovered link that, via dopamine, is established between the gut and the CNS is very attractive in terms of understanding both how our body works and the pathophysiological features of some diseases. In fact, our body is constituted by our cells, but also by exogenous cells, such as those constituting our microbiota. What is the DA production by microbiota in a healthy gut? Does this DA contribute to that keep pathogens under control by impacting DA receptors in the immune cells within the gastrointestinal tract? Or, otherwise, does the excess or defectiveness of DA in the intestine disrupt such homeostatic control?

When PD appears and there is evidence of a “dopamine link” between the gut and the CNS, are events in the gut key for the development of the disease? One conservative hypothesis would be that PD starts in the brain, and that the gut–brain link may serve to impact on the denervation rate. Depending on the content of the microbiota and the status of the immune system components in the gut, primed immune cells ( Figure 2 ) may reach the brain via infiltrating lymphocytes to boost neuroinflammation and the death of dopaminergic cells in the substantia nigra. The hypothesis may be wrong, but addressing it with creative research approaches will surely help to better understand how different systems interact in both healthy and pathological situations.

There are several questions that can be raised in this exciting field of long-distance interactions between different organs, with the participation of exogenous cells and having DA as a mediator.

Author Contributions

R.F. and G.N. searched the literature. I.R.-R. searched the literature to design figures, and made figures and figure legends. R.F. wrote Section 1 , Section 2 , Section 3 , Section 4 , Section 7 , Section 8 and Section 9 , and G.N. Section 5 and Section 6 . All authors edited the manuscript and approved the final version. All authors have read and agreed to the published version of the manuscript.

This work was in part supported by grant # RTI2018-094204-B-I00 from the Spanish “Ministerio de Ciencia, Universidades e Investigación” (it includes EU FEDER funds). The research group of the University of Barcelona is considered of excellence (grup consolidat #2017 SGR 1497) by the Regional Catalonian Government, which does not provide any specific funding for reagents or for payment of services or Open Access fees).

Conflicts of Interest

Authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Social Media Influencers and Dopamine Overdose

Are influencers purveyors of ‘dopamine democracy' and a threat to society.

Posted June 27, 2024 | Reviewed by Ray Parker

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Social media influencers are sometimes called ‘microcelebrities,’ although that term may be a misnomer, as some reach many thousands, if not millions, of people. As influencers can reach those numbers, they can be highly effective advertisers. Improvements in the availability and price of technology extend the reach of influencers, and firms paying influencers for their endorsements can sell more. According to an economic analysis, the ‘influencer economy’ increased from $2 billion in 2020 to $13.8 billion in 2021, with nearly 50 million people engaged as influencers 1 . Those figures were derived during the COVID pandemic, but there is little reason to assume that this market will decline and little reason to assume that this is not a major feature of some societies.

The growth of potential social media impact on choice behaviours provokes questions like: Why is this influence so effective? Is it dangerous to society? The answers to both questions are not comfortable, but no more uncomfortable than answers given about any form of marketing tool over the last couple of centuries. Digital influencers are just another example of social influence, and patterns of social influence in the real and digital worlds are similar. However, consideration of neuroscience findings suggests that understanding dopamine 's roles in social decision-making may illuminate the core of these concerns.

The effectiveness of social media influencers pivots around the ubiquity of digital media and the relative esteem in which opinion-formers from digital and other domains are held. Of course, these issues have always needed consideration when people wish to sell something. When people used to want to open real shops, they discussed ‘footfall’ (numbers of passers-by). If lots of wildebeest go to a watering hole, that’s where the lions and crocodiles will be. It also turns out that younger people often trust social media influencers more than other purveyors of products or ideas 2 . Credibility is important when judging sources of information on social media 3 , but this is nothing different from the real world. If social media influencers are now thought to be more credible, then influencers in the real world, like politicians and salespeople, will just have to ‘up their game.’ The successful lion or crocodile often lies well-hidden until the point of attack, and the rest just starve.

Metaphors about predation in the wild suggest possibilities of destructiveness, and such concern has prompted discussion of the societally negative effects of social media influencers. The apparent scale of turnover and potential influence 1 appears startling, at least, until put into the context of the full marketplace. Advertising represented a $720 billion economy in 2021 (50 times higher than the social media influencer share) 4 . Given this, social media influence may not be as threatening as it first appears. Moreover, it is generally less threatening than the effects of a deranged political leader influencing their country into war. People rarely die from the endorsements of social media influencers, although this can happen when they endorse crazed things 5 . However, while social media influencers can be dangerous, this goes for most things, and overestimating impact is just as misleading as underestimation.

Nevertheless, some are so troubled by social media influencers’ potential for impact that they have been discussed as a threat to democracy based on the power of the digital form. When this worry is unpacked, these above issues, per se, are not key—most commentators recognise that they have happened before. Rather, the apparent ease with which social media impacts the dopamine system is a worry. Social media influencers have been termed a ‘dopamine democracy’: “ Dopamine democracy refers to a general system…in which persons are generally of the belief that they make free choices that directly contribute to governance, even though choices are actually directed by incentive salience, or the immediacy of wanting and seeking, without critical reflection or deliberation. ” 6 . The idea here is that people will become so overwhelmed by a rush of dopamine from social media that they cannot think rationally and will behave impulsively. In fact, there is something to this concern, but it also applies to all socially-mediated decision-making.

Digital exposure makes some people impulsive 7 , and impulsivity can be increased by increasing levels of dopamine 8 . However, it is unclear whether social media exposure always increases dopamine levels. Numerous media articles have claimed that social media increases the amount of, and need for, dopamine 9 , and many discuss dopamine as a sort of ‘reward’ chemical. There are two problems with this. Higher social media use, especially in social contexts, can sometimes reduce dopamine activity and synthesis, which contrasts with the effects of many other behavioural addictions 10 . Moreover, dopamine is involved in regulating several neuro-behavioural systems (e.g., sensory-motor regulation, time perception, saliency and change assessments, and motivation 11 ), but encoding reward-value is not one of them 12 .

Levels of dopamine index changes in the environment . Dopamine levels increase when some aspect of the presented environmental stimuli increase (e.g., presence, number, salience, etc.), and dopamine levels decrease when those environmental stimuli show decreases in something; this especially occurs when that environmental change is unexpected 11,13 . However, as dopamine is associated with many regulatory systems, its levels are also impacted by the nature of the stimuli involved. Importantly, for social media influencers, levels of dopamine increase in the presence of a cue that is perceived to be social 12 .

Levels of dopamine in the system are associated with being able to discriminate change in the environment. However, this is a relative judgment; detecting small increases in dopamine against a relatively low baseline is easier than detecting small increases against a high background level. Indeed, studies have shown that artificially increasing dopamine levels during a discrimination task involving ‘unlearning’ something old and learning something new reduces the ability to learn the new discrimination 13 . The notion of a ‘dopamine overdose’ 14 experienced in some physical and psychological conditions captures this problem—too much dopamine makes adaptation to changing situations more difficult.

Here, we get to the nub of the problem of socially facilitated decision-making, which applies to social media influencers but not uniquely. When people are making judgments (discriminations), changing levels of dopamine are important, as they are associated with detecting change 11 . In a social context, dopamine levels fluctuate with the changing nature of stimuli 11,12 ; however, they also change with the presence of social cues, like people or their representations 12,13 . If judgments are made against an elevated background dopamine level due to the presence of social cues, then those judgments will be less accurate 13 and potentially more impulsive 8 . This is the problem with making judgments in a social setting, under social influence, and it is not just confined to the digital world.

1. Cong, L.W., & Li, S. (2023). A model of influencer economy (No. w31243). National Bureau of Economic Research.

2. Almahdi, M., & Alsayed, N. & Alabbas, A. (2022). In influencers we trust? A model of trust transfer in social media influencer marketing. 10.1007/978-3-030-99000-8_9.

3. Ooi, K.B., Lee, V.H., Hew, J.J., Leong, L.Y., Tan, G.W.H., & Lim, A.F. (2023). Social media influencers: An effective marketing approach? Journal of Business Research , 160 , 113773.

4. Faria, J. (2024). Advertising in time of crises – statistics and facts. Statista . Advertising in times of crisis - statistics & facts | Statista

5. Engel, E., Gell, S., Heiss, R., & Karsay, K. (2024). Social media influencers and adolescents’ health: A scoping review of the research field. Social Science & Medicine , 340 , 116387.

6. Tschaepe, M. (2016). Undermining dopamine democracy through education: Synthetic situations, social media, and incentive salience. Pragmatism Today , 7 (1), 32-40.

7. Reed, P., Osborne, L. A., Romano, M., & Truzoli, R. (2015). Higher impulsivity after exposure to the internet for individuals with high but not low levels of self-reported problematic internet behaviours. Computers in Human Behavior , 49 , 512-516.

8. Pine, A., Shiner, T., Seymour, B., & Dolan, R. J. (2010). Dopamine, time, and impulsivity in humans. Journal of Neuroscience , 30 (26), 8888-8896.

9. Waters, J. (21.8.22). Constant craving: how digital media turned us all into dopamine addicts | Life and style. The Guardian. Constant craving: how digital media turned us all into dopamine addicts | Life and style | The Guardian

10. Westbrook, A., Ghosh, A., van den Bosch, R., Määttä, J. I., Hofmans, L., & Cools, R. (2021). Striatal dopamine synthesis capacity reflects smartphone social activity. iScience , 24 (5).

11. Saunders, B.T., & Robinson, T.E. (2012). The role of dopamine in the accumbens core in the expression of Pavlovian‐conditioned responses. European Journal of Neuroscience , 36 (4), 2521-2532.

12. Batten, S. R., Bang, D., Kopell, B. H., Davis, A. N., Heflin, M., Fu, Q., ... & Montague, P. R. (2024). Dopamine and serotonin in human substantia nigra track social context and value signals during economic exchange. Nature Human Behaviour , 1-11.

13. Kutlu, M. G., Tat, J., Christensen, B. A., Zachry, J. E., & Calipari, E. S. (2023). Dopamine release at the time of a predicted aversive outcome causally controls the trajectory and expression of conditioned behavior. Cell Reports , 42 (8).

14. Vaillancourt, D. E., Schonfeld, D., Kwak, Y., Bohnen, N. I., & Seidler, R. (2013). Dopamine overdose hypothesis: evidence and clinical implications. Movement Disorders , 28 (14), 1920-1929.

Phil Reed, Ph.D., is a professor of psychology at Swansea University.

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