what is dopamine hypothesis of schizophrenia in psychology

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.

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

Posted on: January 27, 2018

Last Updated: July 17, 2024

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]

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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.

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

Howes O, et al . Elevated striatal dopamine function linked to prodromal signs of schizophrenia. Archives of General Psychiatry . 2009

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. D., & Kapur, S. (2009). The dopamine hypothesis of schizophrenia: version III—the final common pathway. Schizophrenia bulletin , 35 (3), 549-562.

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

Remington, G., Kapur, S., Foussias, G., Agid, O., Mann, S., Borlido, C., … & Javaid, N. (2012). Tetrabenazine augmentation in treatment-resistant schizophrenia: a 12-week, double-blind, placebo-controlled trial. Journal of clinical psychopharmacology , 32 (1), 95-99.

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Dr. Sanil Rege is a Consultant Psychiatrist and founder of Psych Scene and Vita Healthcare. He has dual psychiatry qualifications from the United Kingdom and Australia. He currently practices on the Mornington Peninsula. His focus on combining psychiatry with principles of entrepreneurship has uniquely enabled him to not only contribute to the academic world through his several publications but also add value to the real world by establishing two successful enterprises in a short span of 6 years. He was appointed Associate Professor of Psychiatry at a prestigious Australian University at the age of 32 but left the role to focus on his passion of entrepreneurship in psychiatry. Psych Scene was co-founded to enhance psychiatry education, and Vita Healthcare was to provide the highest quality mental health care to the public. He is passionate about learning from multiple disciplines (Medicine, Psychiatry, Neurosciences, Accounting, Entrepreneurship, Finance and Psychology) with the aim of adding value to the world. By taking on multiple roles of a clinician, entrepreneur, father, educator, investor and MBA student, he recognises that personal development is a journey that needs to touch others lives for the better. He lives by the motto “All the knowledge in the world is not found in one academic discipline” and driven by curiosity. Dr. Sanil Rege is a
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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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What did Farde et al. (1990) find in their study into the dopamine hypothesis?

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.  

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Jump to a key chapter

• 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.

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

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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 Relationship Between Schizophrenia and Dopamine

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.

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.

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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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• Published: 31 January 2018

Dopamine, psychosis and schizophrenia: the widening gap between basic and clinical neuroscience

• JP Kesby   ORCID: orcid.org/0000-0002-5814-8062 1 , 2 ,
• DW Eyles 1 , 3 ,
• JJ McGrath   ORCID: orcid.org/0000-0002-4792-6068 1 , 3 , 4 &
• JG Scott 2 , 3 , 5  

Translational Psychiatry volume  8 , Article number:  30 ( 2018 ) Cite this article

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• Schizophrenia

The stagnation in drug development for schizophrenia highlights the need for better translation between basic and clinical research. Understanding the neurobiology of schizophrenia presents substantial challenges but a key feature continues to be the involvement of subcortical dopaminergic dysfunction in those with psychotic symptoms. Our contemporary knowledge regarding dopamine dysfunction has clarified where and when dopaminergic alterations may present in schizophrenia. For example, clinical studies have shown patients with schizophrenia show increased presynaptic dopamine function in the associative striatum, rather than the limbic striatum as previously presumed. Furthermore, subjects deemed at high risk of developing schizophrenia show similar presynaptic dopamine abnormalities in the associative striatum. Thus, our view of subcortical dopamine function in schizophrenia continues to evolve as we accommodate this newly acquired information. However, basic research in animal models has been slow to incorporate these clinical findings. For example, psychostimulant-induced locomotion, the commonly utilised phenotype for positive symptoms in rodents, is heavily associated with dopaminergic activation in the limbic striatum. This anatomical misalignment has brought into question how we assess positive symptoms in animal models and represents an opportunity for improved translation between basic and clinical research. The current review focuses on the role of subcortical dopamine dysfunction in psychosis and schizophrenia. We present and discuss alternative phenotypes that may provide a more translational approach to assess the neurobiology of positive symptoms in schizophrenia. Incorporation of recent clinical findings is essential if we are to develop meaningful translational animal models.

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Introduction.

Our knowledge of the neurobiology of schizophrenia, while still rudimentary, has advanced considerably in recent years. However, these findings have not translated to better treatments for those with schizophrenia. The three primary symptom groups, positive, cognitive and negative (Box 1 ), have been associated with reports of abnormalities in virtually every neurotransmitter system 1 , 2 , 3 , 4 , 5 . The onset of psychotic symptoms, which is strongly associated with alterations in dopamine function, is a key feature underpinning a clinical diagnosis 6 , 7 . However, results from clinical research regarding the specific loci of dopamine dysfunction in schizophrenia 8 , 9 , 10 , have triggered a reappraisal of our perspective on the neurobiology of schizophrenia. Currently there is a disparity between the tests for positive symptoms in animal models and recent clinical evidence for dopaminergic abnormalities in schizophrenia. Therefore, it is critical that this contemporary clinical knowledge actively influences the agenda in applied basic neuroscience.

Box 1: Symptom groups in schizophrenia

Positive symptoms

: Positive symptoms include delusions and hallucinations, linked to aberrant salience. These symptoms are most recognisable during periods of acute psychosis.

Cognitive symptoms

: Impairments in learning, memory, attention and executive functioning are all included as cognitive symptoms.

Negative symptoms: Negative symptoms include blunting of affect (lacking emotional expression), avolition (deficits in motivation) and social withdrawal.

It is widely acknowledged that we cannot recreate the complicated symptom profile of schizophrenia in animal models. However, animal models (the majority and focus of the present article being rodent models) provide an avenue to invasively explore the role of neurotransmitters and circuitry in psychiatric diseases. To improve the poor predictive validity of treatments in animal models 11 , it is critical that our understanding and the use of animal models evolves alongside our knowledge of schizophrenia neurobiology. The delayed incorporation of new clinical findings to develop better animal models highlights the need for better communication between clinical and basic research communities.

In this article, we discuss the challenges clinicians and researchers are facing in understanding the neurobiology of positive symptoms and psychosis in schizophrenia. We discuss the implications this has for current assessments of positive symptoms in rodents and propose a more relevant set of tests for future study. Finally, the need for a joint focus on bi-directional translation between clinical and basic research is outlined.

Challenges in diagnosing schizophrenia

Psychiatric symptoms exist on continua from normal to pathological, meaning the threshold for diagnosis of schizophrenia in clinical practice can be challenging. The clinical diagnosis of schizophrenia relies heavily on the positive symptoms associated with a prolonged psychotic episode. However, a relatively high percentage of the general population (8–30%) report delusional experiences or hallucinations in their lifetime 12 , 13 , 14 , but for most people these are transient 15 . Psychotic symptoms are also not specific to a particular mental disorder 16 . The clinical efficacy of antipsychotic drugs is heavily correlated with their ability to block subcortical dopamine D2 receptors 17 , 18 , suggesting dopamine signalling is important. In spite of this, no consistent relationship between D2 receptors and the pathophysiology of schizophrenia has emerged 19 , 20 . In contrast, the clinical evidence points towards presynaptic dopamine dysfunction as a mediator of psychosis in schizophrenia 19 .

The neurobiology of psychosis: the centrality of dopamine

Dopamine systems: anatomy and function.

An appreciation for the neuroanatomical differences in subcortical dopaminergic projections/circuitry between rodents and primates is essential for effective communication between clinical and basic researchers. For example, primates feature a more prominent substantia nigra and less distinctive ventral tegmental area than rodents. However, more pertinent to the current review are homologous functional subdivisions of the striatum observed in both rodents and primates 21 , 22 , 23 , 24 . These include the limbic, associative and sensorimotor areas (Fig. 1 ). The associative striatum, defined by its dense connectivity from the frontal and parietal associative cortices, is key for goal-directed action and behavioural flexibility. The limbic striatum, defined by connectivity to the hippocampus, amygdala and medial orbitofrontal cortex, is involved in reward and motivation. The sensorimotor striatum, defined by connectivity to sensory and motor cortices, is critical for habit formation. These functional subdivisions are also interconnected by feedforward striato-nigro-striatal projections 25 . The heavy basis on behavioural outcomes in neuropsychiatry has made functional subdivisions such as these more relevant than ever.

Midbrain dopamine neurons are the source of dopamine projections to the striatum in primates (left) and rodents (right). Important neuroanatomical differences exist, especially when considering functional subdivisions of the striatum. In the primate, the limbic system (orange) originates in the dorsal tier of the substantia nigra (the ventral tegmental area equivalent). In the rodent, the limbic system originates in ventral tegmental area, which sits medially to the substantia nigra. The midbrain projections to the associative striatum (yellow) and sensorimotor striatum (blue) follow a dorsomedial-to-ventrolateral topology

Dopaminergic features of psychosis in schizophrenia

In healthy individuals, dopamine stimulants such as amphetamine can induce psychotic symptoms 26 , 27 and people with schizophrenia are more sensitive to these effects 27 , 28 . Studies using positron emission tomography (PET) imaging have shown patients with schizophrenia show increases in subcortical synaptic dopamine content 29 , 30 , abnormally high dopamine release after amphetamine treatment 30 , 31 , 32 , 33 , 34 , 35 and increased basal dopamine synthesis capacity (determined indirectly by increased radiolabelled L-DOPA uptake) 19 , 36 , 37 compared with healthy controls. Increased subcortical dopamine synthesis and release capacity are strongly associated with positive symptoms in patients 33 , 38 , and increased subcortical synaptic dopamine content is predictive of a positive treatment response 29 . It was widely anticipated that the limbic striatum would be confirmed as the subdivision where these alterations in dopamine function would be localised in patients. The basis for this prediction was the belief that reward systems were aberrant in schizophrenia 39 . However, as PET imaging resolution improved it was found that increases in synaptic dopamine content 9 , 10 and synthesis capacity 8 were localised, or more pronounced 37 , in the associative striatum (Fig. 1 ; yellow). Furthermore, alterations in dopamine function within the associative striatum likely contribute to the misappropriate attribution of salience to certain stimuli, a key aspect of delusions and psychosis 40 .

Clinical studies have confirmed that dopamine abnormalities are also present prior to the onset of psychosis in schizophrenia and thus are not a consequence of psychotic episodes or antipsychotic exposure. Similar to what has been observed in patients with schizophrenia, ultra-high risk (UHR) subjects show increased subcortical synaptic dopamine content 41 and basal dopamine synthesis capacity 8 , 42 , 43 , 44 . Importantly, alterations in dopamine synthesis capacity in UHR subjects progress over time 45 and are greater in subjects who transition to psychosis compared with those who do not 46 . Furthermore, higher baseline synaptic dopamine levels in UHR subjects predicts a greater reduction in positive symptoms after dopamine depletion 41 . Overall, these findings in UHR subjects are congruent with those observed in schizophrenia and provide evidence indicating that presynaptic dopaminergic abnormalities are present prior to the onset of psychosis.

Several avenues have been proposed to explain a selective increase in associative striatal dopamine function, such as alterations in hippocampal control of dopamine projections 47 , 48 , alterations in cortical inputs to midbrain dopamine systems 2 , 49 and, although little direct evidence has been observed, developmental alterations in dopamine neurons themselves 50 , 51 . Furthermore, other pathways and/or neurotransmitters may be more critical in treatment-resistant patients 52 . We propose a network model whereby dysfunction in a central circuit, including the associative striatum, prefrontal cortex and thalamus, is critical for the expression of psychotic symptoms in schizophrenia. This model would suggest that dysfunction in auxiliary circuits (both limbic and cortical) contribute to psychotic symptoms by feeding into this primary network. Ascertaining the role of dopaminergic dysfunction, in the context of networks important for psychotic symptoms in schizophrenia, will provide a better base for constructing objective readouts in basic and clinical research.

Psychosis: a consequence of network dysfunction

Psychosis is a condition that features a range of behavioural alterations that relate to a loss of contact with reality and a loss of insight. People with psychosis experience hallucinations (primarily auditory in schizophrenia 53 ) and delusions. In schizophrenia, auditory hallucinations have been associated with altered connectivity between the hippocampus and thalamus 54 . During hallucinations, increased activation of the thalamus, striatum and hippocampus have also been observed 55 . Thus, altered thalamocortical connectivity, especially with the hippocampus, may impede internal/external representations of auditory processing 56 . In contrast, delusions in people with schizophrenia have been associated with overactivation of the prefrontal cortex (PFC) and diminished deactivation of striatal and thalamic networks 57 . Thus, the complexity of psychotic symptoms is congruent with the highly connected nature of implicated brain regions.

Although we still know little about the underlying neurobiology of psychosis, focal brain lesions allow for a better understanding of the networks involved without the confounds of medication and unrelated neuropathology. Generally speaking, lesions that induce hallucinations are often in the brain networks associated with the stimulus of the hallucination (i.e., auditory, visual or somatosensory) 58 . Visual hallucinations have been associated with dysfunction of the occipital lobe, striatum and thalamus, whereas auditory hallucinations are associated with dysfunction of the temporal lobe, hippocampus, amygdala and thalamus 58 . Insight is generally maintained after focal brain lesions that produce hallucinations and subcortical dopamine function is normal 59 , unlike what is observed in schizophrenia 58 . In contrast, a loss of insight (which can manifest as delusionary beliefs) is associated with alterations in cortico-striatal networks. For example, people with basal ganglia or caudate lesions can present with both hallucinations and delusions 60 , 61 . Furthermore, a case study of religious delusions in a patient with temporal lobe epilepsy was associated with overactivity of the PFC 62 , and there are multiple lines of evidence suggesting that the PFC is integral for delusionary beliefs 63 . Therefore, while impairing networks specific to certain sensory modalities can lead to hallucinations, dysfunctional integration of PFC input to the associative striatum may be especially important for delusional symptoms in schizophrenia.

Central to the networks involved in psychosis and schizophrenia, the thalamus acts as a relay for most information going to the cortex 64 . Brain imaging studies have demonstrated that medication-naive patients with schizophrenia have significantly reduced thalamic and caudate volumes relative to healthy controls and medicated patients 65 . Moreover, reduced thalamic volumes has also been observed in UHR subjects 66 . A simplified schematic of the networks that may be especially relevant to psychotic symptoms in schizophrenia is presented in Fig. 2 . The thalamus forms a circuit with the associative striatum and PFC whereby impairments in any of these regions can impair the functionality of the network as a whole. In addition, the hippocampus and amygdala, which are both involved in sensory perception and emotional regulation, can affect this network via their connectivity with the thalamus (but other indirect pathways also exist). Although this is an over simplification, it highlights how psychotic symptoms could arise from multiple sources of neuropathology/dysfunction or abnormal connectivity.

Dysfunction in a variety of brain regions can elicit psychotic symptoms. A primary circuit involved in psychosis includes the thalamus and prefrontal cortex (yellow) feeding into the associative striatum. Alterations in the thalamus and prefrontal cortex are involved in hallucinations and also insight for delusional symptoms. Expression of psychotic symptoms in most cases requires increased activity in the associative striatum and specifically excessive D2 receptor stimulation (red). Other limbic regions such as the hippocampus and amygdala (green) can feed into this circuit contributing to altered sensory perception and emotional context

Why do antipsychotics work?

This raises important questions as to how antipsychotic drugs exert their effects. In most individuals with schizophrenia, antipsychotic treatment is effective in reducing positive symptoms 67 ; therefore, excessive D2 signalling in the associative striatum appears to be critical. Stimulation of D2 and D1 receptor expressing medium spiny neurons (which are largely segregated 68 ) in the associative striatum feedback indirectly to the thalamus, completing a loop that allows for feedforward-based and feedback-based signalling. The basal ganglia acts as a gateway for, or mediator of, cortical inputs 69 , 70 , 71 and may represent a common pathway through which psychotic symptoms present. Therefore, excessive dopamine signalling in the associative striatum may directly lead to psychotic symptoms by compromising the integration of cortical inputs. In treatment-responsive patients, antipsychotics may attenuate the expression of psychotic symptoms by normalising excessive D2 signalling 29 to restore the balance between D1 and D2 receptor pathways 72 . Because they act downstream to schizophrenia-related presynaptic abnormalities, they fail to improve indices of cortical function (i.e., cognitive symptoms). Alternatively, impaired cortical input to the associative striatum via the thalamus, PFC or other regions could dysregulate this system independently of, or in addition to, associative striatal dopamine dysfunction. In this case, D2 receptor blockade may be insufficient to restore normal function, which is one explanation for why some individuals are treatment refractory. For example, increases in subcortical synaptic dopamine content 29 and increases in presynaptic striatal dopamine function 52 are both associated with increased treatment efficacy. Thus, in treatment-resistant subjects, there is little evidence of abnormal dopaminergic function 29 , 52 . Medicated persons with schizophrenia, who remain symptomatic with auditory hallucinations, show increased thalamic, striatal and hippocampal activation 55 . Moreover, treatment-refractory patients who respond positively to clozapine treatment show alterations in cerebral blood flow in fronto-striato-thalamic circuitry, suggesting clozapine is restoring a functional imbalance in these systems 73 . Taken together, this evidence suggests that psychosis is the result of a network dysfunction that includes a variety of brain regions (and multiple neurotransmitter-specific pathways), of which impairment at any level could precipitate psychotic symptoms.

Although increased positive symptom severity has been associated with impaired cognitive flexibility 74 , there is a little evidence for subcortical hyperdopaminergia playing a direct role in the cognitive impairments observed in schizophrenia. Furthermore, antipsychotic treatments do not improve patient’s cognitive function 75 . There is a mounting evidence that cognitive symptoms may present prior to positive symptoms in schizophrenia 76 . Given brain networks involved in hallucinations and delusions all involve cortical regions, the underlying pathology causing cognitive symptoms may also contribute to psychotic symptoms. Thus, in some cases psychosis may represent the summation of broad cognitive impairments inducing local network dysfunction (Fig. 3 ). Regardless, positive symptoms are relatively distinct in the clinical setting but the presence and severity of symptoms are determined interactively with interviews and questionnaires. The inability to do the same in other species means the best avenue for assessing animal models may be to identify outcomes that are sensitive to the underlying neurobiology observed in schizophrenia and psychosis. Given the action/effectiveness of antipsychotics, the primary downstream region of interest, in the context of elevated dopamine transmission, is the associative striatum.

This schematic representation highlights the potential for cognitive symptoms to feed into psychosis networks and create positive feedback loops that spiral to psychosis. Non-specific and heterogeneous deficits in auxiliary neurocircuitry (in the context of psychosis) lead to broad cognitive impairments unique to each individual. These systems feed into the primary psychosis networks leading to destabilisation of associative striatal dysfunction and further cognitive impairment. In most individuals with schizophrenia, excessive dopamine signalling in the associative striatum leads to positive symptoms. Antipsychotics antagonise downstream D2 receptor signalling to blunt the expression of symptoms. In treatment-refractory patients (those who do not respond to first-line antipsychotics) blocking D2 receptors is insufficient to blunt positive symptoms suggesting further upstream dysfunction in the associative striatum or psychosis networks. Clozapine may lead to improvement in some of these individuals by stabilising function throughout these networks in addition to D2 receptor antagonism. Positive symptoms in treatment-refractory patients who fail to respond to clozapine may be the result of severe impairment throughout psychosis networks (and the associative striatum) that are independent of dopamine dysfunction. Thus, our current treatments for positive symptoms act downstream of the source of cognitive impairments, hence their ineffectiveness in treating cognitive symptoms. While the expression of psychotic symptoms may be a discrete outcome, separate to impairments in cognitive function, the upstream cause of these symptoms may share common neuropathology

Modelling psychosis: the use of animal models

Potentially, the most useful avenue for animal models to assist in schizophrenia research will be identifying convergent aetiological pathways 77 . Understanding which neurotransmitter systems and brain regions are most involved may help to identify the core neurobiological features of schizophrenia. For example, changes in dopaminergic systems are observed in animal models after manipulation of factors based on schizophrenia epidemiology 50 , 51 , genetics 78 , pharmacology 79 and related hypotheses 80 . These include changes in early dopamine specification factors 50 , 51 , sensitivities to psychostimulants 50 , 51 , 78 , 80 and alterations in dopamine neurochemistry 50 , 51 , 78 , 79 . Evidence of subcortical dopaminergic hyperactivity or sensitivity in animal models is proposed to represent the face validity (i.e., mimicking the phenomenology of schizophrenia) for psychosis in patients. The most commonly used behavioural assessments of positive symptoms in animal models include enhanced amphetamine-induced locomotion and deficits in prepulse inhibition (PPI) 81 . These tests are widely used because they are relatively simple to perform. However, we propose that given current knowledge of the neurobiology in schizophrenia, they have outlived their usefulness as measures of positive symptoms.

Amphetamine-induced locomotion

Amphetamine increases dopamine release in striatal brain regions of both humans 38 and rats 82 . Amphetamine-related behaviours in rodents are also strongly linked to activity in striatal brain regions 82 , 83 . Thus, an increased locomotor response to amphetamine (and other psychostimulants, which face similar criticisms) is considered a simple test to reflect the subcortical hyperdopaminergia underlying the psychotic symptoms in schizophrenia. Most animal models of schizophrenia report increased locomotor activation after psychostimulants 78 . However, the recent clinical evidence described above suggests that current assessments of animal models does not reflect contemporaneous knowledge of dopamine activity in those with schizophrenia.

The relative contribution of specific dopamine pathways to amphetamine-induced locomotion provides a good example of why a paradigm shift is required for research using animal models for positive symptoms in schizophrenia. For example, amphetamine-induced locomotion is largely driven by limbic dopamine release. Local administration of amphetamine 84 , 85 , 86 , 87 or dopamine 84 , 88 , 89 into the nucleus accumbens induces locomotion. Furthermore, blocking dopamine signalling in the nucleus accumbens attenuates amphetamine-induced locomotion 90 . Specifically activating limbic dopamine projections using chemogenetic tools robustly increases locomotion, but activating associative dopamine projections does not 91 . Thus, there is an anatomical misalignment between the primary behavioural outcome deemed important for positive symptoms in animal models of schizophrenia (i.e, psychostimulant-induced locomotion driven by limbic dopamine), and clinical evidence in patients (hyperactive associative striatal dopamine). Furthermore, clinical studies directly comparing activity levels in patients with schizophrenia and bipolar disorder suggest that hyperactivity may be a core feature of bipolar disorder rather than schizophrenia 92 .

One argument for amphetamine-induced locomotion is that it is predictive of antipsychotic efficacy, but this is merely a serendipitous side effect. Systemically administered amphetamine increases dopamine function in both the limbic striatum (locomotion) and associative striatum (positive symptoms). Systemically administered antipsychotics antagonise D2 receptors throughout the brain. Therefore, amphetamine-induced locomotion acts serendipitously to predict antipsychotic effectiveness via dopamine release in a parallel circuit (limbic vs. associative dopamine). Optimally, antipsychotics that diminish dopamine signalling preferentially in the associative, rather than the limbic, striatum need to be developed. Obviously, amphetamine-induced locomotion would not be predictive for the latter treatment options.

Prepulse Inhibition

One of the most consistently observed neurological impairments in schizophrenia is impaired sensorimotor gating in the form of decreased PPI 93 , 94 . Deficits in PPI may reflect an inability to gate out irrelevant information. PPI deficits also respond to antipsychotics but are not specific to schizophrenia 93 , 94 . Thus, PPI deficits do not represent a specific or diagnostic trait of schizophrenia. Intact cortical and striatal function are critical for PPI 95 and, therefore, deficits in PPI also reflect an interface between positive and cognitive symptom groups 81 .

PPI is assessed almost identically in rodents and humans and, therefore, is one of the most widely studied deficits in schizophrenia. In rodents, the contribution of limbic dopamine projections to PPI are well-known 95 , though the associative striatum has also been implicated 96 , 97 . Thus, PPI deficits clearly lack specificity concerning the hyperdopaminergia observed in schizophrenia. Therefore, when assessing rodent models, PPI impairments alone are insufficient for determining positive symptom phenotypes and their predictive validity suffers from the same criticism as that of amphetamine-induced locomotion (parallel blockade of limbic D2 receptors).

Can we objectively test positive symptom connectivity in rodents?

Clearly, alternative behavioural phenotypes in animal models, consistent with the underlying neuroanatomical/biological features of schizophrenia, need to be established. This does not invalidate our current rodent models; it just emphasises that, in light of the recent compelling PET evidence in patients, we need to review their relevance to the positive symptoms of schizophrenia. Psychosis, an extremely ‘human’ syndrome, will never be truly observable in rodents. However, we can, and should, aim to establish more translationally relevant tests for the underlying neurobiology of psychosis. Ultimately, we need better behavioural tests for positive symptoms in animal models that will lead to therapies efficacious for both positive and cognitive symptoms in patients. We contend that tests aimed at understanding associative striatal function are imperative. We propose that a combination of cognitive behavioural tasks, that can be tested similarly in humans and rodents (Fig. 4a ), represents our best opportunity to assess positive symptom neurobiology in animal models. It is important to consider that neither task alone is a reliable indicator of positive symptom neurobiology (as these tasks assess cognitive function and outcomes are therefore relevant to cognitive symptoms); however, in combination they can help isolate associative striatal function.

Humans and rodents can both perform cognitive tasks that feature actions to obtain rewards (a) The primary differences in testing are that humans can receive monetary rewards whereas rodents tend to be given food rewards. Furthermore, rodents require more initial training to learn the action (i.e., lever pressing or nose poking). To test for goal-directed action (b) both humans and rodents are trained to associate two actions (left and right button/lever presses) with two separate food rewards. One of these rewards is then devalued through an aversive video (cockroaches on the food item) for humans or feeding to satiety in rodents. Healthy controls will demonstrate outcome-specific devaluation by biasing their response towards the food reward that was not devalued. Serial reversal learning (c) requires the subject to learn a simple discrimination between two choices of which one is associated with a reward. Once certain criteria are met, the contingencies are reversed so that the non-rewarded stimulus is now rewarded and the previously rewarded stimulus does not attain a reward. This is classified as the first reversal. Once the criteria are met for the new contingencies, the rewarding stimulus is switched again (back to the original pairings) for the second reversal. This switching back and forth continues until completion of the test

Goal-directed action: sensitivity to outcome devaluation

Goal-directed behaviour is critical for understanding the relationship between actions and their consequences in both humans and rodents. Moreover, goal-directed action heavily depends on the function of the associative striatum 21 , 24 , 98 , 99 , 100 and can be assessed using near identical behavioural paradigms in both humans 101 and rodents 102 (Fig. 4b ). To test impairments in the learning of action-outcome associations in humans and rodents the sensitivity to outcome-specific devaluation can be determined. Outcome-specific devaluation is useful way of establishing that an action is goal-directed and that the correct action–outcome associations have been formed. In order to test this, after training to associate actions with specific outcomes (action–outcome association), one of the outcomes is devalued. After devaluation, when the subject is given the choice between the two action-outcome pairs, healthy controls respond more for the outcome that was not devalued. This demonstrates the ability to establish action-outcome associations correctly and adapt actions based on newly acquired information. The specific neurocircuitry involved in goal-directed behaviour is based on years of associative learning research 103 . Sensitivity to outcome devaluation is dependent on the PFC and associative striatum (Fig. 5a ). Impairments in goal-directed action in schizophrenia have been associated with altered caudate function 101 and disorganised thought 104 . Importantly, the insensitivity to outcome devaluation observed in persons with schizophrenia was not due to impairments in reward sensitivity after devaluation (i.e., limbic systems) but rather, reflected an inability to use this information to direct choice 101 .

a The neurocircuitry involved in goal-directed action can be split into three primary circuits. The associative system (red), including the PFC and ACC, is required for the acquisition and expression of goal-directed action, which is sensitive to outcome devaluation. In contrast, the limbic system (green) is critical for the formation of associations between reward predictive stimuli and action. Habitual behaviours rely on the sensorimotor system (purple). b Behavioural flexibility involves OFC and PFC inputs to the associative striatum. The OFC is critical for reversal learning whereas the PFC is required when shifting to new rules or strategies. The associative striatum is the only common region required for goal-directed action that is sensitive to outcome devaluation and serial reversal learning. OFC orbitofrontal cortex, PFC prefrontal cortex, ACC anterior cingulate cortex, vm ventromedial, m medial, dl dorsolateral, lat lateral

Behavioural flexibility: serial reversal learning

One limitation of outcome-specific devaluation is that it does not allow for the delineation of functional deficits in the PFC vs. associative striatum. Thus, pairing this task with another that relies on the associative striatum, but not the PFC, is required. The basal ganglia is also involved in flexible decision-making and specifically reversal learning (the ability to adapt when outcome contingencies are reversed) which can be tested similarly in humans and rodents (Fig. 4c ). Extensive work in rodents, primates and humans have demonstrated that specific forms of behavioural flexibility are dependent on differing neurocircuitry 69 , 105 , 106 (Fig. 5b ). For example, the orbitofrontal cortex and associative striatum are critical for reversal learning when re-exposed to previous contingencies (e.g., serial reversal learning). In contrast, the PFC is critical for shifting from one rule or strategy to another (i.e., attentional set-shifting). Thus, deficits in serial reversal learning are particularly sensitive to orbitofrontal cortex and associative striatal dysfunction but not PFC dysfunction. Persons with schizophrenia exhibit deficits in both attentional set-shifting and reversal learning 107 . Deficits in reversal learning are independent of working memory deficits and have also been associated with disorganised thought 108 .

A circuit level approach to positive symptoms in animal models

Advances in behavioural neuroscience have helped to delineate specific circuits important for aspects of complex behaviour. Moreover, improvements in circuit isolation using techniques such as optogenetics 109 or chemogenetics 110 mean the field is at a point now where we can focus on particular brain regions and circuits. The proposed tasks, outcome-specific devaluation and serial reversal learning, provide a potential mechanism to focus on associative striatal function (Fig. 5 ). For example, an insensitivity to outcome devaluation and impaired serial reversal learning would be predicted if associative striatal function is compromised. In contrast, an insensitivity to outcome devaluation but maintained serial reversal learning would predict impairments in PFC function. The opposite would be true if orbitofrontal cortex dysfunction is present. Although this is far from perfect, an understanding of the extended connectivity from the associative striatum provides a starting point to probe animal models of schizophrenia to determine whether they demonstrate true associative striatal dysfunction rather than limbic dysfunction. Like psychosis, deficits in goal-directed behaviour 103 and reversal learning 107 are observed in a multitude of disorders other than schizophrenia, meaning that multiple tests assessing cognitive function and other circuitry will still be required to determine how useful one particular animal model will be to an individual psychiatric condition. This combination of tests, however, will allow for a more selective assessment of associative striatal function.

Challenging longstanding assumptions and moving forward

Clozapine, discovered in the 1960’s, remains the most effective antipsychotic medication, although its use is restricted due to its side effect profile 111 . This stagnation in drug development for schizophrenia highlights a key weakness in schizophrenia research; a lack of effective bi-directional translation between basic and clinical research. The fact that the current methods of testing for psychotic symptoms in rodents are now misaligned with recent clinical evidence indicates a need to advance how positive symptoms are examined in animal models. We have proposed a combination of behavioural tests in rodents that are sensitive to dysfunction at the primary site of dopaminergic neurobiology observed in schizophrenia. There will never be a perfect model for psychosis in rodents, but it is critical that we acknowledge the limitations of current methods so that an active dialogue is established.

It is also imperative that basic and clinical researchers maintain active collaborations to prevent the misinterpretation or mistranslation of animal studies. For example, based on the work in monkeys and rodents 112 , 113 , 114 , the results of D1 receptor agonists on working memory function in schizophrenia have been largely negative 115 , 116 , 117 . One contributing factor may have been that the preclinical studies tested delay-dependent working memory (i.e., how long a piece of information is kept in working memory), whereas the clinical studies tested a differing working memory construct, memory span capacity (i.e., how many items can be kept in working memory at one time). Other factors such as medication history 118 may also interfere with the effectiveness of translation between preclinical and clinical studies. To improve translational schizophrenia research it is imperative that we build better avenues for communication between basic and clinical research teams to avoid the aforementioned issues.

Complex syndromes like schizophrenia require a constant reformulation and evolution of ideas and strategies that cannot be achieved by either basic or clinical research in isolation. Clinically, the point at which psychotic symptoms become apparent has dictated our primary diagnostic criteria. Furthermore, it has become evident that a range of complex symptoms emerge before this diagnostic time point. Clinical research must continue to elucidate the features associated with the development of psychosis and better inform a patient’s clinical trajectory throughout the course of schizophrenia. However, our current ability to model psychotic symptoms in animal models is at best questionable and based on historical presumptions rather than recent clinical evidence. Thus, it is imperative that basic research using animal models develops objective measures for the neurobiology underlying psychosis in schizophrenia. Understanding in detail the neurobiological processes that precede these behavioural abnormalities, an avenue of research that cannot be conducted in humans, now becomes a priority. It is only by a synthesis of such approaches that novel therapeutic targets and treatments will emerge.

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Acknowledgements

This work was supported by an Advance Queensland Research Fellowship (to J.P.K.), a National Health and Medical Research Council (NHMRC) Practitioner Fellowship Grant (APP1105807 to J.G.S.), a NHMRC John Cade Fellowship (APP1056929 to J.J.M.) and a Niels Bohr Professorship from the Danish National Research Foundation (to J.J.M.).

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Kesby, J., Eyles, D., McGrath, J. et al. Dopamine, psychosis and schizophrenia: the widening gap between basic and clinical neuroscience. Transl Psychiatry 8 , 30 (2018). https://doi.org/10.1038/s41398-017-0071-9

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The dopamine hypothesis of schizophrenia: current status, future prospects

Affiliation.

• 1 Department of Psychology, University of Wales, Swansea, UK.
• PMID: 9547131
• DOI: 10.1097/00004850-199711000-00002

The dopamine hypothesis of schizophrenia is reviewed in the context of recent advances in dopamine research. These include the following: the discovery that there are several subtypes of dopamine receptor, the recognition that the activity of dopamine neurons is controlled by negative feedback systems; insights into the functions of different subsystems of dopamine neurons; the discovery that different subsystems of dopamine neurons interact with one another; and a growing understanding of the functions and mode of operation of the forebrain regions that the dopamine projections innervate. The paper reviews some of the complexities that the dopamine hypothesis has encountered, and continues to encounter, with a particular focus on three issues: the adequacy of our understanding of neuroleptic drug action, the heterogeneity of schizophrenic symptoms and the paucity of direct evidence to support the hypothesis. It is concluded that schizophrenia does not reflect primary abnormalities of dopamine transmission, but probably does reflect abnormalities in systems that have an intimate interaction with the dopamine system. The primary substrates for schizophrenia will probably be found within the major targets of the ascending dopamine projections: the fronto-striato-pallido-thalamic loops, and the limbic structures, such as amygdala and hippocampus, with which the fronto-striatal system interacts.

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Dopamine, psychosis and schizophrenia: the widening gap between basic and clinical neuroscience

1 Queensland Brain Institute, The University of Queensland, St. Lucia, QLD Australia

2 Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Herston, QLD Australia

3 Queensland Centre for Mental Health Research, The Park Centre for Mental Health, Wacol, QLD Australia

4 National Centre for Register-based Research, Aarhus University, Aarhus C, Denmark

5 Metro North Mental Health, Royal Brisbane and Women’s Hospital, Herston, QLD Australia

The stagnation in drug development for schizophrenia highlights the need for better translation between basic and clinical research. Understanding the neurobiology of schizophrenia presents substantial challenges but a key feature continues to be the involvement of subcortical dopaminergic dysfunction in those with psychotic symptoms. Our contemporary knowledge regarding dopamine dysfunction has clarified where and when dopaminergic alterations may present in schizophrenia. For example, clinical studies have shown patients with schizophrenia show increased presynaptic dopamine function in the associative striatum, rather than the limbic striatum as previously presumed. Furthermore, subjects deemed at high risk of developing schizophrenia show similar presynaptic dopamine abnormalities in the associative striatum. Thus, our view of subcortical dopamine function in schizophrenia continues to evolve as we accommodate this newly acquired information. However, basic research in animal models has been slow to incorporate these clinical findings. For example, psychostimulant-induced locomotion, the commonly utilised phenotype for positive symptoms in rodents, is heavily associated with dopaminergic activation in the limbic striatum. This anatomical misalignment has brought into question how we assess positive symptoms in animal models and represents an opportunity for improved translation between basic and clinical research. The current review focuses on the role of subcortical dopamine dysfunction in psychosis and schizophrenia. We present and discuss alternative phenotypes that may provide a more translational approach to assess the neurobiology of positive symptoms in schizophrenia. Incorporation of recent clinical findings is essential if we are to develop meaningful translational animal models.

Introduction

Our knowledge of the neurobiology of schizophrenia, while still rudimentary, has advanced considerably in recent years. However, these findings have not translated to better treatments for those with schizophrenia. The three primary symptom groups, positive, cognitive and negative (Box 1 ), have been associated with reports of abnormalities in virtually every neurotransmitter system 1 – 5 . The onset of psychotic symptoms, which is strongly associated with alterations in dopamine function, is a key feature underpinning a clinical diagnosis 6 , 7 . However, results from clinical research regarding the specific loci of dopamine dysfunction in schizophrenia 8 – 10 , have triggered a reappraisal of our perspective on the neurobiology of schizophrenia. Currently there is a disparity between the tests for positive symptoms in animal models and recent clinical evidence for dopaminergic abnormalities in schizophrenia. Therefore, it is critical that this contemporary clinical knowledge actively influences the agenda in applied basic neuroscience.

Box 1: Symptom groups in schizophrenia

: Positive symptoms include delusions and hallucinations, linked to aberrant salience. These symptoms are most recognisable during periods of acute psychosis.

: Impairments in learning, memory, attention and executive functioning are all included as cognitive symptoms.

• Negative symptoms: Negative symptoms include blunting of affect (lacking emotional expression), avolition (deficits in motivation) and social withdrawal.

It is widely acknowledged that we cannot recreate the complicated symptom profile of schizophrenia in animal models. However, animal models (the majority and focus of the present article being rodent models) provide an avenue to invasively explore the role of neurotransmitters and circuitry in psychiatric diseases. To improve the poor predictive validity of treatments in animal models 11 , it is critical that our understanding and the use of animal models evolves alongside our knowledge of schizophrenia neurobiology. The delayed incorporation of new clinical findings to develop better animal models highlights the need for better communication between clinical and basic research communities.

In this article, we discuss the challenges clinicians and researchers are facing in understanding the neurobiology of positive symptoms and psychosis in schizophrenia. We discuss the implications this has for current assessments of positive symptoms in rodents and propose a more relevant set of tests for future study. Finally, the need for a joint focus on bi-directional translation between clinical and basic research is outlined.

Challenges in diagnosing schizophrenia

Psychiatric symptoms exist on continua from normal to pathological, meaning the threshold for diagnosis of schizophrenia in clinical practice can be challenging. The clinical diagnosis of schizophrenia relies heavily on the positive symptoms associated with a prolonged psychotic episode. However, a relatively high percentage of the general population (8–30%) report delusional experiences or hallucinations in their lifetime 12 – 14 , but for most people these are transient 15 . Psychotic symptoms are also not specific to a particular mental disorder 16 . The clinical efficacy of antipsychotic drugs is heavily correlated with their ability to block subcortical dopamine D2 receptors 17 , 18 , suggesting dopamine signalling is important. In spite of this, no consistent relationship between D2 receptors and the pathophysiology of schizophrenia has emerged 19 , 20 . In contrast, the clinical evidence points towards presynaptic dopamine dysfunction as a mediator of psychosis in schizophrenia 19 .

The neurobiology of psychosis: the centrality of dopamine

Dopamine systems: anatomy and function.

An appreciation for the neuroanatomical differences in subcortical dopaminergic projections/circuitry between rodents and primates is essential for effective communication between clinical and basic researchers. For example, primates feature a more prominent substantia nigra and less distinctive ventral tegmental area than rodents. However, more pertinent to the current review are homologous functional subdivisions of the striatum observed in both rodents and primates 21 – 24 . These include the limbic, associative and sensorimotor areas (Fig. ​ (Fig.1). 1 ). The associative striatum, defined by its dense connectivity from the frontal and parietal associative cortices, is key for goal-directed action and behavioural flexibility. The limbic striatum, defined by connectivity to the hippocampus, amygdala and medial orbitofrontal cortex, is involved in reward and motivation. The sensorimotor striatum, defined by connectivity to sensory and motor cortices, is critical for habit formation. These functional subdivisions are also interconnected by feedforward striato-nigro-striatal projections 25 . The heavy basis on behavioural outcomes in neuropsychiatry has made functional subdivisions such as these more relevant than ever.

Midbrain dopamine neurons are the source of dopamine projections to the striatum in primates (left) and rodents (right). Important neuroanatomical differences exist, especially when considering functional subdivisions of the striatum. In the primate, the limbic system (orange) originates in the dorsal tier of the substantia nigra (the ventral tegmental area equivalent). In the rodent, the limbic system originates in ventral tegmental area, which sits medially to the substantia nigra. The midbrain projections to the associative striatum (yellow) and sensorimotor striatum (blue) follow a dorsomedial-to-ventrolateral topology

Dopaminergic features of psychosis in schizophrenia

In healthy individuals, dopamine stimulants such as amphetamine can induce psychotic symptoms 26 , 27 and people with schizophrenia are more sensitive to these effects 27 , 28 . Studies using positron emission tomography (PET) imaging have shown patients with schizophrenia show increases in subcortical synaptic dopamine content 29 , 30 , abnormally high dopamine release after amphetamine treatment 30 – 35 and increased basal dopamine synthesis capacity (determined indirectly by increased radiolabelled L-DOPA uptake) 19 , 36 , 37 compared with healthy controls. Increased subcortical dopamine synthesis and release capacity are strongly associated with positive symptoms in patients 33 , 38 , and increased subcortical synaptic dopamine content is predictive of a positive treatment response 29 . It was widely anticipated that the limbic striatum would be confirmed as the subdivision where these alterations in dopamine function would be localised in patients. The basis for this prediction was the belief that reward systems were aberrant in schizophrenia 39 . However, as PET imaging resolution improved it was found that increases in synaptic dopamine content 9 , 10 and synthesis capacity 8 were localised, or more pronounced 37 , in the associative striatum (Fig. ​ (Fig.1; 1 ; yellow). Furthermore, alterations in dopamine function within the associative striatum likely contribute to the misappropriate attribution of salience to certain stimuli, a key aspect of delusions and psychosis 40 .

Clinical studies have confirmed that dopamine abnormalities are also present prior to the onset of psychosis in schizophrenia and thus are not a consequence of psychotic episodes or antipsychotic exposure. Similar to what has been observed in patients with schizophrenia, ultra-high risk (UHR) subjects show increased subcortical synaptic dopamine content 41 and basal dopamine synthesis capacity 8 , 42 – 44 . Importantly, alterations in dopamine synthesis capacity in UHR subjects progress over time 45 and are greater in subjects who transition to psychosis compared with those who do not 46 . Furthermore, higher baseline synaptic dopamine levels in UHR subjects predicts a greater reduction in positive symptoms after dopamine depletion 41 . Overall, these findings in UHR subjects are congruent with those observed in schizophrenia and provide evidence indicating that presynaptic dopaminergic abnormalities are present prior to the onset of psychosis.

Several avenues have been proposed to explain a selective increase in associative striatal dopamine function, such as alterations in hippocampal control of dopamine projections 47 , 48 , alterations in cortical inputs to midbrain dopamine systems 2 , 49 and, although little direct evidence has been observed, developmental alterations in dopamine neurons themselves 50 , 51 . Furthermore, other pathways and/or neurotransmitters may be more critical in treatment-resistant patients 52 . We propose a network model whereby dysfunction in a central circuit, including the associative striatum, prefrontal cortex and thalamus, is critical for the expression of psychotic symptoms in schizophrenia. This model would suggest that dysfunction in auxiliary circuits (both limbic and cortical) contribute to psychotic symptoms by feeding into this primary network. Ascertaining the role of dopaminergic dysfunction, in the context of networks important for psychotic symptoms in schizophrenia, will provide a better base for constructing objective readouts in basic and clinical research.

Psychosis: a consequence of network dysfunction

Psychosis is a condition that features a range of behavioural alterations that relate to a loss of contact with reality and a loss of insight. People with psychosis experience hallucinations (primarily auditory in schizophrenia 53 ) and delusions. In schizophrenia, auditory hallucinations have been associated with altered connectivity between the hippocampus and thalamus 54 . During hallucinations, increased activation of the thalamus, striatum and hippocampus have also been observed 55 . Thus, altered thalamocortical connectivity, especially with the hippocampus, may impede internal/external representations of auditory processing 56 . In contrast, delusions in people with schizophrenia have been associated with overactivation of the prefrontal cortex (PFC) and diminished deactivation of striatal and thalamic networks 57 . Thus, the complexity of psychotic symptoms is congruent with the highly connected nature of implicated brain regions.

Although we still know little about the underlying neurobiology of psychosis, focal brain lesions allow for a better understanding of the networks involved without the confounds of medication and unrelated neuropathology. Generally speaking, lesions that induce hallucinations are often in the brain networks associated with the stimulus of the hallucination (i.e., auditory, visual or somatosensory) 58 . Visual hallucinations have been associated with dysfunction of the occipital lobe, striatum and thalamus, whereas auditory hallucinations are associated with dysfunction of the temporal lobe, hippocampus, amygdala and thalamus 58 . Insight is generally maintained after focal brain lesions that produce hallucinations and subcortical dopamine function is normal 59 , unlike what is observed in schizophrenia 58 . In contrast, a loss of insight (which can manifest as delusionary beliefs) is associated with alterations in cortico-striatal networks. For example, people with basal ganglia or caudate lesions can present with both hallucinations and delusions 60 , 61 . Furthermore, a case study of religious delusions in a patient with temporal lobe epilepsy was associated with overactivity of the PFC 62 , and there are multiple lines of evidence suggesting that the PFC is integral for delusionary beliefs 63 . Therefore, while impairing networks specific to certain sensory modalities can lead to hallucinations, dysfunctional integration of PFC input to the associative striatum may be especially important for delusional symptoms in schizophrenia.

Central to the networks involved in psychosis and schizophrenia, the thalamus acts as a relay for most information going to the cortex 64 . Brain imaging studies have demonstrated that medication-naive patients with schizophrenia have significantly reduced thalamic and caudate volumes relative to healthy controls and medicated patients 65 . Moreover, reduced thalamic volumes has also been observed in UHR subjects 66 . A simplified schematic of the networks that may be especially relevant to psychotic symptoms in schizophrenia is presented in Fig. ​ Fig.2. 2 . The thalamus forms a circuit with the associative striatum and PFC whereby impairments in any of these regions can impair the functionality of the network as a whole. In addition, the hippocampus and amygdala, which are both involved in sensory perception and emotional regulation, can affect this network via their connectivity with the thalamus (but other indirect pathways also exist). Although this is an over simplification, it highlights how psychotic symptoms could arise from multiple sources of neuropathology/dysfunction or abnormal connectivity.

Dysfunction in a variety of brain regions can elicit psychotic symptoms. A primary circuit involved in psychosis includes the thalamus and prefrontal cortex (yellow) feeding into the associative striatum. Alterations in the thalamus and prefrontal cortex are involved in hallucinations and also insight for delusional symptoms. Expression of psychotic symptoms in most cases requires increased activity in the associative striatum and specifically excessive D2 receptor stimulation (red). Other limbic regions such as the hippocampus and amygdala (green) can feed into this circuit contributing to altered sensory perception and emotional context

Why do antipsychotics work?

This raises important questions as to how antipsychotic drugs exert their effects. In most individuals with schizophrenia, antipsychotic treatment is effective in reducing positive symptoms 67 ; therefore, excessive D2 signalling in the associative striatum appears to be critical. Stimulation of D2 and D1 receptor expressing medium spiny neurons (which are largely segregated 68 ) in the associative striatum feedback indirectly to the thalamus, completing a loop that allows for feedforward-based and feedback-based signalling. The basal ganglia acts as a gateway for, or mediator of, cortical inputs 69 – 71 and may represent a common pathway through which psychotic symptoms present. Therefore, excessive dopamine signalling in the associative striatum may directly lead to psychotic symptoms by compromising the integration of cortical inputs. In treatment-responsive patients, antipsychotics may attenuate the expression of psychotic symptoms by normalising excessive D2 signalling 29 to restore the balance between D1 and D2 receptor pathways 72 . Because they act downstream to schizophrenia-related presynaptic abnormalities, they fail to improve indices of cortical function (i.e., cognitive symptoms). Alternatively, impaired cortical input to the associative striatum via the thalamus, PFC or other regions could dysregulate this system independently of, or in addition to, associative striatal dopamine dysfunction. In this case, D2 receptor blockade may be insufficient to restore normal function, which is one explanation for why some individuals are treatment refractory. For example, increases in subcortical synaptic dopamine content 29 and increases in presynaptic striatal dopamine function 52 are both associated with increased treatment efficacy. Thus, in treatment-resistant subjects, there is little evidence of abnormal dopaminergic function 29 , 52 . Medicated persons with schizophrenia, who remain symptomatic with auditory hallucinations, show increased thalamic, striatal and hippocampal activation 55 . Moreover, treatment-refractory patients who respond positively to clozapine treatment show alterations in cerebral blood flow in fronto-striato-thalamic circuitry, suggesting clozapine is restoring a functional imbalance in these systems 73 . Taken together, this evidence suggests that psychosis is the result of a network dysfunction that includes a variety of brain regions (and multiple neurotransmitter-specific pathways), of which impairment at any level could precipitate psychotic symptoms.

Although increased positive symptom severity has been associated with impaired cognitive flexibility 74 , there is a little evidence for subcortical hyperdopaminergia playing a direct role in the cognitive impairments observed in schizophrenia. Furthermore, antipsychotic treatments do not improve patient’s cognitive function 75 . There is a mounting evidence that cognitive symptoms may present prior to positive symptoms in schizophrenia 76 . Given brain networks involved in hallucinations and delusions all involve cortical regions, the underlying pathology causing cognitive symptoms may also contribute to psychotic symptoms. Thus, in some cases psychosis may represent the summation of broad cognitive impairments inducing local network dysfunction (Fig. ​ (Fig.3). 3 ). Regardless, positive symptoms are relatively distinct in the clinical setting but the presence and severity of symptoms are determined interactively with interviews and questionnaires. The inability to do the same in other species means the best avenue for assessing animal models may be to identify outcomes that are sensitive to the underlying neurobiology observed in schizophrenia and psychosis. Given the action/effectiveness of antipsychotics, the primary downstream region of interest, in the context of elevated dopamine transmission, is the associative striatum.

This schematic representation highlights the potential for cognitive symptoms to feed into psychosis networks and create positive feedback loops that spiral to psychosis. Non-specific and heterogeneous deficits in auxiliary neurocircuitry (in the context of psychosis) lead to broad cognitive impairments unique to each individual. These systems feed into the primary psychosis networks leading to destabilisation of associative striatal dysfunction and further cognitive impairment. In most individuals with schizophrenia, excessive dopamine signalling in the associative striatum leads to positive symptoms. Antipsychotics antagonise downstream D2 receptor signalling to blunt the expression of symptoms. In treatment-refractory patients (those who do not respond to first-line antipsychotics) blocking D2 receptors is insufficient to blunt positive symptoms suggesting further upstream dysfunction in the associative striatum or psychosis networks. Clozapine may lead to improvement in some of these individuals by stabilising function throughout these networks in addition to D2 receptor antagonism. Positive symptoms in treatment-refractory patients who fail to respond to clozapine may be the result of severe impairment throughout psychosis networks (and the associative striatum) that are independent of dopamine dysfunction. Thus, our current treatments for positive symptoms act downstream of the source of cognitive impairments, hence their ineffectiveness in treating cognitive symptoms. While the expression of psychotic symptoms may be a discrete outcome, separate to impairments in cognitive function, the upstream cause of these symptoms may share common neuropathology

Modelling psychosis: the use of animal models

Potentially, the most useful avenue for animal models to assist in schizophrenia research will be identifying convergent aetiological pathways 77 . Understanding which neurotransmitter systems and brain regions are most involved may help to identify the core neurobiological features of schizophrenia. For example, changes in dopaminergic systems are observed in animal models after manipulation of factors based on schizophrenia epidemiology 50 , 51 , genetics 78 , pharmacology 79 and related hypotheses 80 . These include changes in early dopamine specification factors 50 , 51 , sensitivities to psychostimulants 50 , 51 , 78 , 80 and alterations in dopamine neurochemistry 50 , 51 , 78 , 79 . Evidence of subcortical dopaminergic hyperactivity or sensitivity in animal models is proposed to represent the face validity (i.e., mimicking the phenomenology of schizophrenia) for psychosis in patients. The most commonly used behavioural assessments of positive symptoms in animal models include enhanced amphetamine-induced locomotion and deficits in prepulse inhibition (PPI) 81 . These tests are widely used because they are relatively simple to perform. However, we propose that given current knowledge of the neurobiology in schizophrenia, they have outlived their usefulness as measures of positive symptoms.

Amphetamine-induced locomotion

Amphetamine increases dopamine release in striatal brain regions of both humans 38 and rats 82 . Amphetamine-related behaviours in rodents are also strongly linked to activity in striatal brain regions 82 , 83 . Thus, an increased locomotor response to amphetamine (and other psychostimulants, which face similar criticisms) is considered a simple test to reflect the subcortical hyperdopaminergia underlying the psychotic symptoms in schizophrenia. Most animal models of schizophrenia report increased locomotor activation after psychostimulants 78 . However, the recent clinical evidence described above suggests that current assessments of animal models does not reflect contemporaneous knowledge of dopamine activity in those with schizophrenia.

The relative contribution of specific dopamine pathways to amphetamine-induced locomotion provides a good example of why a paradigm shift is required for research using animal models for positive symptoms in schizophrenia. For example, amphetamine-induced locomotion is largely driven by limbic dopamine release. Local administration of amphetamine 84 – 87 or dopamine 84 , 88 , 89 into the nucleus accumbens induces locomotion. Furthermore, blocking dopamine signalling in the nucleus accumbens attenuates amphetamine-induced locomotion 90 . Specifically activating limbic dopamine projections using chemogenetic tools robustly increases locomotion, but activating associative dopamine projections does not 91 . Thus, there is an anatomical misalignment between the primary behavioural outcome deemed important for positive symptoms in animal models of schizophrenia (i.e, psychostimulant-induced locomotion driven by limbic dopamine), and clinical evidence in patients (hyperactive associative striatal dopamine). Furthermore, clinical studies directly comparing activity levels in patients with schizophrenia and bipolar disorder suggest that hyperactivity may be a core feature of bipolar disorder rather than schizophrenia 92 .

One argument for amphetamine-induced locomotion is that it is predictive of antipsychotic efficacy, but this is merely a serendipitous side effect. Systemically administered amphetamine increases dopamine function in both the limbic striatum (locomotion) and associative striatum (positive symptoms). Systemically administered antipsychotics antagonise D2 receptors throughout the brain. Therefore, amphetamine-induced locomotion acts serendipitously to predict antipsychotic effectiveness via dopamine release in a parallel circuit (limbic vs. associative dopamine). Optimally, antipsychotics that diminish dopamine signalling preferentially in the associative, rather than the limbic, striatum need to be developed. Obviously, amphetamine-induced locomotion would not be predictive for the latter treatment options.

Prepulse Inhibition

One of the most consistently observed neurological impairments in schizophrenia is impaired sensorimotor gating in the form of decreased PPI 93 , 94 . Deficits in PPI may reflect an inability to gate out irrelevant information. PPI deficits also respond to antipsychotics but are not specific to schizophrenia 93 , 94 . Thus, PPI deficits do not represent a specific or diagnostic trait of schizophrenia. Intact cortical and striatal function are critical for PPI 95 and, therefore, deficits in PPI also reflect an interface between positive and cognitive symptom groups 81 .

PPI is assessed almost identically in rodents and humans and, therefore, is one of the most widely studied deficits in schizophrenia. In rodents, the contribution of limbic dopamine projections to PPI are well-known 95 , though the associative striatum has also been implicated 96 , 97 . Thus, PPI deficits clearly lack specificity concerning the hyperdopaminergia observed in schizophrenia. Therefore, when assessing rodent models, PPI impairments alone are insufficient for determining positive symptom phenotypes and their predictive validity suffers from the same criticism as that of amphetamine-induced locomotion (parallel blockade of limbic D2 receptors).

Can we objectively test positive symptom connectivity in rodents?

Clearly, alternative behavioural phenotypes in animal models, consistent with the underlying neuroanatomical/biological features of schizophrenia, need to be established. This does not invalidate our current rodent models; it just emphasises that, in light of the recent compelling PET evidence in patients, we need to review their relevance to the positive symptoms of schizophrenia. Psychosis, an extremely ‘human’ syndrome, will never be truly observable in rodents. However, we can, and should, aim to establish more translationally relevant tests for the underlying neurobiology of psychosis. Ultimately, we need better behavioural tests for positive symptoms in animal models that will lead to therapies efficacious for both positive and cognitive symptoms in patients. We contend that tests aimed at understanding associative striatal function are imperative. We propose that a combination of cognitive behavioural tasks, that can be tested similarly in humans and rodents (Fig. ​ (Fig.4a), 4a ), represents our best opportunity to assess positive symptom neurobiology in animal models. It is important to consider that neither task alone is a reliable indicator of positive symptom neurobiology (as these tasks assess cognitive function and outcomes are therefore relevant to cognitive symptoms); however, in combination they can help isolate associative striatal function.

Humans and rodents can both perform cognitive tasks that feature actions to obtain rewards (a) The primary differences in testing are that humans can receive monetary rewards whereas rodents tend to be given food rewards. Furthermore, rodents require more initial training to learn the action (i.e., lever pressing or nose poking). To test for goal-directed action (b) both humans and rodents are trained to associate two actions (left and right button/lever presses) with two separate food rewards. One of these rewards is then devalued through an aversive video (cockroaches on the food item) for humans or feeding to satiety in rodents. Healthy controls will demonstrate outcome-specific devaluation by biasing their response towards the food reward that was not devalued. Serial reversal learning (c) requires the subject to learn a simple discrimination between two choices of which one is associated with a reward. Once certain criteria are met, the contingencies are reversed so that the non-rewarded stimulus is now rewarded and the previously rewarded stimulus does not attain a reward. This is classified as the first reversal. Once the criteria are met for the new contingencies, the rewarding stimulus is switched again (back to the original pairings) for the second reversal. This switching back and forth continues until completion of the test

Goal-directed action: sensitivity to outcome devaluation

Goal-directed behaviour is critical for understanding the relationship between actions and their consequences in both humans and rodents. Moreover, goal-directed action heavily depends on the function of the associative striatum 21 , 24 , 98 – 100 and can be assessed using near identical behavioural paradigms in both humans 101 and rodents 102 (Fig. ​ (Fig.4b). 4b ). To test impairments in the learning of action-outcome associations in humans and rodents the sensitivity to outcome-specific devaluation can be determined. Outcome-specific devaluation is useful way of establishing that an action is goal-directed and that the correct action–outcome associations have been formed. In order to test this, after training to associate actions with specific outcomes (action–outcome association), one of the outcomes is devalued. After devaluation, when the subject is given the choice between the two action-outcome pairs, healthy controls respond more for the outcome that was not devalued. This demonstrates the ability to establish action-outcome associations correctly and adapt actions based on newly acquired information. The specific neurocircuitry involved in goal-directed behaviour is based on years of associative learning research 103 . Sensitivity to outcome devaluation is dependent on the PFC and associative striatum (Fig. ​ (Fig.5a). 5a ). Impairments in goal-directed action in schizophrenia have been associated with altered caudate function 101 and disorganised thought 104 . Importantly, the insensitivity to outcome devaluation observed in persons with schizophrenia was not due to impairments in reward sensitivity after devaluation (i.e., limbic systems) but rather, reflected an inability to use this information to direct choice 101 .

a The neurocircuitry involved in goal-directed action can be split into three primary circuits. The associative system (red), including the PFC and ACC, is required for the acquisition and expression of goal-directed action, which is sensitive to outcome devaluation. In contrast, the limbic system (green) is critical for the formation of associations between reward predictive stimuli and action. Habitual behaviours rely on the sensorimotor system (purple). b Behavioural flexibility involves OFC and PFC inputs to the associative striatum. The OFC is critical for reversal learning whereas the PFC is required when shifting to new rules or strategies. The associative striatum is the only common region required for goal-directed action that is sensitive to outcome devaluation and serial reversal learning. OFC orbitofrontal cortex, PFC prefrontal cortex, ACC anterior cingulate cortex, vm ventromedial, m medial, dl dorsolateral, lat lateral

Behavioural flexibility: serial reversal learning

One limitation of outcome-specific devaluation is that it does not allow for the delineation of functional deficits in the PFC vs. associative striatum. Thus, pairing this task with another that relies on the associative striatum, but not the PFC, is required. The basal ganglia is also involved in flexible decision-making and specifically reversal learning (the ability to adapt when outcome contingencies are reversed) which can be tested similarly in humans and rodents (Fig. ​ (Fig.4c). 4c ). Extensive work in rodents, primates and humans have demonstrated that specific forms of behavioural flexibility are dependent on differing neurocircuitry 69 , 105 , 106 (Fig. ​ (Fig.5b). 5b ). For example, the orbitofrontal cortex and associative striatum are critical for reversal learning when re-exposed to previous contingencies (e.g., serial reversal learning). In contrast, the PFC is critical for shifting from one rule or strategy to another (i.e., attentional set-shifting). Thus, deficits in serial reversal learning are particularly sensitive to orbitofrontal cortex and associative striatal dysfunction but not PFC dysfunction. Persons with schizophrenia exhibit deficits in both attentional set-shifting and reversal learning 107 . Deficits in reversal learning are independent of working memory deficits and have also been associated with disorganised thought 108 .

A circuit level approach to positive symptoms in animal models

Advances in behavioural neuroscience have helped to delineate specific circuits important for aspects of complex behaviour. Moreover, improvements in circuit isolation using techniques such as optogenetics 109 or chemogenetics 110 mean the field is at a point now where we can focus on particular brain regions and circuits. The proposed tasks, outcome-specific devaluation and serial reversal learning, provide a potential mechanism to focus on associative striatal function (Fig. ​ (Fig.5). 5 ). For example, an insensitivity to outcome devaluation and impaired serial reversal learning would be predicted if associative striatal function is compromised. In contrast, an insensitivity to outcome devaluation but maintained serial reversal learning would predict impairments in PFC function. The opposite would be true if orbitofrontal cortex dysfunction is present. Although this is far from perfect, an understanding of the extended connectivity from the associative striatum provides a starting point to probe animal models of schizophrenia to determine whether they demonstrate true associative striatal dysfunction rather than limbic dysfunction. Like psychosis, deficits in goal-directed behaviour 103 and reversal learning 107 are observed in a multitude of disorders other than schizophrenia, meaning that multiple tests assessing cognitive function and other circuitry will still be required to determine how useful one particular animal model will be to an individual psychiatric condition. This combination of tests, however, will allow for a more selective assessment of associative striatal function.

Challenging longstanding assumptions and moving forward

Clozapine, discovered in the 1960’s, remains the most effective antipsychotic medication, although its use is restricted due to its side effect profile 111 . This stagnation in drug development for schizophrenia highlights a key weakness in schizophrenia research; a lack of effective bi-directional translation between basic and clinical research. The fact that the current methods of testing for psychotic symptoms in rodents are now misaligned with recent clinical evidence indicates a need to advance how positive symptoms are examined in animal models. We have proposed a combination of behavioural tests in rodents that are sensitive to dysfunction at the primary site of dopaminergic neurobiology observed in schizophrenia. There will never be a perfect model for psychosis in rodents, but it is critical that we acknowledge the limitations of current methods so that an active dialogue is established.

It is also imperative that basic and clinical researchers maintain active collaborations to prevent the misinterpretation or mistranslation of animal studies. For example, based on the work in monkeys and rodents 112 – 114 , the results of D1 receptor agonists on working memory function in schizophrenia have been largely negative 115 – 117 . One contributing factor may have been that the preclinical studies tested delay-dependent working memory (i.e., how long a piece of information is kept in working memory), whereas the clinical studies tested a differing working memory construct, memory span capacity (i.e., how many items can be kept in working memory at one time). Other factors such as medication history 118 may also interfere with the effectiveness of translation between preclinical and clinical studies. To improve translational schizophrenia research it is imperative that we build better avenues for communication between basic and clinical research teams to avoid the aforementioned issues.

Complex syndromes like schizophrenia require a constant reformulation and evolution of ideas and strategies that cannot be achieved by either basic or clinical research in isolation. Clinically, the point at which psychotic symptoms become apparent has dictated our primary diagnostic criteria. Furthermore, it has become evident that a range of complex symptoms emerge before this diagnostic time point. Clinical research must continue to elucidate the features associated with the development of psychosis and better inform a patient’s clinical trajectory throughout the course of schizophrenia. However, our current ability to model psychotic symptoms in animal models is at best questionable and based on historical presumptions rather than recent clinical evidence. Thus, it is imperative that basic research using animal models develops objective measures for the neurobiology underlying psychosis in schizophrenia. Understanding in detail the neurobiological processes that precede these behavioural abnormalities, an avenue of research that cannot be conducted in humans, now becomes a priority. It is only by a synthesis of such approaches that novel therapeutic targets and treatments will emerge.

Acknowledgements

This work was supported by an Advance Queensland Research Fellowship (to J.P.K.), a National Health and Medical Research Council (NHMRC) Practitioner Fellowship Grant (APP1105807 to J.G.S.), a NHMRC John Cade Fellowship (APP1056929 to J.J.M.) and a Niels Bohr Professorship from the Danish National Research Foundation (to J.J.M.).

Conflict of interest

The authors declare that they have no conflict of interest.

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