The Dopamine Hypothesis of Schizophrenia - Advances in Neurobiology (2023)

Posted on:January 27, 2018

Last Updated: November 24, 2022

The Dopamine Hypothesis of Schizophrenia - Advances in Neurobiology (1) Time to read: 7 minutes

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

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


Dopamine 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.

The Dopamine Hypothesis of Schizophrenia - Advances in Neurobiology (2)

Dopamine Receptors:

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

(Video) Psychopharmacology - Antipsychotics & The Dopamine Hypothesis Schizophrenia

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

The Dopamine Hypothesis of Schizophrenia - Advances in Neurobiology (3)

Dopamine Breakdown

The Dopamine Hypothesis of Schizophrenia - Advances in Neurobiology (4)

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:

  1. 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]
  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.
  3. 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).
  4. Valbenazine a highly selective VMAT2 inhibitor has been approved by the FDA for the treatment of tardive dyskinesia.
  5. 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]

The Dopamine Hypothesis of Schizophrenia - Advances in Neurobiology (5)

  1. 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 Dopamine Hypothesis of Schizophrenia - Advances in Neurobiology (6)

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

(Video) Dopamine hypothesis of schizophrenia - Intro to Psychology

  • 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.

The Dopamine Hypothesis of Schizophrenia - Advances in Neurobiology (7)

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.


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]

(Video) Part-2 Schizophrenia Pathophysiology - Dopamine hypothesis

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.

The Dopamine Hypothesis of Schizophrenia - Advances in Neurobiology (8)

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

The Dopamine Hypothesis of Schizophrenia - Advances in Neurobiology (9)

Dysregulation of the dopamine system ultimately leads to irrelevant stimuli becoming more prominent which provides a basis forpsychotic 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.

(Video) 2-Minute Neuroscience: Schizophrenia

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]


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

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

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

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

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

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

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

Learn more:

Simplified Guide to Mechanisms of Action of Oral Antipsychotics



What does the dopamine hypothesis say about schizophrenia? ›

The “original dopamine hypothesis” states that hyperactive dopamine transmission results in schizophrenic symptoms. This hypothesis was formed upon the discovery of dopamine as a neurotransmitter in the brain by Arvid Carlsson (6–12).

Why is the dopamine hypothesis insufficient in the explanation of schizophrenia? ›

Research on dopamine concentrations in postmortem brain tissue, on homovanillic acid concentrations, and on dopamine receptors has been negative or inconclusive. Therefore, the idea that the symptoms of psychosis or schizophrenia are caused by the overactivity of dopamine is not supported by current evidence.

Does the dopamine hypothesis of schizophrenia explain the development and symptoms of the schizophrenia condition? ›

Finally, dopamine does explain the pathophysiology of schizophrenia, but not necessarily the cause per se. Rather, dopamine acts as the common final pathway of a wide variety of predisposing factors, either environmental, genetic, or both, that lead to the disease.

What evidence has been discovered for the dopamine hypothesis? ›

Evidence for the dopamine hypothesis. Stimulants such as amphetamine, and cocaine increase the levels of dopamine in the brain and can cause symptoms of psychosis, particularly after large doses or prolonged use.

What is the role of dopamine in the cause of schizophrenia? ›

The authors hypothesize that schizophrenia is characterized by abnormally low prefrontal dopamine activity (causing deficit symptoms) leading to excessive dopamine activity in mesolimbic dopamine neurons (causing positive symptoms).

What are the limitations of the dopamine hypothesis 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.

Can schizophrenia be caused by too much dopamine? ›

Increases in dopamine activity in certain parts of the brain can contribute to the positive symptoms of schizophrenia. Meanwhile, reduced dopamine activity in other parts of the brain may affect negative and cognitive symptoms. Dopamine is just one of many factors involved in schizophrenia symptoms.

Which of the following was a problem with the dopamine hypothesis quizlet? ›

Certain issues that arose in this version of the dopamine hypothesis: there were no direct evidence of low dopamine levels, just low CSF levels of dopamine metabolites. Also, did not elucidate the origins of this hypodopaminergia and hyperdopaminergia.

What is the hypothesis for the development of schizophrenia? ›

According to the neurodevelopmental hypothesis, the etiology of schizophrenia may involve pathologic processes, caused by both genetic and environmental factors, that begin before the brain approaches its adult anatomical state in adolescence.

What is the role of dopamine in schizophrenia from a neurobiological and evolutionary perspective? ›

Dopamine is an inhibitory neurotransmitter involved in the pathology of schizophrenia. The revised dopamine hypothesis states that dopamine abnormalities in the mesolimbic and prefrontal brain regions exist in schizophrenia.

What does current research on dopamine's role in schizophrenia emphasize? ›

The dopamine hypothesis is shown to reflect an attitude towards schizophrenia that emphasizes acute, florid symptoms. It is suggested that research directed towards studying dopaminergic mechanisms in specific psychopathological symptoms, not syndromes, might prove fruitful.

How does the dopamine hypothesis and aberrant salience explain the positive symptoms of schizophrenia? ›

The “aberrant salience” model proposes that psychotic symptoms first emerge when chaotic brain dopamine transmission leads to the attribution of significance to stimuli that would normally be considered irrelevant.

What is the revised dopamine hypothesis? ›

The revised dopamine (DA) hypothesis states that clinical symptoms of schizophrenia are caused by an imbalance of the DA system. In this article, we aim to review evidence for this hypothesis by evaluating functional magnetic resonance imaging studies in schizophrenia.

How does the dopamine hypothesis explain addiction? ›

“In brief, the hypothesis contends that decreased dopamine function in addicted subjects results in a decreased interest to non-drug-related stimuli and increased sensitivity to the drug of choice, leading to propose that restoring dopamine function might be therapeutically advantageous.”

What neurotransmitter was first believed to be the cause of schizophrenia? ›

Research suggests schizophrenia may be caused by a change in the level of 2 neurotransmitters: dopamine and serotonin. Some studies indicate an imbalance between the 2 may be the basis of the problem.

What neurobiological changes are associated with schizophrenia patients? ›

Specific regions of gray and white matter changes are observed in patients with schizophrenia; gray matter changes being more significant after the onset of psychosis. These pathological changes may be implicated in the impairment of executive functioning, attention, and working memory.

Do schizophrenia drugs decrease dopamine? ›

Dopamine is a neurotransmitter, which means that it passes messages around your brain. Most antipsychotic drugs are known to block some of the dopamine receptors in the brain. This reduces the flow of these messages, which can help to reduce your psychotic symptoms.

What are the main limitations of the biological theory as explanations of schizophrenia? ›

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.

What is the dopamine hypothesis quizlet? ›

The dopamine hypothesis states that messages from neurons that transmit dopamine fire too easily or too often, leading to characteristic symptoms of schizophrenia. Schizophrenia is caused by abnormally high levels of dopamine in dopamine receptors.

What are functional limitations of schizophrenia? ›

Patients with schizophrenia experience impairments in multiple domains of everyday life, including the ability to maintain social relationships, sustain employment, and live independently. These impairments typically persist after patients achieve symptom remission.

What happens when your brain gets too much dopamine? ›

Having too much dopamine — or too much dopamine concentrated in some parts of the brain and not enough in other parts — is linked to being more competitive, aggressive and having poor impulse control. It can lead to conditions that include ADHD, binge eating, addiction and gambling.

What part of the brain is most affected by dopamine? ›

The MIT team found that in addition to the motor cortex, the remote brain area most affected by dopamine is the insular cortex. This region is critical for many cognitive functions related to perception of the body's internal states, including physical and emotional states.

What are some effects of the drop in the dopamine levels in the brain? ›

Low levels of dopamine have been linked to Parkinson's disease, restless legs syndrome and depression. Low levels of dopamine can make you feel tired, moody, unmotivated and many other symptoms. Treatments are available for many of the medical conditions linked to low dopamine levels.

Which disease has been linked to not enough dopamine in the brain? ›

Low Dopamine: An Unexpected Cause of Depression

No one knows for sure what causes depression, but the most popular theory is that it's due to a lack of the mood-elevating brain chemical serotonin. But there's a growing body of evidence that dopamine deficiency may be the underlying cause of depression in many cases.

What theory works best for schizophrenia? ›

Cognitive behavior therapy (CBT).

This treatment helps you change how you think and react to things. It also teaches you to deal with negative feelings by thinking about them in a different way so you feel good instead.

What is the most commonly accepted theory of schizophrenia today? ›

The most widely accepted theory of schizophrenia is that it is a neurodevelopmental disorder, which means that normal brain development during fetal life is disrupted due to various genetic factors and/or environmental factors.

What are some of the theories that attempt to explain the cause of schizophrenia? ›

The cause of schizophrenia is still unclear. Some theories about the cause include : genetics (heredity); biology (abnormalities in the brain's chemistry or structure); and/or possible viral infections and immune disorders.

Which dopamine pathway is associated with schizophrenia? ›

A number of investigators propose that negative and cognitive symptoms of schizophrenia are associated with hypofunction of the mesocortical pathway. This tract is made up of dopaminergic neurons that project from the ventral tegmental area to the prefrontal cortex.

What is the evolutionary purpose of dopamine? ›

A dopaminergic expansion during early hominid evolution could have enabled successful chase-hunting in the savannas of sub-Saharan Africa, given the critical role of dopamine in counteracting hyperthermia during endurance activity.

How can the positive symptoms of schizophrenia be explained by salience? ›

The aberrant salience model might therefore explain both positive and negative symptoms by appealing to a common neurobiological mechanism, namely a loss of signal:noise ratio in the mesolimbic dopamine system, possibly as a result of increased tonic dopamine activity (Grace, 1991; Winterer & Weinberger, 2004).

What does the dopamine theory of addiction suggest about recovery from addiction? ›

One interpretation of these data is that low levels of dopamine release indicate a vulnerability to addiction, thus turning the dopamine theory on its head; instead of being the cause of addiction, dopamine might, if anything, have a role in resilience against becoming dependent and may be crucial for recovery from ...

What is the dopamine hypothesis of depression? ›

The dopamine hypothesis of bipolar disorder proposes that faulty homoeostasis between dopamine transporter and receptors underlies depressive and manic phases of the illness.

What is the dopamine hypothesis of schizophrenia A level psychology? ›

The Dopamine Hypothesis was proposed by Arvid Carlsson and suggests that schizophrenia is caused by too much dopamine - or too many dopamine receptors - in key areas of the brain. Dopamine systems in the mesolimbic pathway may contribute to the positive symptoms of schizophrenia (such as hallucinations).

What is a leading hypothesis of schizophrenia? ›

The glutamate and dopamine hypotheses are leading theories of the pathoaetiology of schizophrenia. Both were initially based on indirect evidence from pharmacological studies supported by post-mortem findings, but have since been substantially advanced by new lines of evidence from in vivo imaging studies.

What is dopamine hypothesis in psychology? ›

the influential theory that schizophrenia is caused by an excess of dopamine in the brain, due either to an overproduction of dopamine or a deficiency of the enzyme needed to convert dopamine to norepinephrine (adrenaline).

What is the role of dopamine in behavior psychological functioning? ›

Dopamine is known as the “feel-good” hormone. It gives you a sense of pleasure. It also gives you the motivation to do something when you're feeling pleasure. Dopamine is part of your reward system.

What is the dopamine vs glutamate hypothesis of schizophrenia? ›

This hypothesis predicts that a disrupted glutamatergic transmission causes the core cognitive deficits of schizophrenia and may lead to a secondary disruption in dopamine transmission that in turn causes psychosis.

What are the biological explanations of schizophrenia? ›

Research suggests schizophrenia may be caused by a change in the level of 2 neurotransmitters: dopamine and serotonin. Some studies indicate an imbalance between the 2 may be the basis of the problem. Others have found a change in the body's sensitivity to the neurotransmitters is part of the cause of schizophrenia.


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