NEURAL CORRELATES AND THE DOPAMINE HYPOTHESIS
KEYWORDS
NEUROTRANSMITTERS: A neurotransmitter is a chemical that allows neurons in the brain to communicate. They do this by producing a bridge across the synapse between the axon terminals and dendrites, which allows the continuation of the nerve impulse to progress.
NEURAL CORRELATES: Specific brain activity, structure, or function patterns associated with schizophrenia symptoms. These provide insights into how brain chemistry or anatomy disruptions contribute to the disorder.
GLUTAMATE: The brain's most abundant excitatory neurotransmitter, often called the "on switch." It plays a vital role in synaptic transmission, learning, memory, and regulating other neurotransmitters like dopamine. Dysregulation of glutamate, mainly through NMDA receptors, is associated with schizophrenia symptoms.
SEROTONIN: A neurotransmitter influencing mood, emotion, sleep, and appetite. While serotonin is primarily associated with depression, its interaction with dopamine in the brain has implications for schizophrenia, particularly in the efficacy of atypical antipsychotic drugs, which target serotonin receptors as well as dopamine receptors.
NMDA RECEPTORS: A glutamate receptor subtype crucial for synaptic plasticity, memory, and learning. Dysfunction of NMDA receptors is a key feature of the glutamate hypothesis of schizophrenia and is thought to contribute to both positive and negative symptoms.
GLYCINE: An amino acid and co-agonist for NMDA receptors. Glycine enhances NMDA receptor function, and deficits in glycine activity are linked to schizophrenia, particularly its cognitive and negative symptoms.
CALCIUM (CA²⁺): A vital ion in the brain that regulates neurotransmitter release, neuronal excitability, and synaptic plasticity. Calcium plays a role in signal transmission within neurons and interacts with glutamate through NMDA receptor activation. Disruptions in calcium signalling are associated with neuropsychiatric disorders, including schizophrenia.
DOPAMINE: A neurotransmitter that controls movement, motivation, and reward. It is crucial in various brain functions, including attention, learning, and emotional regulation.
Dopamine receptors are divided into two prominent families:
D1-LIKE RECEPTORS (D1, D5): Generally stimulate neuron activity (excitatory effects).
D2-LIKE RECEPTORS (D2, D3, D4): Generally inhibit neuron activity (inhibitory effects).
Different dopamine receptors are distributed in specific areas of the brain, enabling them to control distinct functions:
D1 AND D2 RECEPTORS: Found in the basal ganglia, important for motor control.
D3 RECEPTORS: Found in the limbic system, linked to emotional regulation and reward.
D4 RECEPTORS: Found in the frontal cortex, associated with attention and decision-making.
D5 RECEPTORS: Found in the hippocampus, linked to learning and memory.
Having multiple receptor types allows the dopamine system to adapt to varying demands. For example:
In the REWARD SYSTEM, dopamine binding to D1 receptors strengthens positive reinforcement.
In the STRESS RESPONSE, D2-like receptors help regulate mood and avoid overreaction.
Specific drugs target different dopamine receptors:
ANTIPSYCHOTICS: Often block D2 receptors to reduce overactivity in conditions like schizophrenia.
STIMULANTS (E.G., AMPHETAMINES): Enhance dopamine action, often affecting D1 and D2 receptors.
PARKINSON’S TREATMENTS: Target D1 and D2 receptors to compensate for dopamine loss
DOPAMINE FUNCTION: Dopamine has many functions in the brain, including important roles in behaviour and cognition (thinking), voluntary movement, motivation, punishment and reward, pleasure and focus.
AGONISTS/STIMULANTS: These drugs increase the availability of a neurotransmitter in the brain. There are many illegal agonists, e.g., street drugs: cocaine, crack, and PCP. LSD, amphetamines (speed), ecstasy cannabis, heroin, and crack, etc. Legal agonists are L-dopa, methadone, Prozac, and Valium. L-dopa is often used in Parkinson’s patients to increase dopamine availability in the brain.
ANTAGONISTS/BLOCKERS: These drugs block the availability of a neurotransmitter in the brain. There are no street drugs that do this. Antagonists used to block dopamine are known as antipsychotics and neuroleptics (phenothiazines such as chlorpromazine (Thorazine), Risperidone, and Clozapine are some examples).
HYPO AND HYPER: These two prefixes are easily confused as they sound similar, but they have, in fact, more or fewer opposite meanings. Hyper- means over, excessive, more than normal, as in such words as hyperbole (extravagant and obvious exaggeration) and hyperactive (abnormally or pathologically active). Hypo means low, under, beneath, down, or below normal, as in hypoglycemia (low blood sugar) and hyposensitivity (under sensitivity). About neurotransmitters, a hyperneurotransmitter system means too many neurotransmitters are being secreted into the synapses within a specific neural circuit. Because of this, it produces over-stimulation of the cells and causes an exaggeration of functions.
WHAT ARE NEURAL CORRELATES?
A neural correlate for schizophrenia is a physical difference in the brain that is linked to the symptoms of the disorder. This means that certain brain structures or activities are different in people with schizophrenia compared to those without it.
Research has identified many neural correlates for schizophrenia, meaning areas of brain damage or differences that correspond with schizophrenic behaviour. However, because this is a large area, AQA specifically requires you to focus on the dopamine hypotheses as the neural correlate to discuss in your essay.
Dopamine dysregulation is one of the key neural correlates of schizophrenia. This theory suggests that excess dopamine activity in the mesolimbic pathway is linked to positive symptoms such as hallucinations and delusions, while reduced dopamine activity in the mesocortical pathway is associated with negative symptoms like avolition and speech poverty. This makes dopamine dysfunction a crucial biological explanation of schizophrenia.
That said, it is important to be aware that dopamine is not the only neural correlate for schizophrenia. For example, research has found that people with schizophrenia often have enlarged brain ventricles. These are fluid-filled spaces in the brain, and their enlargement suggests a loss of brain tissue, which has been linked to negative symptoms and cognitive impairment. While this is a well-documented neural correlate, AQA’s focus remains on dopamine as the primary explanation in exams.
THE ORIGINAL DOPAMINE HYPOTHESIS
AO1 OUTLINE OF THE THEORY
It should be noted that biochemical theories do not compete with genetic theories. They can be complementary; for example, genes could cause a person to produce too much dopamine.
The dopamine hypothesis was discovered accidentally after it was found that giving patients antihistamines before surgery reduced surgical shock by making patients sleepier and less fearful about their impending operations. This breakthrough finding encouraged pharmaceutical companies to re-examine antihistamines and find out why they had tranquilising effects.
Research soon showed that the nucleus of the antihistamines (phenothiazine) was causing this sedative effect in patients. Shortly after that, the French chemist Paul Charpentier prepared a new phenothiazine derivative, which he called chlorpromazine; thus, the first typical antipsychotic was created.
At first, chlorpromazine was given to a variety of patients who had disturbed and agitated behaviour. Still, it was soon discovered that it was very effective in calming patients with schizophrenia and psychosis.
As phenothiazines derive their therapeutic properties by blocking dopamine receptors in the brain, it was hypothesised that Schizophrenia might be caused by excess dopamine. As a result, the original dopamine hypothesis was born.
Van Rossum put forward the original dopamine hypothesis in 1967. He hypothesised that there was a was hyperactivity of dopamine transmission, which resulted in the symptoms of schizophrenia, i.e., the unusual behaviour and experiences associated with schizophrenia (sometimes extended to psychosis in general) can be fully or explained mainly by hyperactivity of dopamine D2 receptor neurotransmission in subcortical and limbic regions of the brain.
Schizophrenia is associated with poor attention and an inability to stay focused on one thing (knight’s move thinking and clang associations, for example); this is because dopamine’s role is to mediate motivation and attention, thereby giving a person the ability to determine what stimulus grabs their attention and drives the subsequent behaviour.
Overstimulation of the dopamine system ultimately leads to irrelevant stimuli becoming more prominent, which provides a basis for psychotic phenomena such as ‘delusions of reference’, where everyday occurrences may be layered with a heightened sense of bizarre significance. Furthermore, this misattribution of focus can lead to paranoid behaviour and persecutory delusions. This is because excess dopamine has a profound influence on thought, feelings and behaviour.
A01: RESEARCH ANTI-PSYCHOTICS
The primary evidence used to support the dopamine hypothesis is the theory behind the success of typical and atypical antipsychotic drugs such as Thorazine (chlorpromazine), e.g., as they reduce dopamine firing, schizophrenia must be caused by excess dopamine. Activity. Moreover, not only do anti-psychotic drugs (dopamine antagonists) reduce positive symptoms (hallucinations, delusions) in type one schizophrenics, but when the same individuals are given drugs with a dopamine agonist, e.g., medications such as L-dopa that increase dopamine availability, then their symptoms became much worse. According to Kapur, dopamine inflames the cognitive tendencies that people with schizophrenia exhibit even before they become ill. He says: ‘If you could test patients before they were psychotic, you’d probably find they tend to jump to conclusions or choose extreme explanations. When you add to this a biochemical fuel – excess dopamine – you inflame this way of thinking; that is what dopamine does. The antipsychotic drugs douse the flames and take away the fuel – they do not fundamentally change the patients’ tendencies, and that’s why relapse usually occurs when medication is stopped.
A03: RESEARCH ANALYSIS: ANTI-PSYCHOTICS
Also adding support to the theory is research on Parkinson’s sufferers and dopamine agonists. A lack of dopamine causes Parkinson's disease. As a result, Parkinson’s patients are treated with synthetic legal agonists to increase their dopamine availability (e.g., L-Dopa). However, if Parkinson’s patients are given high levels of L-dopa, they can suffer from positive symptoms, e.g., they can experience psychotic side effects which mimic the symptoms of schizophrenia. Conversely, Type 1 schizophrenics can suffer from Parkinson’s symptoms when on antipsychotic drugs.
A01: RESEARCH ILEGAL STREET DRUGS
This conclusion is further supported by the research of drug addicts who use street drugs with dopamine agonist properties, such as LSD, cocaine, amphetamine, methamphetamine and other similar substances, as all illegal drugs dramatically increase the levels of dopamine in the brain. Indeed, drug addicts often have symptoms that resemble those present in psychosis, particularly after large doses or prolonged use. This type of addiction is usually referred to as "amphetamine psychosis" or "cocaine psychosis," which may produce experiences virtually indistinguishable from the positive symptoms associated with schizophrenia. In the early 1970s, several studies experimentally induced amphetamine psychosis in ordinary participants to better document the clinical pattern of schizophrenia.
It is also worth noting that when schizophrenics abuse street drugs (it should be noted that schizophrenia is comorbid with drug addiction), positive symptoms become much worse. For example, up to 75% of patients with schizophrenia have increased signs and symptoms of their psychosis when given moderate doses of amphetamine or other dopamine-like compounds/drugs, all given at doses that neuro-typical volunteers do not have any psychologically disturbing effects. Lastly, repeated exposure to high doses of antipsychotics (dopamine antagonists gradually reduced paranoid psychosis in these neurotypical participants. There are ethical issues with the above studies.
A03: RESEARCH ANALYSIS ILEGAL DRUGS
However, this type of research has also fallen out of favour with the scientific research community, as drug-induced psychosis is now thought to be qualitatively different from schizophrenia psychosis. Differences between the drug-induced states and the typical presentation of schizophrenia have now become more apparent, e.g., euphoria, alertness, and over-confidence. Some researchers believe these symptoms are more reminiscent of mania (manic side of bipolar depression) than schizophrenia.
A01: RESEARCH RATS
Chemical stimulation in rats is thought to support the dopamine hypothesis. In brief, rats are given dopamine antagonists (e.g., antipsychotic drugs such as chlorpromazine) and dopamine agonists (e.g., L-dopa, PCP and amphetamines). The behaviour that rats show when given agonists is thought to be like the positive and negative symptoms of schizophrenia in humans. For example, several animal models of schizophrenia are based on the experimental observation that phencyclidine (PCP) and amphetamines can induce behavioural changes that include locomotor hyperactivity, stereotyped behaviour, and social withdrawal (Murray and Horita 1979).
A03: RESEARCH ANALYSIS RATS
Of course, rats are not comparable to humans; not only do they not have a language, which is one of the key problem areas in schizophrenics, but psychologists do not have a viable way of assessing how disorganised or hallucinogenic a rat’s thoughts are whilst on L-dopa as they can’t ask a rat if it is hallucinating or delusional. Moreover, as the clinical interview is the only valid way of assessing schizophrenia in humans, one wonders how the researchers got over that problem when determining the rats ‘supposedly’ positive schizophrenic symptoms; schizophrenia may be unique only to humans.
On the other hand, rats and humans share many similarities, including comparable hormonal and nervous systems. Plus, we have almost identical hind, mid-, and forebrains. More importantly, rats and humans share similar mesolimbic systems, the pathway in which dopamine is processed, so the research would be valuable in assessing how antagonists and agonists affect dopamine receptors.
ANALYSIS SPECIFIC TO THE ORIGINAL DOPAMINE HYPOTHESIS.
An important observation is that schizophrenia is not the only disorder associated with dopamine; bipolar I, II (manic depression), schizoaffective disorder and acute transient psychosis are just some of the disorders related to this neurotransmitter. This means that excess dopamine might have more to do with psychosis than schizophrenia and is, therefore, only a partial explanation.
Also relevant is the fact that current research shows that one-third of individuals with schizophrenia do not respond to antipsychotics despite high levels of D2-receptor occupancy. In other words, they fit the criteria for dopamine hypothesis 1, but drugs that reduce dopamine activity do not alleviate their positive symptoms. This finding undermines the idea that excess dopamine causes schizophrenia. On the other hand, some health professionals believe that this result occurs when patients start chemotherapy too long after the start of their symptoms.
More importantly, a large subset of schizophrenics do not suffer from positive symptoms and instead present with “negative” symptoms. In these cases, antipsychotics do not affect type-two negative symptoms whatsoever. Interestingly, if dopamine agonists such as L-dopa are given, these symptoms can improve. Thus, a significant problem with the original dopamine hypothesis is that dopamine is not implemented in type 2 schizophrenia, where negative symptoms predominate.
THE REFORMULATED DOPAMINE HYPOTHESIS: DOPAMINE 2 AND THE HYPO AND HYPER THEORIES
Over the years, researchers have recognised that the original dopamine hypothesis, which explained positive symptoms(e.g., hallucinations, delusions) as a result of hyperdopaminergic activity, failed to account for negative symptoms(e.g., apathy, flattened affect, and social withdrawal) and cognitive deficits (e.g., poor working memory, attention problems). These symptoms are often resistant to D2 receptor antagonist drugs, such as typical antipsychotics.
To address these limitations, the reformulated dopamine hypothesis was developed. This updated hypothesis proposes that schizophrenia involves both hyperdopaminergic and hypodopaminergic activity in different brain regions, contributing to the wide range of symptoms seen in the disorder. Importantly, this reformulation also introduced the concept of neural correlates—specific dopamine activity and receptor involvement patterns that underlie distinct symptom clusters.
Research has identified many neural correlates for schizophrenia, meaning areas of brain damage or differences that correspond with schizophrenic behaviour. However, because this is a large area, AQA specifically requires you to focus on the dopamine hypotheses as the neural correlate to discuss in your essay.
LIMITATIONS OF THE ORIGINAL DOPAMINE HYPOTHESIS
The original dopamine hypothesis proposed that positive symptoms (e.g., hallucinations, delusions) were caused by excess dopamine activity (hyperdopaminergia) in the mesolimbic pathway. While this explained psychotic symptoms well, it failed to account for negative symptoms (e.g., apathy, flattened affect, and social withdrawal) and cognitive deficits (e.g., poor working memory, attention problems).
Further research showed that these symptoms are often resistant to typical antipsychotic drugs, which block D2 receptors. This suggested that dopamine dysregulation was more complex than just an overall increase in activity, leading to the reformulated dopamine hypothesis.
THE REFORMULATED DOPAMINE HYPOTHESIS: HYPER- AND HYPO-DOPAMINERGIA
The updated model proposes that schizophrenia involves both excessive and insufficient dopamine activity in different regions of the brain. This introduced the idea that dopamine dysfunction itself can be considered a neural correlate, as specific dopamine pathways and receptor activity are linked to distinct symptom clusters.
HYPERDOPAMINERGIC ACTIVITY AND POSITIVE SYMPTOMS
Hyperdopaminergic activity is most prominent in subcortical regions, particularly the striatum, which is involved in the brain’s reward and salience network. Dopamine in the striatum helps assign importance to stimuli, a process known as salience attribution.
When dopamine activity is excessive, especially at D2 receptors, the brain assigns too much importance to irrelevant stimuli, leading to positive symptoms, such as:
Hallucinations, where individuals perceive things that aren’t there.
Delusions, such as paranoia or believing unrelated events have personal significance (delusions of reference).
Disorganised thinking, where logical connections between thoughts are disrupted.
D2 receptors are normally inhibitory, meaning they help control neural activity. However, in schizophrenia, overstimulation of D2 receptors causes overactivation of neural circuits in the striatum, contributing to psychotic symptoms.
HYPODOPAMINERGIC ACTIVITY AND NEGATIVE/CORRELATIVE SYMPTOMS
In contrast to hyperdopaminergic activity in the striatum, hypodopaminergic activity occurs in the prefrontal cortex, a brain area responsible for attention, decision-making, memory, and emotional regulation.
Dopamine in this region primarily acts through D1 receptors, which are excitatory and enhance neural communication. When dopamine levels are too low, D1 receptor activity decreases, leading to:
Negative symptoms, such as apathy, reduced emotional expression, and withdrawal from social interactions.
Cognitive deficits, including impaired working memory, attention, and decision-making.
D1 receptors are crucial for maintaining cognitive flexibility and emotional processing. When dopamine function is reduced in the prefrontal cortex, the brain struggles to regulate emotions and thoughts, contributing to the persistent difficulties seen in schizophrenia.
NEURAL CORRELATES BEYOND DOPAMINE
While dopamine dysfunction is a key neural correlate, research has also identified structural abnormalities linked to schizophrenia. One of the most well-documented findings is enlarged brain ventricles—fluid-filled spaces in the brain that are often larger than normal in individuals with schizophrenia. This enlargement suggests a loss of brain tissue, which has been associated with negative symptoms and cognitive impairments.
These findings indicate that schizophrenia involves both neurotransmitter imbalances and structural brain differences, making it a complex disorder with multiple biological factors contributing to its symptoms.
SIGNIFICANCE OF NEURAL CORRELATES
The distinction between hyperdopaminergic and hypodopaminergic activity helps explain why typical antipsychotic drugs, which primarily block D2 receptors, are effective for treating positive symptoms but have limited impact on negative and cognitive symptoms. This also highlights why newer atypical antipsychotics, which affect both dopamine and serotonin, are sometimes more effective.
SIX-MARK A01 RESPONSE
The reformulated dopamine hypothesis suggests that schizophrenia is caused by both excessive and insufficient dopamine activity in different areas of the brain. This model refines the original dopamine hypothesis, which only focused on hyperdopaminergic activity in the mesolimbic pathway as the cause of positive symptoms such as hallucinations and delusions. The revised version accounts for negative symptoms and cognitive deficits by incorporating hypodopaminergic activity in the prefrontal cortex.
Hyperdopaminergic activity is associated with positive symptoms and occurs primarily in the striatum, where excess dopamine at D2 receptors causes abnormal salience processing. This means the brain assigns too much importance to irrelevant stimuli, leading to hallucinations, delusions, and disorganised thinking.
In contrast, hypodopaminergic activity is linked to negative and cognitive symptoms and occurs in the prefrontal cortex, which is responsible for higher-order functions like decision-making and emotional regulation. A lack of dopamine at D1 receptors in this region disrupts cognitive processes, contributing to apathy, reduced motivation, and impaired memory and attention.
The reformulated dopamine hypothesis is a neural correlate of schizophrenia because it links specific dopamine dysfunction in different pathways to distinct symptom clusters, offering a more comprehensive biological explanation of the disorder.
THREE-MARK A01 RESPONSE
The reformulated dopamine hypothesis proposes that schizophrenia involves both excessive and insufficient dopamine activity in different brain areas. Hyperdopaminergic activity in the striatum is linked to positive symptoms, as excess dopamine at D2 receptors causes the brain to assign too much importance to irrelevant stimuli, leading to hallucinations and delusions.
At the same time, hypodopaminergic activity in the prefrontal cortex is associated with negative symptoms and cognitive deficits. A lack of dopamine at D1 receptors in this region disrupts thinking, memory, and motivation, contributing to symptoms like apathy and poor decision-making. This updated model explains a wider range of symptoms than the original dopamine hypothesis, making it a more complete biological explanation of schizophrenia.
EVIDENCE FOR HYPERDOPAMINERGIC ACTIVITY AND POSITIVE SYMPTOMS
Lindström et al. (1999) used PET scans to measure dopamine synthesis in people with schizophrenia and found increased dopamine production in the striatum compared to controls. This supports the idea that hyperdopaminergic activity in the striatum contributes to positive symptoms like hallucinations and delusions.
Howes et al. (2012) also used PET imaging and found that people at high risk of developing schizophrenia had elevated dopamine synthesis in the striatum, suggesting that dopamine overactivity occurs before the onset of symptoms, supporting its role in causing psychosis rather than being a result of the disorder.
Amphetamine challenge studies (e.g., Laruelle et al., 1996) found that individuals with schizophrenia released more dopamine in response to amphetamines than control participants. Since amphetamines increase dopamine levels, this suggests that people with schizophrenia already have excess dopamine activity in the striatum, reinforcing the link between hyperdopaminergia and positive symptoms.
EVIDENCE FOR HYPODOPAMINERGIC ACTIVITY AND NEGATIVE SYMPTOMS
Davis et al. (1991) proposed the reformulated dopamine hypothesis, arguing that while positive symptoms are linked to excess dopamine in the striatum, negative symptoms are caused by dopamine underactivity in the prefrontal cortex.
Juckel et al. (2006) found that individuals with schizophrenia showed reduced dopamine activity in the prefrontal cortex, which was correlated with negative symptoms such as avolition and emotional flattening.
Weinberger et al. (1986) found that patients with prefrontal cortex damage displayed negative and cognitive symptoms similar to those seen in schizophrenia. This suggests that dopamine underactivity in the prefrontal cortex plays a key role in these symptom clusters.
Goldman-Rakic et al. (2004) found that lower D1 receptor density in the prefrontal cortex was associated with cognitive deficits in schizophrenia, supporting the idea that hypodopaminergia in the prefrontal cortex contributes to working memory and decision-making impairments.
EVIDENCE FOR NEURAL CORRELATES LINKING DOPAMINE DYSFUNCTION TO SCHIZOPHRENIA
Patel et al. (2010) found that dopamine dysfunction in both the striatum and prefrontal cortex was present in patients with schizophrenia, confirming the dual role of hyperdopaminergic and hypodopaminergic activity in different pathways.
Takahashi et al. (2006) used MRI and PET scans to show that prefrontal cortex dysfunction was linked to reduced dopamine receptor availability and impaired cognitive function, further supporting the role of hypodopaminergic activity in negative symptoms.
CONCLUSION
The reformulated dopamine hypothesis is supported by strong research evidence from brain imaging, post-mortem studies, and pharmacological experiments. Increased dopamine activity in the striatum is linked to positive symptoms, while reduced dopamine activity in the prefrontal cortex is linked to negative and cognitive symptoms. This dual-pathway model provides a more comprehensive biological explanation of schizophrenia than the original dopamine hypothesis.
OTHER EVALUATION POINTS FOR THE DOPAMINE HYPOTHESIS
OTHER NEURAL CORRELATES
The dopamine hypothesis explains many symptoms of schizophrenia, but it is not the only neural correlate. Brain imaging studies have found other biological differences in people with schizophrenia, such as:
Enlarged ventricles – People with schizophrenia often have larger fluid-filled spaces in the brain, which suggests brain tissue loss. This is linked to negative symptoms like lack of motivation and social withdrawal.
Prefrontal cortex abnormalities – This area of the brain is involved in decision-making and planning. In schizophrenia, it often shows reduced activity, which may explain cognitive impairments such as poor memory and attention.
These findings suggest that schizophrenia is not just about dopamine—other brain structures and functions are involved.
THE ROLE OF GLUTAMATE
More recent research suggests that glutamate, another neurotransmitter, may play a key role in schizophrenia. Glutamate helps regulate dopamine activity, and studies show that:
Low glutamate activity in the prefrontal cortex is linked to negative symptoms and cognitive problems.
Glutamate and dopamine interact, meaning that imbalances in one can affect the other.
This suggests that the dopamine hypothesis alone may be too simplistic—schizophrenia likely involves multiple neurotransmitters, not just dopamine.
A03: RESEARCH ANALYSIS OF DOPAMINE 2 HYPOTHESIS
If schizophrenia is caused by a dopamine imbalance, there should be evidence of unusual dopamine activity in the brains of individuals with the disorder. Early and contemporary studies provide both support and critique for this hypothesis. Below is a summary of the key research evidence, from historical methods to modern imaging techniques.
POST-MORTEM STUDIES AND EARLY FINDINGS
Early studies often relied on post-mortem examinations to investigate dopamine receptors in the brains of individuals diagnosed with schizophrenia. Many of these studies reported increased dopamine receptor density, particularly in the striatum. However, this method is highly problematic for several reasons:
Real-Time Limitations: Post-mortem studies cannot measure live dopamine activity, which is crucial for understanding neurotransmitter function.
Medication Effects: Many individuals studied had taken antipsychotic drugs, which affect brain chemistry and receptor density. As a result, changes observed in post-mortem brains may reflect medication effects rather than the underlying biology of schizophrenia.
Generalisability Issues: Case studies from post-mortems often lack generalisability, as the brains studied may not represent the broader population of individuals with schizophrenia.
Diagnostic Ambiguity: Before the introduction of the DSM-5, schizophrenia samples often included individuals with bipolar disorder, catatonia, or a mix of negative and positive symptoms, which could skew findings.
These methodological issues explain why historical research findings on dopamine activity in schizophrenia were often inconsistent.
ADVANCES IN BRAIN IMAGING AND NEURAL CORRELATES
Modern techniques, such as PET (positron emission tomography) and fMRI (functional magnetic resonance imaging), have revolutionised the study of dopamine activity in living brains. These imaging methods provide real-time evidence of neurotransmitter function and structural changes in the brains of individuals with schizophrenia.
BRAIN IMAGING EVIDENCE FOR POSITIVE SYMPTOMS
Positive symptoms, such as hallucinations and delusions, have been linked to hyperdopaminergic activity in subcortical regions, particularly the mesolimbic system. Key findings include:
Increased Dopamine Receptors: Studies consistently show an excess of dopamine D2 receptors in the striatum, caudate nucleus, and amygdala.
Faster Dopamine Metabolism: Individuals with schizophrenia often exhibit increased dopamine turnover, reflecting faster synthesis and breakdown of dopamine in the brain.
Enhanced Dopamine Release: After taking amphetamines, which increase dopamine availability, individuals with schizophrenia release significantly more dopamine (particularly in the striatum) compared to neurotypical controls. This supports the link between dopamine overactivity and psychotic symptoms.
Auditory Hallucinations: Reduced activity in the superior temporal gyrus and anterior cingulate gyrus has been directly associated with auditory hallucinations. Patients experiencing these symptoms show lower activation in these brain areas compared to healthy individuals.
These findings suggest that hyperactivity in dopamine pathways and reduced activity in specific cortical areas act as neural correlates of positive symptoms.
BRAIN IMAGING EVIDENCE FOR NEGATIVE SYMPTOMS
Negative symptoms, such as avolition (loss of motivation) and social withdrawal, have been linked to hypodopaminergic activity in cortical regions. Key findings include:
Reduced Activity in the Ventral Striatum: The ventral striatum is key in anticipating rewards and driving motivation. Abnormalities in this area are strongly linked to avolition.
Prefrontal Cortex and D1 Receptors: The under-functioning of D1 receptors in the prefrontal cortex correlates with the cognitive and motivational impairments observed in schizophrenia. The prefrontal cortex is responsible for higher-order functions such as planning, problem-solving, and emotional regulation.
Neuroimaging Evidence: Patients with negative symptoms show significantly lower activation in the prefrontal cortex during tasks requiring executive function, further supporting the role of dopamine hypoactivity in these symptoms.
These findings highlight the importance of dopamine hypoactivity in cortical areas as a neural correlate for negative symptoms.
THE REFORMULATED DOPAMINE HYPOTHESIS: WHAT IT DID NOT ADDRESS
The reformulated dopamine hypothesis was a significant improvement over the original theory. It explained how positive symptoms like hallucinations and delusions arise from hyperdopaminergic activity (excess dopamine) in the striatum and how negative symptoms like apathy, emotional withdrawal, and poor concentration are linked to hypodopaminergic activity (reduced dopamine) in the prefrontal cortex. However, despite its advancements, this hypothesis still left key questions unanswered.
NEGATIVE SYMPTOMS AND COGNITIVE DEFICITS
The reformulated hypothesis struggled to explain negative symptoms and cognitive deficits fully. While reduced dopamine activity in the prefrontal cortex provides some answers, it is clear that dopamine alone does not account for the complexity of these symptoms. For example:Why do negative symptoms vary so widely across patients?
Why do cognitive deficits, such as poor working memory and decision-making, persist even when dopamine levels normalise?
Furthermore, the therapeutic delay of antipsychotics—despite their immediate blocking of dopamine receptors—indicates that dopamine likely interacts with other systems, complicating a simple cause-and-effect explanation.
MULTIPLE NEUROTRANSMITTERS
Researchers like Carlsson proposed that dopamine is just one piece of a larger neurochemical puzzle. Schizophrenia likely involves disruptions in other neurotransmitter systems, such as serotonin and glutamate. This idea is supported by the efficacy of atypical antipsychotics, such as clozapine, which targets serotonin and glutamate receptors in addition to dopamine receptors.DELAYED THERAPEUTIC RESPONSE
Another major challenge is the therapeutic delay observed with antipsychotic drugs. These medications block dopamine receptors immediately, yet their effects on symptoms often take several weeks to appear. This suggests that dopamine imbalances interact with other neurotransmitter systems over time and that schizophrenia cannot be fully explained by dopamine alone.
THE ROLE OF GLUTAMATE: THE FINAL PIECE OF THE PUZZLE
Recent research has identified glutamate, the brain’s "on-switch" neurotransmitter, as a crucial regulator of dopamine activity. This has led to the development of an updated dopamine hypothesis, which integrates glutamate into our understanding of schizophrenia.
DOPAMINE AND GLUTAMATE: BEST FRIENDS IN THE BRAIN
Dopamine and glutamate work together in the brain to maintain balance. You can think of dopamine as the "reward and motivation signal" that drives attention and behaviour, while glutamate is the "on switch" that controls dopamine’s activity. Without glutamate, dopamine can’t function properly.
Glutamate essentially gives orders to dopamine, telling it when to:
Turn up and get active (e.g., when focusing on a task or responding to a threat).
Calm down to avoid overstimulation (e.g., during rest or emotional regulation).
If glutamate signalling breaks down, this regulatory system collapses. Think of glutamate as a traffic light for dopamine:
When the traffic light works, dopamine flows smoothly, maintaining balance in the brain.
If the traffic light (glutamate) is broken, dopamine levels can crash or overflow, leading to chaos in the brain’s pathways.
WHEN GLUTAMATE FAILS: IMPACT ON SYMPTOMS
POSITIVE SYMPTOMS
Dysfunctional glutamate signalling, particularly through NMDA receptors, can cause excess dopamine activity in the striatum. This hyperactivity leads to symptoms like hallucinations and delusions.NEGATIVE SYMPTOMS AND COGNITIVE DEFICITS
At the same time, insufficient glutamate activity can reduce dopamine activity in the prefrontal cortex, resulting in symptoms such as apathy, social withdrawal, and difficulty concentrating.
EVIDENCE FOR GLUTAMATE’S ROLE IN SCHIZOPHRENIA
NMDA RECEPTOR HYPOTHESIS
Studies have shown that NMDA receptor dysfunction is a core feature of schizophrenia. NMDA receptors are glutamate receptors responsible for regulating neural activity. If these receptors don’t work properly, dopamine pathways become unbalanced.DRUG STUDIES
Drugs like ketamine and PCP, which block NMDA receptors, can induce psychotic symptoms in healthy individuals. These symptoms closely mimic those seen in schizophrenia, further supporting the link between glutamate dysfunction and the disorder.BRAIN IMAGING
Neuroimaging studies have identified disruptions in brain regions rich in NMDA receptors, such as the prefrontal cortex and striatum, providing additional evidence for glutamate’s role.
CONCLUSION
Glutamate provides the missing piece to the puzzle of schizophrenia. While dopamine explains some aspects of the disorder, it’s not the whole story. Glutamate is the traffic light that keeps dopamine in check, ensuring the brain’s reward, motivation, and emotional systems work together smoothly. When glutamate pathways fail, they destabilise dopamine, leading to the diverse symptoms of schizophrenia. This updated understanding highlights the complexity of schizophrenia and the need for treatments that address not just dopamine but also glutamate and other neurotransmitters.
HISTORICAL DEVELOPMENT OF SCHIZOPHRENIA'S BIOLOGICAL EXPLANATIONS
The understanding of schizophrenia’s biological causes has evolved over time, progressing from dopamine-based theories to broader neural explanations. The development followed this general sequence:
ORIGINAL DOPAMINE HYPOTHESIS
The original dopamine hypothesis emerged after the accidental discovery that antihistamines (which later became antipsychotics) had a calming effect on psychotic patients. Further research found that these drugs blocked dopamine receptors (D2 receptors), leading to the idea that schizophrenia was caused by excess dopamine activity.
This early model proposed that overactivity in the mesolimbic dopamine pathway was responsible for positive symptoms such as hallucinations and delusions. However, this explanation was soon criticised as it did not account for negative symptoms like avolition or speech poverty.
REFORMULATED DOPAMINE HYPOTHESIS
To address these limitations, the dopamine hypothesis was revised to explain both positive and negative symptoms. The revised model proposed that:
Excess dopamine in the mesolimbic pathway leads to positive symptoms such as hallucinations and delusions.
Reduced dopamine in the mesocortical pathway (linked to the prefrontal cortex) is responsible for negative symptoms such as avolition and speech poverty.
This revision improved the dopamine hypothesis by explaining a wider range of symptoms and linking dopamine dysfunction to prefrontal cortex abnormalities, which became a key focus in later research.
NEURAL CORRELATES AND BROADER BIOLOGICAL EXPLANATIONS
Advances in brain imaging techniques revealed that schizophrenia was not solely a dopamine disorder but also involved structural and functional abnormalities in the brain. This led to the study of neural correlates, which refer to biological features associated with symptoms of schizophrenia.
Key neural correlates include:
Enlarged ventricles → linked to negative symptoms and cognitive impairment.
Prefrontal cortex dysfunction → associated with negative symptoms and cognitive deficits (consistent with the revised dopamine hypothesis).
Superior temporal gyrus and anterior cingulate dysfunction → linked to auditory hallucinations.
These findings expanded the biological explanation of schizophrenia beyond dopamine alone, showing that both neurotransmitter imbalances and structural brain abnormalities contribute to the disorder.
CONCLUSION
The understanding of schizophrenia has evolved from a simple dopamine excess theory to a more complex model that includes both neurotransmitter imbalances and brain structure abnormalities. The reformulated dopamine hypothesis recognised the role of dopamine underactivity in negative symptoms, and neural correlates researchfurther expanded this by identifying physical brain abnormalities associated with the disorder. Today, schizophrenia is understood as a disorder involving both chemical and structural brain dysfunctions, rather than just a problem with dopamine alone.
HOW THESE EXPLANATIONS FIT TOGETHER
A03 FOR ALL NEUROTRANSMITTER THEORIES OF SCHIZOPHRENIA
Here’s the rewritten version, incorporating the changes and removing the APFC section while presenting the content in clear prose:
Overall, both the original and reformulated dopamine hypotheses shed light on the aetiology of schizophrenia, with various research methods demonstrating the link between neurotransmitter imbalances and the disorder. However, a significant question remains unresolved: the cause-and-effect dilemma. To put it simply, which came first, schizophrenia or the neurotransmitter imbalance? This "chicken-and-egg" problem raises the possibility that schizophrenia might disrupt or alter brain chemistry, rather than being caused by it. Conversely, it is equally plausible that imbalances in neurotransmitter receptors, such as dopamine or glutamate, could trigger schizophrenia. Both propositions hold validity. Behaviour can also influence neurochemical changes, adding further complexity; for example, something as simple as smiling has been shown to affect serotonin production.
Beyond dopamine, other neural correlates have been identified in schizophrenia, including structural abnormalities. One key finding is that individuals with schizophrenia often have abnormally large ventricles, which are fluid-filled cavities in the brain. In a study, researchers compared 16 patients with "large" ventricles (more than one standard deviation above the control mean) to 16 patients with the smallest ventricles from a sample of 52 individuals with schizophrenia. They found that patients with enlarged ventricles were more likely to exhibit negative symptoms, such as alogia, affective flattening, avolition, and anhedonia. By contrast, patients with smaller ventricles tended to display positive symptoms, such as delusions, hallucinations, and bizarre behaviour. These findings suggest that combining structural imaging with symptom profiles could provide a more nuanced approach to classifying schizophrenia. However, it has been proposed that enlarged ventricles may not be a cause of the disorder but rather a result of prolonged use of antipsychotic medication, adding a layer of complexity to the interpretation of these findings
A03 FOR ALL BIOLOGICAL THEORIES - GENETIC AND NEURAL CORRELATES
DETERMINISM
All biological theories of schizophrenia are deterministic and suggest that you have no free will against developing or personally overcoming Schizophrenia. There are negative and positive aspects to this. On the plus side, parents will not be blamed for causing schizophrenia in their offspring, and individuals will not be perceived to be at fault either, as their illness is a result of their genes and/or neurotransmitters. There will, therefore, be less social stigma about being schizophrenic. However, other people may not want to procreate with schizophrenics because subsequent kids might inherit the gene.
On the negative side, excuses, excuses, excuses! Individuals and families may see it pointless to try to change their behaviour and rely on drugs to alleviate symptoms. Individuals may believe they are predestined to have Schizophrenia, which is very depressing.
PHYSIOLOGICAL REDUCTIONISM & NATURE V NURTURE
Biological explanations of schizophrenia are reductionist as they attempt to explain a complex, multi-faceted disorder at the level of genes and dopamine. Their rationale is that humans are biological organisms, and reducing even complex behaviours to neurophysiological components should be possible. As a result, biological theories disregard the importance of looking at a person holistically, e.g., how biology, parenting and stress, for example, might combine as risk factors in developing the disorder.
It is now known that biology is not the only case, as only 48% of MZ twins are concurrent for schizophrenia, so psychological processes must also contribute. For example, highly expressed emotion in families has been shown to cause relapse. This demonstrates that complex phenomena cannot easily be explained simply by reference to physiological imbalance. The influence of these brain chemicals is indisputable, but to argue that they only cause schizophrenia is to neglect all other potential influences during this disorder. It may well be that, for example, stress is the ultimate cause of the disorder, creating physiological imbalances – the proximate cause.
Indeed, DSM V now believes that Schizophrenia is an aetiologically heterogeneous disorder and has thus renamed it a “spectrum” disorder. In other words, schizophrenia is a disorder that has not only a multitude of different things that can cause it, but it is also a disorder with no defining features. The addition of the term “spectrum” and the less stringent guidelines show that the DSM 5 acknowledges that it sees schizophrenia as an umbrella term and recognises that any risk factor for developing Schizophrenia will combine biology and the environment. Therefore, its cause is no longer seen as a fight between nature and nurture.
The Diathesis-Stress Model (DSM) interprets schizophrenia as a result of brain impairment in areas responsible for language and cognition. It suggests that specific brain regions, particularly those with dopamine D2 receptors, like in Broca's area, maybe underactive or overactive. This could explain the linguistic differences in patients exhibiting positive versus negative symptoms. According to the DSM, the origins of such brain impairments in schizophrenia are multifaceted, involving a blend of genetic factors, exposure to pathogens or viruses, complications during birth, etc., all of which may interact with external stressors like abuse, bullying, or family discord.
This comprehensive perspective defines the diathesis-stress model (DS), offering a nuanced view that combines biological predispositions with environmental pressures.
