NEURAL CORRELATES AND THE DOPAMINE HYPOTHESIS
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.
KEYWORDS
ANTAGONISTS/BLOCKERS: These drugs block the availability of a neurotransmitter in the brain. Antagonists used to block dopamine are known as antipsychotics and neuroleptics (phenothiazines such as chlorpromazine (Thorazine), Risperidone, and Clozapine are some examples).
ILLEGAL DRUGS THAT FUNCTION AS BLOCKERS (ANTAGONISTS):
PCP (Phencyclidine) – NMDA receptor antagonist
Ketamine – NMDA receptor antagonist
Scopolamine (Datura, Devil’s Breath) – Acetylcholine receptor antagonist
Diphenhydramine (DPH, Benadryl abuse) – Histamine (H1) and acetylcholine receptor antagonist
AGONISTS/STIMULANTS: These drugs enhance neurotransmitter activity in the brain, either by increasing neurotransmitter release, preventing its breakdown, or mimicking its effects at receptor sites. Many substances act as agonists for different neurotransmitter systems. There are many illegal agonists, e.g., street drugs: cocaine, crack, 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.
ANTIHISTAMINE: A drug that blocks histamine receptors to reduce allergic reactions. Some antihistamines, like promethazine, were later found to have sedative and tranquillising effects.
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.
CHLORPROMAZINE: A phenothiazine antipsychotic, developed initially as an antihistamine, that reduces psychotic symptoms by blocking dopamine D2 receptors in the brain
DOPAMINE: A neurotransmitter that controls movement, motivation, and reward. It is crucial in various brain functions, including attention, learning, and emotional regulation.
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.
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.
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.
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.
HYPER- AND HYPO-: UNDERSTANDING NEUROTRANSMITTER IMBALANCES
The prefixes hyper- and hypo- are often confused due to their similar sounds but have opposite meanings. Hyper- means excessive, overactive, or above normal, as seen in words like hyperbole (extreme exaggeration) and hyperactive (excessively active). In contrast, hypo- means low, underactive, or below normal, as in hypoglycemia (low blood sugar) and hyposensitivity (reduced sensitivity).
When referring to neurotransmitters, a hyperdopaminergic system occurs when too much dopamine is released into synapses, leading to overstimulation of neurons and exaggerated responses. This is seen in schizophrenia’s positive symptoms, such as hallucinations and delusions, where excessive dopamine activity in the mesolimbic pathway disrupts normal perception and thought processing.
Conversely, a hypodopaminergic system indicates insufficient dopamine activity, causing reduced neuronal stimulation. In schizophrenia, low dopamine levels in the mesocortical pathway contribute to negative symptoms, such as apathy, lack of motivation, and social withdrawal, due to the interactivity of dopamine-dependent cognitive and emotional functions.
Understanding the distinction between hyperdopaminergic and hypodopaminergic states helps explain why schizophrenia presents with both excessive and diminished mental activity, affecting different brain pathways in various ways.
NEURAL CORRELATES: Physical differences in the brain linked to specific disorder symptoms. In schizophrenia, changes in dopamine activity in particular brain areas are associated with symptoms like hallucinations, delusions, or lack of motivation.
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 enables the continuation of the nerve impulse to progress.
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.
PHENOTHIAZINE: A class of drugs derived from antihistamines used to treat schizophrenia by blocking dopamine receptors, with chlorpromazine being the first and most well-known.
PROMAZINE: A first-generation antipsychotic related to chlorpromazine, used for sedation and the treatment of agitation but less commonly prescribed for schizophrenia.
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.
THORAZINE: The brand name for chlorpromazine, the first antipsychotic drug, was introduced in 1952 to treat schizophrenia and severe psychiatric agitation.
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 specific 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 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. In contrast, 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 vital 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 linked to negative symptoms and cognitive impairment. While this is a well-documented neural correlate,
AQA focuses on dopamine hypotheses as the primary explanation in exams.
HISTORICAL TIMELINE OF SCHIZOPHRENIA'S CAUSES
1950–1952: Discovery of the first antipsychotic drug
Scientists developed chlorpromazine, the first drug found to reduce schizophrenia symptoms. It worked in a way they didn’t yet understand.
1958–1966: Early research into dopamine and antipsychotics
A new drug, haloperidol, was created, and researchers found that antipsychotics changed brain chemistry by affecting chemicals called neurotransmitters. They later discovered that these drugs specifically acted on dopamine receptors.1971–1975: Discovery of dopamine receptor subtypes
Scientists found that dopamine receptors were not all the same. Some, like D2 receptors, were directly involved in psychosis. This led to the idea that blocking D2 receptors could reduce schizophrenia symptoms.1979–1988: Refining the dopamine hypothesis
More dopamine receptors, such as D3, were discovered. Scientists also learned that not everyone with schizophrenia had the same dopamine receptor activity, which explained why people responded differently to treatment.1990s: A significant shift—dopamine isn’t the whole story
New studies showed that drugs like PCP and ketamine, which block a different brain chemical called glutamate, could cause symptoms similar to schizophrenia. This led researchers to suspect that glutamate might also play a role in the disorder.1999–2010: A more complex view of schizophrenia emerges
Scientists discovered that schizophrenia is not just caused by too much dopamine. They found that dopamine interacts with other brain chemicals, including glutamate and serotonin, and that some brain regions had too much dopamine while others had too little.2017–2021: Understanding schizophrenia at the molecular level
Advanced imaging allowed scientists to see the structure of dopamine receptors in detail, improving how drugs are designed. They also found that dopamine receptors can change shape and function, explaining why some medications work better for certain people.
HISTORY OF THE DOPAMINE HYPOTHESIS
ANTIHISTAMINES AND SURGICAL SHOCK (1940s)
In the 1940s, the French surgeon Henri Laborit researched ways to prevent surgical shock, a life-threatening drop in blood pressure that sometimes occurred during operations. He experimented with antihistamines, particularly promethazine, to stabilise patients.
An antihistamine is a drug that blocks the effects of histamine, a chemical involved in allergic reactions. However, some antihistamines also have sedative and tranquilising properties. Laborit found that patients given promethazine (a type of antihistamine) before surgery were not only physiologically more stable but also appeared less anxious and emotionally detached from their surroundings. Even patients who were not particularly fearful before surgery seemed emotionally blunted and unbothered.
PSYCHIATRIC TESTING OF CHLORPROMAZINE (1951-1952)
Laborit’s findings caught the attention of psychiatrists Jean Delay and Pierre Deniker, who speculated that a drug that induced emotional detachment might help patients with severe psychiatric agitation.
1951: Preliminary testing of chlorpromazine began on agitated psychiatric patients.
1952: Delay and Deniker expanded trials to schizophrenia patients at Sainte-Anne Hospital in Paris.
The results were unexpected and groundbreaking:
Unlike traditional sedatives, which only made patients drowsy, chlorpromazine alleviated psychotic symptoms.
The drug did not just sedate patients—it actively reduced delusions, hallucinations, and agitation.
Research soon showed that the phenothiazine nucleus of these drugs was responsible for their tranquilising and antipsychotic effect.
INTRODUCTION OF THORAZINE (1953)
Because of its unprecedented effectiveness in psychiatric trials, chlorpromazine (later marketed as Thorazine) was officially introduced as the first antipsychotic in 1952. Initially synthesised in 1950 by French chemist Paul Charpentier at Rhône-Poulenc, it was later recognised for its antipsychotic properties, distinguishing it from traditional sedatives. This discovery marked the beginning of modern pharmacological treatment for schizophrenia and established chlorpromazine as the first typical antipsychotic drug.
THE DOPAMINE HYPOTHESIS: LINKING CHLORPROMAZINE TO SCHIZOPHRENIA
HOW SCIENTISTS DISCOVERED DOPAMINE'S ROLE
When chlorpromazine (Thorazine) was first introduced in the early 1950s, scientists did not know how it alleviated psychotic symptoms. Researchers had no clear understanding of which brain chemicals were involved in schizophrenia nor how chlorpromazine exerted its effects. Early explanations were vague, with some theorising that it simply "calmed the nerves"—a phrase lacking scientific precision but implying a general sedative or tranquillising effect.
However, unlike traditional sedatives, which merely suppressed brain activity and caused drowsiness, chlorpromazine reduced hallucinations and delusions without making patients unconscious. This suggested that its effects were not just general sedation but rather a specific alteration of brain function. At the time, neuroscience was still in its infancy, and the idea that mental illness was linked to chemical imbalances had not yet been established.
The first neurotransmitter, acetylcholine, was discovered in 1921 by Otto Loewi, proving that neurons communicate using chemicals, not just electrical signals. Even so, it took decades before scientists identified other neurotransmitters. For example, dopamine was not recognised as a neurotransmitter until 1957, when Swedish scientist Arvid Carlsson discovered its role in voluntary movement. Before this, it was believed to be a precursor (a building block) for norepinephrine, with no independent function.
Since brain chemistry was still poorly understood, researchers did not suspect that chlorpromazine’s effects were related to dopamine. It was only in the 1960s and 1970s that scientists began to connect dopamine to schizophrenia, leading to the first version of the dopamine hypothesis.
HOW SCIENTISTS LINKED DOPAMINE TO SCHIZOPHRENIA
Once chlorpromazine was shown to reduce psychotic symptoms, researchers sought to understand how and why it worked. Since early explanations were vague, scientists needed to determine what specific changes the drug caused in the brain. This led to several key areas of research that ultimately connected dopamine dysfunction to schizophrenia.
Initially, researchers investigated how chlorpromazine affected brain chemistry. Some hypothesised that it worked by altering norepinephrine activity, as this neurotransmitter was already linked to alertness and stress. However, studies failed to show a clear link between norepinephrine and psychosis. It was not until scientists began investigating amphetamines that the role of dopamine became clearer.
In the late 1950s and early 1960s, researchers observed that high doses of amphetamines could induce paranoia, hallucinations, and delusions, symptoms strikingly similar to schizophrenia. These observations were first noted in recreational drug users and later confirmed through controlled studies in psychiatric research. Since amphetamines were known to increase dopamine release, this raised the possibility that excess dopamine activity might be involved in psychosis. Further studies showed that when schizophrenia patients were given amphetamines, their symptoms worsened, reinforcing this idea.
At the same time, scientists investigating other drugs similar to chlorpromazine, such as haloperidol (synthesised in 1958), found that all effective antipsychotic drugs shared a common property: they blocked dopamine receptors. If amphetamines, which increase dopamine, could induce psychotic symptoms, and antipsychotic drugs, which block dopamine, could reduce them, then dopamine appeared to play a central role in schizophrenia.
By the 1960s, researchers suspected that schizophrenia involved dopamine overactivity, but they could only infer this from drug studies. The dopamine hypothesis of schizophrenia was formally proposed by Jacques van Rossum in 1967, based on the idea that psychotic symptoms resulted from excessive dopamine activity in specific brain regions.
This breakthrough reshaped schizophrenia research and led to decades of studies exploring dopamine’s role in the disorder.
THE ORIGINAL DOPAMINE HYPOTHESIS
HOW DOPAMINE CAUSES SCHIZOPHRENIA
Dopamine is crucial in attention, motivation, and determining essential stimuli. It helps the brain decide what is relevant and what can be ignored, ensuring that a person stays focused on meaningful information rather than being overwhelmed by every minor detail in their environment. However, when too much dopamine floods certain brain areas, this ability to filter and prioritise information breaks down.
THE EFFECT OF EXCESS DOPAMINE ON THINKING
Schizophrenia is associated with disorganised thinking and an inability to stay focused on one idea. This can manifest in thought patterns such as:
Knight’s move thinking – jumping from one unrelated idea to another without logical connection.
Clang associations – choosing words based on their sounds rather than their meaning, leading to nonsensical speech.
This occurs because dopamine overstimulation makes irrelevant stimuli seem as crucial as relevant ones. Typically, the brain filters out unimportant information, allowing a person to focus on a conversation or a specific task. In schizophrenia, this filter breaks down, making random, meaningless stimuli feel significant.
HOW DOPAMINE LEADS TO DELUSIONS
When irrelevant information feels necessary, the brain tries to make sense of it. This is one of the reasons why schizophrenia is often accompanied by delusions of reference, where a person believes that unrelated events are personally significant.
For example, a person with schizophrenia might believe that a newsreader on television is sending them secret messages or that random strangers on the street are discussing them. This happens because excess dopamine makes neutral stimuli feel deeply meaningful.
This misattribution of significance can also lead to:
Paranoid behaviour – a belief that others are watching, judging, or planning against them.
Persecutory delusions – the conviction that one is being targeted, spied on, or conspired against.
Since dopamine heavily influences thought, emotion, and behaviour, an overactive dopamine system fuels these distorted perceptions, making delusions more intense and resistant to logic.
THE DOPAMINE HYPOTHESIS AND COGNITIVE INFLAMMATION
According to psychiatrist Shitij Kapur, dopamine is a biochemical fuel that amplifies specific ways of thinking. He argues that people who develop schizophrenia tend to jump to conclusions or interpret events in extreme ways. Excess dopamine inflames these cognitive patterns, pushing them into full psychosis.
Kapur explains:
“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.”
This suggests that dopamine dysregulation does not create new ways of thinking but amplifies already present tendencies, making them far more extreme and challenging to control.
SUMMARY
Dopamine controls attention and motivation, helping filter what is important and what is not.
Excess dopamine causes everything to seem meaningful, making it challenging to ignore irrelevant details.
This breakdown in filtering leads to psychotic symptoms, such as delusions of reference and paranoia.
Kapur argues that dopamine fuels pre-existing cognitive tendencies, making them more extreme rather than introducing new thought patterns.
ORIGINAL DOPAMINE HYPOTHESIS RESEARCH
If a dopamine imbalance causes schizophrenia, 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.
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.
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.
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.
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
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 the original dopamine hypothesis, 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.
THE LIMITATIONS OF THE ORIGINAL DOPAMINE HYPOTHESIS
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.
Over the years, researchers recognised that the original dopamine hypothesis, which explained positive symptoms (e.g., hallucinations, delusions) as a result of increased dopamine 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).
But why did it take so long for researchers to recognise negative symptoms as a core feature of schizophrenia? And why did they initially assume blocking dopamine would improve all symptoms?
WHY WERE NEGATIVE SYMPTOMS INITIALLY IGNORED
For much of the 20th century, schizophrenia was primarily understood in terms of its positive symptoms, as these were the most obvious and disruptive. Early psychiatrists did recognise that some patients exhibited a form of progressive mental decline, including apathy and withdrawal. In 1899, Emil Kraepelin compared these symptoms to dementia, describing how specific individuals with schizophrenia seemed to deteriorate over time. In 1911, Eugen Bleuler introduced the term schizophrenia and identified features such as affective flattening, poverty of speech, and anhedonia as core symptoms of the disorder.
Despite these early observations, negative symptoms were largely ignored. They were not as dramatic as hallucinations and delusions, making them harder to study. Clinicians often assumed they were simply a reaction to psychosis rather than a distinct issue, believing that symptoms such as withdrawal and reduced speech were a byproduct of delusions or hallucinations. The focus of treatment was primarily on psychotic agitation, as this was considered the most pressing issue in hospitalised patients. As a result, positive symptoms took priority in both research and treatment. It was not until the 1970s and 1980s that negative symptoms were recognised as a distinct feature of schizophrenia, requiring separate investigation.
When antipsychotics were introduced in the 1950s, researchers initially believed they would improve all symptoms of schizophrenia, including negative ones. However, even as positive symptoms responded to treatment, many patients remained withdrawn and unmotivated, suggesting that negative symptoms were not merely a consequence of psychosis but an independent aspect of the disorder.
THE REFORMULATED DOPAMINE HYPOTHESIS
Further research revealed that dopamine does not function the same way throughout the brain. Instead, it operates in distinct pathways, each responsible for different aspects of behaviour. The mesolimbic pathway, which regulates emotion and reward, was found to be overactive, leading to positive symptoms such as hallucinations and delusions. Meanwhile, the mesocortical pathway, which is responsible for motivation, cognition, and decision-making, was found to be underactive, contributing to negative symptoms such as apathy, social withdrawal, and lack of motivation. This helped explain why schizophrenia could present with both excessive mental activity (psychosis) and a complete lack of drive and emotional expression.
WHAT IS THE MESOLIMBIC SYSTEM?
The mesolimbic system is a subcortical dopamine pathway, meaning it is located beneath the cerebral cortex in deeper brain structures that control emotion, motivation, and reward processing. It connects two key brain areas:
The Ventral Tegmental Area (VTA) is where dopamine-producing neurons are located.
The Nucleus Accumbens receives dopamine signals and helps process reward, pleasure, and motivation.
When you experience something enjoyable, such as eating food or receiving praise, dopamine is released from the VTA and travels to the nucleus accumbens, reinforcing that behaviour. In schizophrenia, too much dopamine is released in this pathway, overstimulating the system and leading to positive symptoms.
HOW DOES DOPAMINE WORK? (D1 AND D2 RECEPTORS EXPLAINED)
Dopamine affects the brain by binding to dopamine receptors, which act like locks that dopamine "keys" can activate. These receptors come in two main types:
D1 receptors are excitatory, meaning they increase activity in neurons when stimulated. They are important for cognition, motivation, and decision-making, especially in the prefrontal cortex.
D2 receptors are inhibitory, meaning they reduce activity in neurons when dopamine binds to them. They play a key role in reward processing, motor control, and psychotic symptoms, particularly in subcortical regions like the mesolimbic system and the striatum.
WHY DOES TOO MUCH DOPAMINE IN THE MESOLIMBIC SYSTEM CAUSE POSITIVE SYMPTOMS?
D2 receptors in the mesolimbic system usually act as a brake, helping regulate emotional and sensory information. However, when dopamine levels are too high, these brakes become dysfunctional, leading to an overload of emotional and sensory information that the brain struggles to filter out. This overstimulation causes hallucinations, delusions, and thought disturbances.
The striatum, part of the basal ganglia (another subcortical structure), also plays a role in positive symptoms. The associative striatum, involved in learning and cognitive processing, has been found to have excess dopamine activity in schizophrenia. When D2 receptors in the striatum are overstimulated, they interfere with the brain’s ability to organise thoughts, contributing to disorganised speech and erratic thinking.
WHY DOES TOO LITTLE DOPAMINE IN THE MESOCORTICAL SYSTEM CAUSE NEGATIVE SYMPTOMS?
In contrast, the mesocortical pathway, which connects the VTA to the prefrontal cortex, is underactive in schizophrenia. The prefrontal cortex controls higher-order thinking, planning, motivation, and emotional control.
Dopamine in the prefrontal cortex primarily binds to D1 receptors, which are excitatory—meaning they increase neuronal activity and help maintain cognitive and motivational processes. When dopamine levels in this region are too low, D1 receptors receive insufficient stimulation, reducing neural activity and leading to:
Avolition (lack of motivation): Individuals struggle to initiate and sustain activities related to essential self-care.
Affective flattening: Emotional expression becomes diminished, leading to reduced facial expressions, a monotone voice, and social withdrawal.
Cognitive impairments: Attention, planning, and decision-making deficits make complex tasks challenging.
DIFFERENT TRAJECTORIES OF POSITIVE AND NEGATIVE SYMPTOMS
One key distinction between positive and negative symptoms is their progression over time. The difference in how these symptoms emerge and progress is due to how dopamine dysfunction unfolds in different brain pathways.
WHY POSITIVE SYMPTOMS ARE ACUTE AND EPISODIC
Positive symptoms suddenly fluctuate because they are linked to dopamine surges in the mesolimbic system. Dopamine release in this region is influenced by external and internal triggers, such as stress, drug use, and even normal brain activity fluctuations. These factors can cause dopamine spikes, leading to episodes of psychosis that seem to appear rapidly.
This explains why hallucinations and delusions can be episodic—they often emerge during acute psychotic episodes, sometimes triggered by environmental factors or stress. Positive symptoms usually show rapid improvement with treatment because the mesolimbic pathway can be temporarily stabilised with dopamine-blocking medication.
WHY NEGATIVE SYMPTOMS DEVELOP SLOWLY AND ARE CHRONIC
In contrast, negative symptoms progress slowly and persist over time because they are linked to a gradual loss of dopamine function in the mesocortical pathway. Unlike the mesolimbic system, which reacts dynamically to dopamine changes, the mesocortical system declines progressively, much like how neurodegenerative diseases affect brain function over time.
This slow decline in dopamine transmission to the prefrontal cortex means that motivational and cognitive impairments worsen gradually rather than appearing suddenly. Since dopamine surges or episodic spikes do not drive this process, negative symptoms tend to be persistent and resistant to change, making them more long-lasting and difficult to treat compared to positive symptoms.
SUMMARY
The original dopamine hypothesis only explained positive symptoms, assuming all schizophrenia symptoms resulted from too much dopamine.
Negative symptoms were initially ignored or assumed to be a reaction to psychosis, not a separate dysfunction.
Early researchers did not yet understand that dopamine affects different brain regions differently, leading to false assumptions about treatment.
By the 1970s, it became clear that positive symptoms were caused by too much dopamine, while negative symptoms were linked to too little dopamine.
The reformulated dopamine hypothesis recognised that schizophrenia involves both hyperdopaminergic and hypodopaminergic activity, leading to a broader understanding of the disorder.
This updated model paved the way for research into cognition, motivation, and other neurotransmitters, moving beyond dopamine alone as the cause of schizophrenia.
RESEARCH ANALYSIS OF THE REFORMULATED DOPAMINE HYPOTHESIS
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 excess 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 and anterior cingulate gyrus has been directly associated with auditory hallucinations. Patients experiencing these symptoms show lower activation in these brain areas than healthy individuals.
RESEARCH STUDIES
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. They 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 hyperdopaminergic and positive symptoms.
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.
RESEARCH STUDIES
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 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 hypodopaminergic in the prefrontal cortex contributes to working memory and decision-making impairments.
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.
THE REFORMULATED DOPAMINE HYPOTHESIS: WHAT IT DID NOT ADDRESS
The reformulated dopamine hypothesis was a significant improvement over the original theory. However, despite its advancements, this hypothesis still left key questions unanswered.
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:
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 likelier 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.
Prefrontal cortex abnormalities – This brain area 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.
NEGATIVE SYMPTOMS ARE STILL NOT FULLY ADDRESSED
NEGATIVE SYMPTOMS AND COGNITIVE DEFICITS
The reformulated hypothesis struggled to fully explain negative symptoms and cognitive deficits. 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.
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. This suggests that dopamine imbalances interact with other neurotransmitter systems over time and that schizophrenia cannot be fully explained by dopamine alone.
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.
Carlsson did not reject the dopamine hypothesis, but he argued that it did not fully explain schizophrenia. His main question was: What is causing dopamine imbalances in the first place? He suggested that glutamate, another neurotransmitter, might be the key to understanding schizophrenia.
DOPAMINE IMBALANCES MAY BE A SECONDARY EFFECT
The dopamine hypothesis explains which brain areas are affected but not why dopamine is abnormal in schizophrenia.
Carlsson suggested that glutamate regulates dopamine, meaning that problems with glutamate function could be the root cause of dopamine overactivity and underactivity.
GLUTAMATE CONTROLS DOPAMINE LEVELS
Glutamate helps keep dopamine balanced in the brain.
If glutamate levels are too low, dopamine becomes unstable, leading to too much dopamine in some areas (causing psychosis) and too little in others (causing negative symptoms).
WHY DOES CLOZAPINE WORK WHEN OTHER DRUGS DON’T?
Traditional antipsychotics block D2 receptors, which help with positive symptoms but do not treat negative symptoms. Clozapine, a drug that works on both dopamine and glutamate, is effective in people who don’t respond to D2 blockers. This suggests that glutamate, not just dopamine, plays a role in schizophrenia.
A03 FOR ALL NEUROTRANSMITTER THEORIES OF SCHIZOPHRENIA
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.
ISSUES AND DEBATES FOR 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.
ASSESSMENT
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GAME PIN: 08596640
https://kahoot.it/challenge/08596640
QUESTIONS
What is meant by the term "neural correlate" in the context of schizophrenia? (2 marks)
Read the item and then answer the question that follows.
Louise comes from a family with a history of schizophrenia, as both her grandfather and an aunt have been diagnosed with the disorder. Louise’s father has recently died from cancer, and she has just moved out of the family home to start a university course. Although she has always been healthy in the past, she has just begun to experience symptoms of schizophrenia, such as delusions and hallucinations.
Using your knowledge of schizophrenia, explain why Louise is now showing symptoms of schizophrenia. (4 marks)
What does hyperdopaminergic activity refer to in schizophrenia? (2 marks)
What does hypodopaminergic activity refer to in schizophrenia? (2 marks)
Which symptoms of schizophrenia are associated with excess dopamine in the mesolimbic system? (2 marks)
Which symptoms of schizophrenia are associated with reduced dopamine in the mesocortical system? (2 marks)
What is the primary function of the mesolimbic dopamine pathway in the brain? (3 marks)
What is the primary function of the mesocortical dopamine pathway in the brain? (3 marks)
Outline one psychological explanation of schizophrenia. (4 marks)
Explain the role of D1 and D2 dopamine receptors in schizophrenia. (4 marks)
Why was the original dopamine hypothesis considered an incomplete explanation of schizophrenia? (4 marks)
How did the reformulated dopamine hypothesis improve upon the original version? (4 marks)
Outline how brain imaging studies support the dopamine hypothesis of schizophrenia. (6 marks)
How do animal studies contribute to the understanding of dopamine’s role in schizophrenia, and what are their limitations? (6 marks)
Why are post-mortem studies problematic in researching the dopamine hypothesis? (6 marks)
Evaluate the use of drug studies in supporting the dopamine hypothesis. (8 marks)
To what extent do brain imaging studies support the dopamine hypothesis? (8 marks)
Critically evaluate the dopamine hypothesis in explaining schizophrenia. (8 marks)
Discuss how alternative neurotransmitter systems, such as glutamate, challenge the dopamine hypothesis. (10 marks)
Evaluate the strengths and weaknesses of the reformulated dopamine hypothesis. (10 marks)
Discuss the role of dopamine in schizophrenia, referring to both positive and negative symptoms. (12 marks: AO1 – 6, AO3 – 6)
"The dopamine hypothesis alone cannot fully explain schizophrenia." Discuss this statement concerning research evidence. (16 marks: AO1 – 6, AO3 – 10)
Discuss one or more biological explanations for schizophrenia.(Total 16 marks)
Jay has schizophrenia. His speech is rapid and confusing, constantly changing from one idea to something completely different. Jay’s father was treated for mental health problems when he was younger. Jay’s mother worries excessively about Jay. She often criticises his behaviour and tells him what to do. Jay’s doctor prescribes medication, which seems to reduce his symptoms.
Discuss one or more explanations for schizophrenia. Refer to Jay in your answer. (16 marks: AO1 – 6, A02 - 4, AO3 – 6)
WRITING ESSAYSWORD COUNT GUIDELINES FOR AQA A-LEVEL PSYCHOLOGY RESPONSES
6-mark A01 response: ~225 words approx.
3-mark A01 response: ~112 words approx.
SIX-MARK A01 RESPONSE (APPROX. 225 WORDS)
The dopamine hypothesis is a neural correlate of schizophrenia, as it identifies dopamine imbalances in specific brain regions as a cause of symptoms. The original dopamine hypothesis suggested that positive symptoms, such as hallucinations and delusions, result from excess dopamine (hyperdopaminergic activity) in the mesolimbic pathway. This pathway connects the ventral tegmental area (VTA) to the nucleus accumbens, a structure involved in reward and motivation. Overactivation of D2 receptors in this system disrupts standard information processing, leading to distorted perception and thought.
However, this model did not explain negative symptoms, such as apathy and cognitive dysfunction, leading to the reformulated dopamine hypothesis. This version proposes that negative symptoms arise due to too little dopamine (hypodopaminergic activity) in the mesocortical pathway. This connects the VTA to the prefrontal cortex, a region responsible for higher-order thinking, planning, and motivation. D1 receptors in the prefrontal cortex are excitatory, meaning they enhance brain activity, but dopamine underactivity in this pathway reduces prefrontal function, leading to persistent negative symptoms.
Since distinct patterns of dopamine dysfunction correspond to different symptom types, the dopamine hypothesis provides a biological explanation for schizophrenia. It is considered a neural correlate because it links specific brain abnormalities to the development of symptoms, helping to explain why schizophrenia presents with both excessive and diminished mental activity.
THREE-MARK A01 RESPONSE (APPROX. 112 WORDS)
The dopamine hypothesis is a neural correlate of schizophrenia, as it links dopamine dysfunction in specific brain pathways to distinct symptoms. The original dopamine hypothesis suggested that positive symptoms, such as hallucinations and delusions, result from too much dopamine (hyperdopaminergic activity) in the mesolimbic pathway. This system connects the ventral tegmental area (VTA) to the nucleus accumbens, which processes reward and emotion. Overactivation of D2 receptors in this system disrupts thought processing, leading to perceptual distortions.
The reformulated dopamine hypothesis explains negative symptoms, such as apathy, by suggesting that they result from too little dopamine (hypodopaminergic activity) in the mesocortical pathway. This pathway links the VTA to the prefrontal cortex, which controls motivation and cognitive function. D1 receptors in this region require sufficient dopamine, and when levels are too low, negative symptoms such as reduced motivation and cognitive impairment emerge.
WRITING A03
RESEARCH ANALYSIS: LEGAL DOPAMINE ANTAGONISTS (ANTIPSYCHOTIC MEDICATIONS)
Strengths:
The most substantial empirical support for the dopamine hypothesis comes from the success of typical antipsychotic drugs (e.g., chlorpromazine) in reducing positive symptoms of schizophrenia. These drugs block dopamine D2 receptors, reducing dopamine transmission in the mesolimbic pathway.
Atypical antipsychotics (e.g., clozapine, risperidone) are also effective, and while they target dopamine, they additionally affect serotonin (5-HT2A receptors), which helps alleviate negative symptoms such as avolition and affective flattening.
The effectiveness of these medications directly supports the idea that excess dopamine contributes to psychotic symptoms, as reducing dopamine levels alleviates hallucinations and delusions.
Weaknesses:
While typical antipsychotics support the dopamine hypothesis by reducing positive symptoms, they fail to address negative symptoms like social withdrawal and cognitive dysfunction. This suggests dopamine alone cannot fully explain schizophrenia.
Some patients with schizophrenia do not respond to dopamine antagonists, implying other neurotransmitter systems (e.g., glutamate, serotonin) contribute to the disorder.
Dopamine dysfunction does not account for all neural correlates of schizophrenia. Brain imaging studies suggest structural abnormalities (e.g., enlarged ventricles, prefrontal cortex dysfunction) are also involved, indicating that schizophrenia is not just a chemical imbalance but a disorder with broader neurobiological underpinnings.
Conclusion:
The efficacy of dopamine-blocking drugs in treating positive symptoms supports the dopamine hypothesis. Still, their limited effect on negative symptoms and individual differences in response suggest additional factors contribute to schizophrenia.
The fact that atypical antipsychotics also target serotonin and show greater effectiveness in treating negative symptoms highlights the need for a broader neurotransmitter model beyond dopamine alone.
RESEARCH ANALYSIS: ANIMAL STUDIES (RATS)
Strengths: Rats share a similar mesolimbic dopamine system with humans, making them valuable for studying the effects of dopamine agonists and antagonists.
Weaknesses: Rats lack human-specific cognitive functions, particularly language, central to schizophrenia. The inability to directly assess hallucinations or delusions in rats raises validity concerns. Furthermore, schizophrenia may be uniquely human, limiting generalisability.
Conclusion: While rat studies provide insight into dopamine pathways, their inability to replicate the full human experience of schizophrenia weakens their applicability.
RESEARCH ANALYSIS: ANTIPSYCHOTICS & PARKINSON'S DISEASE
Strengths: The link between Parkinson’s disease and schizophrenia provides compelling evidence for dopamine’s role. L-Dopa (a dopamine agonist) can induce psychotic symptoms in Parkinson’s patients, mirroring schizophrenia. Conversely, dopamine antagonists used in schizophrenia treatment can cause Parkinsonian symptoms.
Weaknesses: The exact mechanisms of schizophrenia differ from drug-induced psychosis. Parkinson’s patients do not develop all schizophrenia symptoms, suggesting additional neurochemical or structural abnormalities.
Conclusion: The Parkinson’s-schizophrenia link supports the dopamine hypothesis but does not account for all symptoms or underlying causes.
RESEARCH ANALYSIS: ILLEGAL DRUGS
Strengths: Drug-induced psychosis mimics schizophrenia symptoms, supporting the role of dopamine excess in positive symptoms. Studies from the 1970s induced amphetamine psychosis to examine schizophrenia-like behaviours, reinforcing the dopamine hypothesis.
Weaknesses: Drug-induced psychosis is now considered qualitatively different from schizophrenia, with additional symptoms like euphoria and hyperactivity resembling mania rather than schizophrenia.
Conclusion: While illicit drug studies reinforce dopamine’s role in psychosis, they cannot fully explain schizophrenia’s complexity.
POST-MORTEM STUDIES
Strengths: Early post-mortem studies found increased dopamine receptor density, suggesting a biological basis for schizophrenia.
Weaknesses: Post-mortem brains often belonged to medicated individuals, meaning receptor density changes could result from long-term drug use rather than schizophrenia itself. These studies also lack real-time dopamine activity data.
Conclusion: While post-mortem studies provided early evidence for the dopamine hypothesis, their methodological limitations make modern imaging techniques more reliable.
BRAIN IMAGING: POSITIVE SYMPTOMS
Strengths: PET and fMRI studies have confirmed hyperdopaminergic activity in schizophrenia. Increased dopamine receptor density in the striatum correlates with psychotic symptoms.
Key Studies:
Lindström et al. (1999): Increased dopamine synthesis in the striatum of schizophrenic patients.
Howes et al. (2012): Elevated dopamine synthesis in individuals at high risk of schizophrenia, supporting dopamine's causal role.
Laruelle et al. (1996): Amphetamine challenge studies show greater dopamine release in schizophrenics than controls.
Weaknesses: Correlational nature—dopamine imbalances may be a consequence, not a cause, of schizophrenia.
Conclusion: Strong evidence links dopamine excess in the mesolimbic pathway to positive symptoms, but causation remains uncertain.
BRAIN IMAGING: NEGATIVE SYMPTOMS
Strengths: Negative symptoms correlate with dopamine hypoactivity in cortical areas, particularly:
Ventral striatum: Reduced activation linked to avolition.
Prefrontal cortex: Lower dopamine D1 receptor function associated with cognitive deficits.
Weaknesses: Imaging studies cannot establish causation—dopamine dysfunction could be a result rather than a cause.
Conclusion: Dopamine hypoactivity in cortical areas likely underlies negative symptoms, supporting a more nuanced dopamine hypothesis.
BEYOND DOPAMINE: GLUTAMATE & OTHER NEUROTRANSMITTERS
Glutamate's Role: Carlsson suggested dopamine imbalances may result from glutamate dysfunction. Glutamate regulates dopamine, and its disruption can cause both hyperdopaminergic (positive symptoms) and hypodopaminergic (negative symptoms) states.
Supporting Evidence: Clozapine, an effective antipsychotic for treatment-resistant schizophrenia, affects both dopamine and glutamate, suggesting multiple neurotransmitter involvement.
Conclusion: The dopamine hypothesis alone is insufficient—glutamate and serotonin likely play crucial roles in schizophrenia.
DOPAMINE AND OTHER PSYCHIATRIC DISORDERS
Dopamine imbalances are not unique to schizophrenia and are implicated in other psychiatric conditions, reinforcing the idea that dopamine dysfunction alone is insufficient to explain schizophrenia.
Bipolar Disorder (Mania): Elevated dopamine activity is associated with manic episodes, supporting the idea that dopamine dysregulation can lead to psychotic symptoms beyond schizophrenia.
Acute and Transient Psychotic Disorder: This disorder presents with brief episodes of psychosis linked to dopamine fluctuations, but unlike schizophrenia, it lacks persistent cognitive and negative symptoms.
Schizoaffective Disorder: This disorder has both schizophrenic and mood disorder symptoms, indicating dopamine dysfunction interacts with serotonin and glutamate imbalances.
Parkinson’s Disease and Dopamine Agonists: Parkinson’s is caused by dopamine deficiency in the substantia nigra. When treated with dopamine agonists (e.g., L-Dopa), some patients develop hallucinations and delusions, supporting the link between dopamine excess and psychotic symptoms.
CONCLUSION:
Dopamine imbalances contribute to multiple psychiatric conditions, demonstrating that dopamine dysfunction is not specific to schizophrenia.
The fact that schizophrenia shares dopamine abnormalities with other disorders suggests additional neural mechanisms must be involved, such as glutamate dysfunction, structural abnormalities, and prefrontal cortex deficits.
The dopamine hypothesis remains central to understanding schizophrenia but must be considered alongside other neural correlates and neurotransmitter theories.
ISSUES & DEBATES:
DETERMINISM
Positive: Removes blame from individuals and families.
Negative: This could lead to fatalism, discouraging behavioural interventions.
Conclusion: While a deterministic view has benefits, it risks reinforcing helplessness.
REDUCTIONISM
Positive: Identifying biological mechanisms allows for targeted treatments.
Negative: Oversimplifies schizophrenia by ignoring environmental and psychological factors (e.g., stress, trauma).
Conclusion: Integrating biological and environmental factors, a diathesis-stress model offers a more comprehensive explanation.
FINAL EVALUATION
Strengths of the Dopamine Hypothesis:
Supported by drug studies, imaging, and antipsychotic efficacy.
Explains positive and negative symptoms through differential dopamine activity.
Weaknesses:
Causality issue—dopamine imbalances may be a consequence rather than a cause.
It cannot fully explain schizophrenia’s complexity—other neurotransmitters are involved.
Structural abnormalities (e.g., enlarged ventricles) suggest a broader neuropathological basis.
Conclusion: The dopamine hypothesis remains a cornerstone of schizophrenia research but must be integrated with newer models considering glutamate, serotonin, and structural abnormalities.