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The Dopamine Hypothesis
Dopamine Hypothesis Of SZP
Since the discovery of chlorpromazine in 1952 to treat schizophrenia, the overwhelming
majority of studies have been focused on dopamine dysfunction as an explanation for
psychosis
...
However, with increased research,
recognition has increased that the aetiology of schizophrenia extends beyond this hypothesis
...

This assumption was supported by evidence such as: (5)
-Clinical effectiveness of AP drugs being directly related to their affinity for dopamine
receptors
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-Drugs that deplete DA levels (such as reserpine) showing a reduction in psychotic
symptoms
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, 2014)
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- In animal studies, hyperactivity of subcortical DA neurons was found to be related to
hypoactivity of frontal cortical DA neurons
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Led to……
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It was reformulated to propose that hypodopaminergia in PFC causes negative
symptoms, and hyperdopaminergia in sub-cortical regions causes positive symptoms (Davis
et al
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The revision was prompted by an advancement of the available post-mortem
and metabolite findings, as well as new insights from animal studies
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- the mechanism by which clozapine acts (i
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that it has low affinity for and occupancy at
D2Rs) indicated that hyperdopaminergia may not be the full story
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-PET studies showed reduced cerebral blood flow in the frontal cortex (called
hypofrontality)
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However, this theory (3)
-relies on the inferences from animal studies
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-there is no direct evidence for low DA levels in PFC (was only hypothesised based on
similarities between behaviour of animals and humans with frontal lobe lesions and negative
symptoms), and limited evidence for elevated dopamine in the striatum

-does not take into account the environmental and neurodevelopmental factors that are
thought to influence SZP development
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(3) Howes and Kapur (2009) put forward the hypothesis that striatal dopaminergic
dysfunction was the final common pathway leading to psychosis in schizophrenia
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‘Multiple hits’ A genetic predisposition (i) interacting with an environmental development
insult (ii) that occurs at the “right” stage (iii), all needed for developing schizophrenia
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2
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Dopamine dysregulation is linked to psychosis rather than SZP
4
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This ultimately leads to irrelevant stimuli becoming more
prominent which provides a basis for psychotic phenomena such as ideas of reference,
leading to paranoid behaviour and persecutory delusions
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They may paradoxically worsen the
primary abnormality by blocking presynaptic D2 receptors, resulting in a compensatory
increase in dopamine synthesis
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Evidence:
Since version II, there have been over 6700 articles about dopamine and schizophrenia
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-PET and SPECT to measure striatal synaptic DA transmission
(2) Genetic evidence
-4 of the top 10 gene variants most associated with SZP are directly involved in dopaminergic
pathways
(3)
a) Findings on environmental risk factors
-psychoactive substances
b) interaction between environmental/genetic factors
-social isolation rearing potentials effects of stimulants and stress on the DA system
-family history of psychosis (Vans Os et al
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-Reward learning task compared a group of patients with active psychotic symptoms with a
group of controls and the mesolimbic responses were captured using fMRI
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show reduced activation in the mesolimbic

pathway upon presentation of reward-predicting stimuli, and exaggerated neuronal
responses to “neutral” stimuli, compared to control subjects
Patients were less able to discriminate between salient and neutral stimuli
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, 2008)
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In order for the
hypothesis to be rigorously tested, however:
-the evidence gathered in animal models must be translated in humans
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g
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-Finally, longitudinal studies investigating patients at multiple stages of the disease
process, from the prodrome to established psychosis and relapse, will test whether
aberrant salience attribution is causally implicated in psychosis
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- dopaminergic dysfunction accounts poorly for symptom classes in schizophrenia other than
positive symptoms
-atypicals with weaker antidopaminergic activity such as clozapine have better efficacy
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In turn, the
arising dopaminergic dysregulation might further disrupt glutamatergic signalling at NMDA
receptors
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In fact, lower glutamate levels in hippocampal areas of individuals in the
prodromal states of schizophrenia, but not in healthy controls, have been found to be linked
to increased dopaminergic neurotransmission (Coyle et al
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Limitations
1) Metabotropic GluRs 2+3 inhibit OR stimulate DA release
2) The psychotogenic effects of ketamine in humans could be attributed to an increase in DA
release (Can et al 2016)
Conclusion
If DA abnormalities were the only cause or aetiology for schizophrenia then currently
available antipsychotic agents should be remarkably more effective than they currently are

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