Summarize the findings simply: Dopamine occupies a central role in the pathophysiology of
schizophrenia [144–146]. In preclinical models, increased dopamine signalling is associated with schizophrenia-like behaviours
[147]. In patients, post-mortem studies show dopamine receptor
upregulation [148], and the potency of antipsychotic medications
is tightly linked to their affinity for the D2 receptor [4, 149].
Neuroimaging studies indicate that schizophrenia is associated
with presynaptic hyperdopaminergia in the dorsal striatum [150],
and experimental stimulation of striatal dopaminergic transmission (e.g., following administration of amphetamine) can induce
and exacerbate psychosis [151, 152].
Although dopamine dysfunction has mainly been linked to
positive psychotic symptoms, striatal dopamine signalling normally has widespread effects on cortical function [153–156], and
its dysregulation can also cause cognitive symptoms [157].
Measures of striatal dopamine signalling appear to index ‘state’
aspects of psychosis, increasing during acute psychosis and
demonstrating an association with the severity of positive
psychotic symptoms, positioning striatal dopamine as ‘the wind
of the psychotic fire’ [158–160]. Cognitive symptoms, however,
follow a much more constant trajectory than positive symptoms,
and as such, it is less likely that they are directly tied to
neurochemical measures that fluctuate over the illness course
[161, 162].
In vivo measurement of cortical dopamine signalling is
challenging given the relative sparsity of the receptors. However,
data from recent studies are consistent with the hypothesis that
schizophrenia is associated with a hypodopaminergic state in the
cortex [163–165]. Moreover, cortical hypodopaminergia may be
linked to striatal hyperdopaminergia in schizophrenia: preclinical
work has demonstrated that depletion of cortical dopamine
increases striatal dopamine levels [166, 167], and there is
preliminary in vivo evidence that the same relationship applies
in people with schizophrenia [165]. The lack of effect of dopamine
antagonists on cognitive symptoms may reflect the fact that
correcting the dysregulated striatal signalling in schizophrenia
requires not only the blocking of aberrant signals, but also the
restoration of the signal-to-noise ratio of adaptive signals [168].
Cortical dopamine signalling plays a role in normal attention,
working memory, and executive function, so impaired dopamine
function in schizophrenia may therefore affect these processes
[169–171]. Dopamine promotes the persistent cortical activity
required for the maintenance of working memory, while inhibiting
unrelated signalling so that relevant information is precisely
represented [172]. Studies in people with Parkinson’s disease, and
in non-human primates with experimental lesions of prefrontal
dopamine function indicate that impaired dopamine signalling
leads to working memory and executive functioning deficits
[173, 174]. Conversely, The effectiveness of pro-dopaminergic
compounds in the treatment of ADHD suggests that augmentation of cortical dopamine signalling has the potential to exert
cognitive benefits [175]. Recently the dopaminergic partial agonist
cariprazine has demonstrated some advantages on cognitive
subscales of the PANSS when compared to antagonists, but more
in-depth testing of its cognitive effects is required [176].
However, despite some promising signals in experimental
medicine studies [177], pro-dopaminergic treatments have not
been approved as treatments for the cognitive deficits of schizophrenia. This may reflect the complexity of the system
involved. The effects of dopamine in the cortex are distinct to
those in the striatum, and only a fraction of cortical pyramidal
neurons express dopamine receptors, with cortical interneurons
showing proportionally greater expression [178]. For both
pyramidal cells and interneurons, dopamine’s presynaptic effects
predominantly reduce neurotransmitter release. Postsynaptically,
dopamine enhances the excitability of deep-layer pyramidal
neurons, and increases the frequency of interneuron spiking.
The net effect of these various mechanisms is that cortical
dopamine depresses pyramidal cell firing via its action on
interneurons. A link with E/I balance is therefore apparent, in that
reduced cortical dopamine signalling is associated with a reduced
net inhibitory input, termed disinhibition.\