Trends in Neurosciences
ReviewDopaminergic basis of salience dysregulation in psychosis
Section snippets
Dopamine and schizophrenia
Dopaminergic systems have been implicated in the pathophysiology of schizophrenia and psychosis for more than 40 years, following seminal early work showing that reserpine depleted dopamine stores [1] and that neuroleptics are dopamine receptor antagonists [2]. Box 1 summarises the early lines of evidence linking dopaminergic alterations to schizophrenia. Subsequent studies (reviewed below) have refined this understanding, and led to the hypothesis that the dopamine system is altered in
What is salience? Vision, attention, and goal-directed behaviour
The broad challenge for any organism negotiating a sensorially complex world is how to efficiently and effectively choose and respond to relevant stimuli, whether predator, prey, or potential mate. The human world is particularly complex and the demands of seemingly limitless and changing perceptual inputs compete for limited cognitive and, particularly, limited motor resources. This allocation involves the processes of attention [3], filtering, sensory and behavioural orientation, motivation,
What does dopamine do? Reward prediction, prediction error, and learning
A key influence on goal-directed behaviour is the pursuit of reward and the avoidance of punishment. Reward here refers to the positive value given to an object, a behavioural act, or an internal state [10] (Table 1). The role of dopamine has received particular attention in this context: many drugs of addiction work by increasing or prolonging the action of dopamine in its main projection targets [11], and animals with electrodes implanted in dopamine-related areas will repeatedly choose to
Non-reward aspects of dopamine and salience: novelty, aversion, and emotion
It has been suggested that dopamine-driven prediction error signalling may not be selective for rewards, but instead may reflect general salience 21, 22, 23. In support of this suggestion, animal studies demonstrate that novel lights and tones (which do not appear to be overtly rewarding) often excite dopamine neurons 24, 25 and faster (50–100 ms) than would allow accurate reward prediction calculations [22]. Like reward, novel stimuli have a high propensity for behavioural interrupt and also
The experience of aberrant salience in early psychosis
Clinicians have long noted that, prior to the onset of frank psychosis, there is typically a prodromal period, often lasting months or longer, during which the patient often has the sense that something odd but important or threatening is going on around them that they cannot quite explain. This has been referred to as ‘delusional mood’, which was well known to early phenomenologists of psychosis. Conrad termed this period ‘trema’ (stage fright) [59], whereas Jaspers described that a ‘general
Animal models of schizophrenia and the link to salience dysregulation
Electrophysiological studies in animal models of schizophrenia suggest that dopamine neuron activity may be altered in a way that is likely to strongly affect the salience prediction error signal and may therefore contribute to salience dysregulation. For example, in a rat developmental model of schizophrenia, administration of the mitotoxin methylazoxymethanol acetate (MAM) to pregnant rats, leads to increased numbers of spontaneously active dopamine neurons in their offspring [49]. It is
Neurochemical imaging studies of dopaminergic neurotransmission in psychosis
Molecular imaging with positron emission tomography (PET) or single-photon computed tomography has enabled dopaminergic neurotransmission to be studied in vivo in humans. There have now been over fifty studies using these techniques to probe presynaptic and postsynaptic aspects of striatal dopamine neurotransmission in patients with psychotic disorders [57]. The first step in neurotransmission is the synthesis of dopamine ready for release from nerve terminals. Dopamine synthesis capacity can
fMRI studies of salience in psychosis
fMRI studies allow the direct measurement of functional activation during salience processing in psychosis. fMRI has a temporal resolution of about 10 s and thus cannot be used to directly measure abnormalities relating to the phasic increase in dopamine firing, which ranges in the milliseconds scale [23]. However, it can address changes in neuronal network activation, which may result from a brief dopaminergic input. Early studies tested the hypothesis that the increase in dopaminergic
Can antipsychotics modulate reward learning?
All currently licensed antipsychotic drugs bind to D2/3 receptors to some degree [108]. Furthermore, the level of antipsychotic D2/3 occupancy in the striatum is related to therapeutic response 109, 110, and although some antipsychotic drugs also bind to other receptors, they are no more effective than highly selective D2/3 receptor antagonists 108, 111. Taken together, this is strong evidence that blocking dopaminergic neurotransmission is central to the therapeutic response. Given this and
Specificity of salience dysregulation to schizophrenia or psychosis
Although psychosis is a cardinal feature of schizophrenia, it is also seen in a number of other psychiatric conditions, particularly bipolar affective disorders and severe depression. Psychosis is also seen in epilepsy, particularly temporal lobe epilepsy, and of course is associated with the use and abuse of drugs that alter dopamine neurotransmission, such as amphetamine and L-DOPA. Elevated dopamine synthesis capacity has been detected in patients with temporal lobe epilepsy who experienced
Concluding remarks
A substantial body of evidence indicates that there are dopaminergic abnormalities in psychosis and links these to the onset of the disorder. Preclinical studies in non-human primates and rodents have indicated that dopamine neurons signal unexpected stimuli, coding their salience, and respond to aversive and novel stimuli as well as rewarding stimuli. This involves midbrain dopamine neurons and their projections to the ventral and dorsal striatum and temporal and frontal cortical regions.
Acknowledgements
T.W.B. was supported by the Wellcome Trust and the National Institute of Health Research. P.F.P. was supported by King's College London and the South London and Maudsley (SLaM) National Health Service (NHS) Foundation Trust. M.A.U. was supported by the UK Medical Research Council (U120085816) and a University Research Fellowship from the Royal Society. O.D.H. was supported by the UK Medical Research Council (MC-A656-5QD30) and the National Institute of Health Research Biomedical Research
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These authors contributed equally to this work.