ReviewAn Integrative Perspective on the Role of Dopamine in Schizophrenia
Section snippets
Computational roles of dopamine
Striatal medium spiny neurons (MSNs) containing D1 receptors are part of the direct (Go) pathway, which facilitates (gates) the most appropriate actions; striatal MSNs containing D2 receptors are part of the indirect (NoGo) pathway, which suppresses inappropriate actions (27, 28, 29). Computationally, Go and NoGo pathways likely reflect the positive and negative values of actions, respectively, with actions being selected as a function of the difference between these two values (Box 1; Figure 2
Findings
Behaviorally and autonomically, schizophrenia patients, compared to controls, respond less to relevant cues (i.e., cues that predict reinforcement) and more to neutral cues, although they respond more to relevant than to neutral cues (51, 52, 53, 54). In a task in which one cue feature predicts reward and another does not, psychotic (or psychotic-like) symptoms correlate with an increased tendency to consider the irrelevant feature also predictive of reward in unmedicated participants at
Reinforcement learning in schizophrenia
Schizophrenia patients show preserved hedonic responses (60), which is not surprising from a dopaminergic perspective, as dopamine is not involved in hedonics (61).
Delusions and hallucinations: aberrant gating of thoughts and percepts
How can increases in striatal spontaneous dopamine transients or tonic dopamine cause psychosis? One hypothesis suggests that inappropriately timed dopaminergic signals assign aberrant incentive salience (61) to external and internal stimuli and events (14). The equivalent idea under our computational conceptualization is that spontaneous dopamine transients assign aberrant value to irrelevant stimuli, events, thoughts, percepts, and other external and internal experiences (Figure 4). Value and
Increased spontaneous dopamine transients versus increased tonic dopamine
Thus far in the article, increased spontaneous dopamine transients and increased tonic dopamine explained the same findings, making it difficult to adjudicate between them. Tonic dopamine and spontaneous transients may both be increased in schizophrenia; indeed, tonic and phasic dopamine may correlate positively because possibly only neurons that are firing tonically can be recruited to burst-fire (106). However, the hypothesis that schizophrenia involves increased spontaneous dopamine
Effects of Antipsychotics on Positive and Negative Symptoms
As discussed previously, schizophrenia involves impaired Go learning and blunted PE signaling, which may relate to negative symptoms, and antipsychotics may aggravate these reinforcement-learning deficits and some negative symptoms. Indeed, antipsychotics, administered chronically, reduce dopamine-neuron firing (112), so they may blunt adaptive dopamine transients, in addition to blunting their postsynaptic effects through D2 blockade. The consequent aggravation in reinforcement-learning
Relation to other deficits and neural systems
We have focused on the role of disturbances in striatal dopamine in schizophrenia. Others have explored computationally the role of other biological disturbances (126, 127, 128, 129, 130, 131, 132). Hierarchical predictive-coding models generalize some of the issues we addressed (Box 2).
The disturbances in striatal dopamine could originate in upstream brain regions or cognitive processes. For example, schizophrenia patients have deficits in pattern separation (133), possibly due to hippocampal
Conclusions
The hypothesis that schizophrenia involves increased spontaneous transients and reduced adaptive transients explains multiple findings (Figures 4 and 5) and makes novel predictions (Supplement). Increased spontaneous transients explain many findings that correlate with positive symptoms and may help explain positive symptoms themselves (Figure 4); reduced adaptive transients explain many findings that correlate with negative symptoms and may help explain primary negative symptoms themselves (
Acknowledgments and Disclosures
This work was supported by funding from the Tourette Syndrome Association (to TVM), from a Breakthrough Idea Grant from the Institute for Molecular Medicine, School of Medicine, University of Lisbon (to TVM), and from National Institute of Mental Health (NIMH) (Grant No. NIMH R01 MH080066-01 to MJF).
We thank the four anonymous reviewers for their thoughtful comments and suggestions.
TVM has no biomedical financial interests or potential conflicts of interest. MJF is a consultant for F.
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