Elsevier

Biological Psychiatry

Volume 81, Issue 1, 1 January 2017, Pages 52-66
Biological Psychiatry

Review
An Integrative Perspective on the Role of Dopamine in Schizophrenia

https://doi.org/10.1016/j.biopsych.2016.05.021Get rights and content

Abstract

We propose that schizophrenia involves a combination of decreased phasic dopamine responses for relevant stimuli and increased spontaneous phasic dopamine release. Using insights from computational reinforcement-learning models and basic-science studies of the dopamine system, we show that each of these two disturbances contributes to a specific symptom domain and explains a large set of experimental findings associated with that domain. Reduced phasic responses for relevant stimuli help to explain negative symptoms and provide a unified explanation for the following experimental findings in schizophrenia, most of which have been shown to correlate with negative symptoms: reduced learning from rewards; blunted activation of the ventral striatum, midbrain, and other limbic regions for rewards and positive prediction errors; blunted activation of the ventral striatum during reward anticipation; blunted autonomic responding for relevant stimuli; blunted neural activation for aversive outcomes and aversive prediction errors; reduced willingness to expend effort for rewards; and psychomotor slowing. Increased spontaneous phasic dopamine release helps to explain positive symptoms and provides a unified explanation for the following experimental findings in schizophrenia, most of which have been shown to correlate with positive symptoms: aberrant learning for neutral cues (assessed with behavioral and autonomic responses), and aberrant, increased activation of the ventral striatum, midbrain, and other limbic regions for neutral cues, neutral outcomes, and neutral prediction errors. Taken together, then, these two disturbances explain many findings in schizophrenia. We review evidence supporting their co-occurrence and consider their differential implications for the treatment of positive and negative symptoms.

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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