Abstract
Schizophrenia is characterized by positive, negative and cognitive symptoms. All current antipsychotic treatments feature dopamine-receptor antagonism that is relatively effective at addressing the psychotic (positive) symptoms of schizophrenia. However, there is no clear evidence that these medications improve the negative or cognitive symptoms, which are the greatest predictors of functional outcomes. One of the most robust pathophysiological observations in patients with schizophrenia is increased subcortical dopamine neurotransmission, primarily in the associative striatum. This brain area has an important role in a range of cognitive processes. Dopamine is also known to play a major part in regulating a number of cognitive functions impaired in schizophrenia but much of this research has been focused on cortical dopamine. Emerging research highlights the strong influence subcortical dopamine has on a range of cognitive domains, including attention, reward learning, goal-directed action and decision-making. Nonetheless, the precise role of the associative striatum in the cognitive impairments observed in schizophrenia remains poorly understood, presenting an opportunity to revisit its contribution to schizophrenia. Without a better understanding of the mechanisms underlying cognitive dysfunction, treatment development remains at a standstill. For this reason, improved preclinical animal models are needed if we are to understand the complex relationship between subcortical dopamine and cognition. A range of new techniques are facillitating the discrete manipulation of dopaminergic neurotransmission and measurements of cognitive performance, which can be investigated using a variety of sensitive translatable tasks. This has the potential to aid the successful incorporation of recent clinical research to address the lack of treatment strategies for cognitive symptoms in schizophrenia. This review will give an overview on the current state of research focused on subcortical dopamine and cognition in the context of schizophrenia research. We also discuss future strategies and approaches aimed at improving the translational outcomes for the treatment of cognitive deficits in schizophrenia.
Highlights
The dopaminergic system is thought to be involved in both the etiology of schizophrenia and the regulation of a number of cognitive domains
If we choose to examine cognitive processes that are selective for the associative striatum, such as goal-directed action and serial reversal learning, we will be able to understand the cognitive effects of subcortical dopamine alterations in schizophrenia, we will be able to examine the effects on other components of cortico-striato-thalamic circuit loops
We suggest that in schizophrenia, impairments in goal-directed behavior and serial reversal learning may be due to perturbations in multiple components of the cortico-striatal-thalamic circuit loop
Summary
The dopaminergic system is thought to be involved in both the etiology of schizophrenia and the regulation of a number of cognitive domains. A number of studies attempted to delineate the effects of both types of antipsychotics, with most suggesting second-generation antipsychotic administration had a more marked improvement in cognitive functioning (Lee et al, 1994; Meltzer and McGurk, 1999; Meltzer and Sumiyoshi, 2003; Sumiyoshi et al, 2013). The associative striatum is heavily involved in a range of cognitive and decision-making processes and is anatomically defined as being part of the medial caudate and ventral putamen (Kesby et al, 2018) This suggests that understanding the role of subcortical dopamine in the cognitive deficits observed in schizophrenia may provide a better understanding of cognition in general, and identify novel approaches to treating these complex symptoms. With advances in genetic tools for use in animal models, manipulations of the neural circuitry and measurement of the consequent effects on cognition will provide an avenue to improve translational outcomes
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