Targeting the dopamine D1 receptor in schizophrenia:: insights for cognitive dysfunction

Background and rationale: Reinstatement of the function of working memory, the cardinal cognitive process essential for human reasoning and judgment, is potentially the most intractable problem for the treatment of schizophrenia. Since deficits in working memory are associated with dopamine dysregulation and altered D-1 receptor signaling within prefrontal cortex, we present the case for targeting novel drug therapies towards enhancing prefrontal D-1 stimulation for the amelioration of the debilitating cognitive deficits in schizophrenia. Objectives: This review examines the role of dopamine in regulating cellular and circuit function within prefrontal cortex in order to understand the significance of the dopamine dysregulation found in schizophrenia and related non-human primate models. By revealing the associations among prefrontal neuronal function, dopamine and D-1 signaling, and cognition, we seek to pinpoint the mechanisms by which dopamine modulates working memory processes and how these mechanisms may be exploited to improve cognitive function. Results and conclusions: Dopamine deficiency within dorsolateral prefrontal cortex leads to abnormal recruitment of this region by cognitive tasks. Both preclinical and clinical studies have demonstrated a direct relationship between prefrontal dopamine function and the integrity of working memory, suggesting that insufficient D-1 receptor signaling in this region results in cognitive deficits. Moreover, working memory deficits can be ameliorated by treatments that augment D-1 receptor stimulation, indicating that this target presents a unique opportunity for the restoration of cognitive function in schizophrenia.