Dopamine Receptor Supersensitivity and Schizophrenia

Abstract

Despite decades of clinical and preclinical research, the etiopathology of schizophrenia remains unknown. One of the most long-standing theories suggests dysregulation of the dopamine system is responsible for the development and progression of the disorder. Findings from postmortem brains of schizophrenia patients and preclinical animal studies have found dopamine receptor supersensitivity, particularly of the dopamine D2 (DAD2) receptor subtype, to be a consistent biomarker, lending strength to the dopamine hypothesis. DAD2 supersensitivity results in an enhanced response to both endogenous and exogenous dopamine, behaviorally manifesting in symptoms of psychoses and increased locomotor activity in response to drugs such as amphetamine in humans and rodents, respectively. Though the biological mechanisms underlying DAD2 receptor supersensitivity remain largely unknown, changes in both G-protein-dependent and G-protein-independent pathways are affected, and proteins involved in both pathways are suggested to participate in the development of supersensitivity. The DAD2 receptor is critically important for the treatment of schizophrenia, as blockade of this receptor is a common feature of all effective antipsychotic drugs. Chronic blockade of the DAD2 receptor has been linked to additional supersensitivity in patients with schizophrenia, resulting in relapse psychosis in many patients. The DAD2 receptor is also involved in the rewarding effects of drugs of abuse. As such, supersensitization of the DAD2 receptor has implications for the commonly comorbid substance use disorder, which negatively impacts overall treatment success. DAD2 supersensitivity is therefore of interest in the development of novel pharmaceutical treatments for the disorder.