Dopamine D₂ Receptor Supersensitivity as a Spectrum of Neurotoxicity and Status in Psychiatric Disorders

Abnormality of dopamine D₂ receptor (D₂R) function, often observed as D₂R supersensitivity (D₂RSS), is a commonality of schizophrenia and related psychiatric disorders in humans. Moreover, virtually all psychotherapeutic agents for schizophrenia target D₂R in brain. Permanent D₂RSS as a feature of a new animal model of schizophrenia was first reported in 1991, and then behaviorally and biochemically characterized over the next 15-20 years. In this model of schizophrenia characterized by production of D₂RSS in ontogeny, there are demonstrated alterations of signaling processes, as well as functional links between the biologic template of the animal model and ability of pharmacotherapeutics to modulate or reverse biologic and behavioral modalities toward normality. Another such animal model, featuring knockout of trace amine-associated receptor 1 (TAAR1), demonstrates D₂RSS with an increase in the proportion of D₂R in the high-affinity state. Currently, TAAR1 agonists are being explored as a therapeutic option for schizophrenia. There is likewise an overlay of D₂RSS with substance use disorder. The aspect of adenosine A_2A-D₂ heteroreceptor complexes in substance use disorder is highlighted, and the association of adenosine A_2A receptor antagonists in discriminative and rewarding effects of psychostimulants is outlined. In summary, these new animal models of schizophrenia have face, construct, and predictive validity, and distinct advantages over earlier models. While the review summarizes elements of D₂RSS in schizophrenia per se, and its interplay with substance use disorder, a major focus is on presumed new molecular targets attending D₂RSS in schizophrenia and related clinical entities.