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

Abnormality of dopamine D ₂ receptor (D ₂ R) function, often observed as D ₂ R supersensitivity (D ₂ RSS), is a commonality of schizophrenia and related psychiatric disorders in humans. Moreover, virtually all psychotherapeutic agents for schizophrenia target D ₂ R in brain. Permanent D ₂ RSS 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 D ₂ RSS 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 D ₂ RSS with an increase in the proportion of D ₂ R in the high-affinity state. Currently, TAAR1 agonists are being explored as a therapeutic option for schizophrenia. There is likewise an overlay of D ₂ RSS with substance use disorder. The aspect of adenosine A _2A -D ₂ 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 D ₂ RSS in schizophrenia per se, and its interplay with substance use disorder, a major focus is on presumed new molecular targets attending D ₂ RSS in schizophrenia and related clinical entities.