PT  - JOURNAL ARTICLE
AU  - Richard M. Kostrzewa
AU  - Karolina Wydra
AU  - Malgorzata Filip
AU  - Cynthia Crawford
AU  - Sanders A. McDougall
AU  - Russell W. Brown
AU  - Dasiel O. Borroto-Escuela
AU  - Kjell Fuxe
AU  - Raul R. Gainetdinov
TI  - Dopamine D2 Receptor Supersensitivity as a Spectrum of Neurotoxicity and Status in Psychiatric Disorders
AID  - 10.1124/jpet.118.247981
DP  - 2018 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - jpet.118.247981
4099  - http://jpet.aspetjournals.org/content/early/2018/06/19/jpet.118.247981.short
4100  - http://jpet.aspetjournals.org/content/early/2018/06/19/jpet.118.247981.full
AB  - 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, 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 biological and behavioral modalities towards normality. Another such animal model, featuring knockout of Trace Amine-Associated Receptor 1 (TAAR1), demonstrates D2RSS with an increase of 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 A2A-D2 heteroreceptor complexes in substance use disorder is highlighted, and the association of A2AR antagonists in discriminative and rewarding effects of psychostimulants is outlined. In summary, these new animal models of schizophrenia have face validity, construct validity and predictive validity, and with 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.