Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee (R.M.K., R.W.B.); Institute of Pharmacology, Polish Academy of Sciences, Department of Drug Addiction Pharmacology, Krakow, Poland (K.W., M.F.); Department of Psychology, California State University, San Bernardino, California (C.A.C., S.A.M.); Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden (D.O.B.-E., K.F.); Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia (R.R.G.); and Skolkovo Institute of Science and Technology, Skolkovo, Moscow, Russia (R.R.G.)
Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee (R.M.K., R.W.B.); Institute of Pharmacology, Polish Academy of Sciences, Department of Drug Addiction Pharmacology, Krakow, Poland (K.W., M.F.); Department of Psychology, California State University, San Bernardino, California (C.A.C., S.A.M.); Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden (D.O.B.-E., K.F.); Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia (R.R.G.); and Skolkovo Institute of Science and Technology, Skolkovo, Moscow, Russia (R.R.G.).
J Pharmacol Exp Ther. 2018 Sep;366(3):519-526. doi: 10.1124/jpet.118.247981. Epub 2018 Jun 19.
Abnormality of dopamine D receptor (DR) function, often observed as DR supersensitivity (DRSS), is a commonality of schizophrenia and related psychiatric disorders in humans. Moreover, virtually all psychotherapeutic agents for schizophrenia target DR in brain. Permanent DRSS 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 DRSS 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 DRSS with an increase in the proportion of DR in the high-affinity state. Currently, TAAR1 agonists are being explored as a therapeutic option for schizophrenia. There is likewise an overlay of DRSS with substance use disorder. The aspect of adenosine A-D heteroreceptor complexes in substance use disorder is highlighted, and the association of adenosine A 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 DRSS in schizophrenia per se, and its interplay with substance use disorder, a major focus is on presumed new molecular targets attending DRSS in schizophrenia and related clinical entities.
多巴胺 D 受体 (DR) 功能异常，通常表现为 DR 超敏性 (DRSS)，是人类精神分裂症和相关精神障碍的共同特征。此外，几乎所有用于精神分裂症的心理治疗药物都以大脑中的 DR 为靶点。1991 年首次报道了作为精神分裂症新动物模型特征的永久性 DRSS，随后在接下来的 15-20 年中对其进行了行为和生化特征描述。在这种以发育过程中产生 DRSS 为特征的精神分裂症模型中，已经证明了信号转导过程的改变，以及动物模型的生物学模板与药物治疗调节或逆转生物学和行为模式向正常状态的功能联系。另一种这样的动物模型，特征是痕量胺相关受体 1 (TAAR1) 的缺失，表现出 DRSS，高亲和力状态下的 DR 比例增加。目前，正在探索 TAAR1 激动剂作为精神分裂症的治疗选择。DRSS 也与物质使用障碍重叠。强调了物质使用障碍中腺苷 A-D 异源受体复合物的方面，并概述了腺苷 A 受体拮抗剂在精神兴奋剂的辨别和奖赏作用中的关联。总之，这些新的精神分裂症动物模型具有面部、结构和预测效度，并且优于早期模型。虽然该综述总结了精神分裂症中 DRSS 本身及其与物质使用障碍的相互作用的元素，但主要重点是假定的与精神分裂症和相关临床实体中的 DRSS 相关的新分子靶点。
