altered ratio of d1 and d2 dopamine receptors in mouse striatum is associated with behavioral sensitization to cocaine改变的比率d1和d2多巴胺受体在小鼠纹状体与行为敏化可卡因.pdfVIP

Altered Ratio of D1 and D2 Dopamine Receptors in Mouse Striatum Is Associated with Behavioral Sensitization to Cocaine 1 1 1,2 Dawn Thompson , Lene Martini , Jennifer L. Whistler * 1 Ernest Gallo Clinic and Research Center, University of California San Francisco, Emeryville, California, United States of America, 2 Department of Neurology, University of California San Francisco, San Francisco, California, United States of America Abstract Background: Drugs of abuse elevate brain dopamine levels, and, in vivo, chronic drug use is accompanied by a selective decrease in dopamine D2 receptor (D2R) availability in the brain. Such a decrease consequently alters the ratio of D1R:D2R signaling towards the D1R. Despite a plethora of behavioral studies dedicated to the understanding of the role of dopamine in addiction, a molecular mechanism responsible for the downregulation of the D2R, in vivo, in response to chronic drug use has yet to be identified. Methods and Findings: Ethics statement: All animal work was approved by the Gallo Center IACUC committee and was performed in our AAALAC approved facility. In this study, we used wild type (WT) and G protein coupled receptor associated sorting protein-1 (GASP-1) knock out (KO) mice to assess molecular changes that accompany cocaine sensitization. Here, we show that downregulation of D2Rs or upregulation of D1Rs is associated with a sensitized locomotor response to an acute injection of cocaine. Furthermore, we demonstrate that disruption of GASP-1, that targets D2Rs for degradation after endocytosis, prevents cocaine-induced downregulation of D2Rs. As a consequence, mice with a GASP-1 disruption show a reduction in the sensitized locomotor response to cocaine. Conclusions: Together, our data suggests that