Cocaine addiction is a chronic, relapsing disorder characterized by maladaptation in the brain mesolimbic and nigrostriatal dopamine system. Although changes in the properties of D2-receptor-expressing medium spiny neurons (D2-MSNs) and connected striatal circuits following cocaine treatment are known, the contributions of altered D2-receptor (D2R) function in mediating the rewarding properties of cocaine remain unclear. Here, we describe how a 7-day exposure to cocaine alters dopamine signaling by selectively reducing the sensitivity, but not the expression, of nucleus accumbens D2-MSN D2Rs via an alteration in the relative expression and coupling of G protein subunits. This cocaine-induced reduction of D2R sensitivity facilitated the development of the rewarding effects of cocaine as blocking the reduction in G protein expression was sufficient to prevent cocaine-induced behavioral adaptations. These findings identify an initial maladaptive change in sensitivity by which mesolimbic dopamine signals are encoded by D2Rs following cocaine exposure.

可卡因成瘾是一种慢性、复发性疾病，其特征是大脑中边缘和黑质纹状体多巴胺系统适应不良。尽管可卡因治疗后表达 D2 受体的中型多棘神经元 (D2-MSN) 和连接的纹状体回路的特性发生变化是已知的，但 D2 受体 (D2R) 功能改变在调节可卡因的奖赏特性中的贡献仍不清楚。在这里，我们描述了接触可卡因 7 天如何通过改变 G 蛋白亚基的相对表达和偶联来选择性降低伏核 D2-MSN D2R 的敏感性而不是表达，从而改变多巴胺信号传导。可卡因诱导的 D2R 敏感性降低促进了可卡因奖励效应的发展，因为阻止 G 蛋白表达的减少足以防止可卡因诱导的行为适应。这些发现确定了可卡因暴露后 D2R 编码的中脑边缘多巴胺信号的最初敏感性不适应变化。