可卡因安非他明调节(CART)肽是成瘾药物奖赏的关键调控因子。研究报道证实定位注射至伏隔核的CART活性肽稀释成瘾药物产生的奖赏效应。前期实验证实，CART活性肽呈剂量依赖型抑制伏隔核神经细胞内钙离子浓度，并且稀释可卡因激活的钙离子内流。CART活性肽被定位注射至伏隔核可阻断可卡因行为敏感化的产生。因此推测，伏隔核存在的CART肽负反馈调控可卡因奖赏效应，但调控机制尚未清楚。本研究通过一系列实验观察定位注射至伏隔核区域内的CART肽调节可卡因增强的行为活动性和神经元内Ca2+/calmodulin/CaMKⅡ和cAMP-PKA信号通路活性变化，及观察CaMKⅡ调节D3R突变和功能的变化； 使用高表达CaMKⅡ病毒载体和D3R基因敲除小鼠，进一步证实CART肽负调控可卡因奖赏效应与伏隔核内CaMKⅡ调节D3R功能密切相关。

Cocaine- and amphetamine- regulated transcript (CART) peptides in nucleus accuments (NAcc) is as a key modulator in the rewarding and reinforcing effects of addiction drugs. The other studies demonstrated that the microinjection of CART 55-102 peptides into NAcc had no effect on locomotion， even attenuated the increase of locomotor activity produced by systemic cocaine and amphetamine administration. Our previous studies shown that CART 55-102 peptides dose-dependently inhibited the Ca2+ influx, and attenuated the cocaine-induced Ca2+ influx in cultured NAcc neurons. Moreover, microinjection of CART 55-102 peptides into NAcc blocked the cocaine-induced behavioral sensitization. Thus, CART in NAcc generate a negative regulation as they modulated the development of the rewarding and reinforcing effects of addiction drugs, but the associated regulated molecular mechanisms are not yet answered. The present studies will elucidate the activity alternation of the Ca2+/calmodulin/CaMKⅡand cAMP/PKA/pCREB signaling pathway; the protein-prtein interaction between CaMKⅡand D3R, and the functional alternation of D3R in NAcc after the microinjection of CART 55-102 peptides into NAcc using the series experiments of electrophysiology and immunobiochemicy, such as the tissue-attached configuration of the patch clamp, the Co-immunoprecipitation and autoradiography et al. Further, these studies will explore that effects of the over-expression of CaMKⅡ levels with microinjection of the herpes simplex virus (HSV) vector into NAcc on the sensitization and cAMP/PKA/pCREB signaling induced by cocaine will be inhibited by the microinjections of CART peptides into NAcc. The microinjection of CART peptides into NAcc in D3R-Knockout mice will have no effect on the cocaine-induced behavioral sensitiztion. Accordingly, CART peptides as the negative modulator in NAcc may eventually prove to be potential targets for the design of pharmacotherapies to treat addiction.