CART/GABAB受体负性调控海马-伏隔核奖赏环路参与药物成瘾行为敏感化的功能和机制研究

药物成瘾会诱发个人精神问题，对社会和家庭造成巨大危害。但是，药物成瘾行为敏感化产生过程并不清楚。伏隔核脑区可卡因安非他命调节肽（CART）负性调节被抑制与行为敏感化产生过程密切相关。我们前期发现：可卡因诱导的伏隔核脑区基因CART与GABABR正相关；进一步发现CART可通过促进GABABR上膜阻断行为敏感化产生。鉴于海马-伏隔核奖赏环路的新发现，因此假说：该环路存在CART/GABABR负性调节并影响行为敏感化产生。本课题拟：①通过成瘾动物和细胞明确CART/GABABR负性调节功能及其协同作用；②激活/抑制CaMKIIa表达明确CART促进GABABR上膜分子机制；③通过逆行追踪、光遗传、电生理和行为学分析，观察成瘾动物海马-伏隔核环路与负性调节相关的特定细胞和解剖组织；④激活/抑制CART和GABABR表达明确该环路负性调节分子机制。本课题对研发特异性戒断成瘾的药物有着十分重要意义。

Drug addiction can lead to personal mental problems, causing significant health and social harms for society and their families. However, the process of behavioral sensitization for drug addiction remains unknown. The inhibition of the negative regulation of cocaine amphetamine regulatory peptide (CART) in the nucleus accumbens is closely related to the process of behavioral sensitization. Our previous studies have shown that gene CART is significantly related to GABABR in cocaine induced-NAc, and the production of CART blocking behavior sensitization is associated to the promotion of GABABR membrane trafficking. In view of the new findings of the hippocampal-NAc reward circuits, it is hypothesized that there is a negative regulation of CART/GABABR in this circuit and it affects the generation of behavioral sensitivity. In this study, we will identify ① the synergistic effect of CART/GABABR on the negative regulation of behavioral sensitization, and ② to clarify the molecular mechanism of CART promoting GABABR membrane trafficking by activating/inhibiting expression of CaMKIIa. ③We will then observe hippocampal-NAc circuits and the specific cells and anatomical tissues related to negative regulation of behavioral sensitization. ④ Activation / inhibition of the expression of CART and GABABR and understanding of the negative regulatory molecular mechanism of this circuit. This study will be of great significance for the research and development of specific drug for withdrawal addiction.