CREB Mediated GABA-B Receptor Regulation in the Nucleus Accumbens

描述（由申请人提供）：可卡因滥用是一个重要问题：据估计，仅在美国，2000年就有500多万可卡因使用者。研究表明，GABA-B受体（GABABR）激动剂和调节剂在减少人类和/或动物成瘾模型中的可卡因消耗方面是有效的。GABABR介导缓慢代谢。抑制和表达两个亚基GABABR 1（R1）和GABABR 2（R2）被认为是受体功能所必需的。R1亚型（R1 a和R1 b）的表达受R1基因中的替代启动子控制。这些启动子受CREB家族成员和上游刺激因子（USF）的差异调节，USF识别R1 b中的复合CRE/Ebox位点。有趣的是，慢性可卡因暴露导致磷酸化CREB增加。在这个提议中，我们将测试CREB，ATF 4和USF在控制R1 a和R1 b在丘脑核（NAc）中的内源性表达中发挥的作用（目的1）。然后，我们将解决是否R1 a和R1 b调节NAc的影响，慢性巴氯芬治疗（目的2）和可卡因自我管理的大鼠模型（目的3）。

DESCRIPTION (provided by applicant): Cocaine abuse is an important problem: in the US alone it is estimated that there over 5 million cocaine users in 2000. Studies have shown that GABA-B receptor (GABABR) agonists and modulators are effective in reducing cocaine consumption in humans and/or animal models of addiction. The GABABR mediates slow metabotropic. inhibition, and expression of two subunits GABABR1 (R1) and GABABR2 (R2) is believed required for receptor function. Expression of the R1 isoforms (R1a and R1b) is under the control of alternative promoters in the R1 gene. The promoters are differentially regulated by CREB family members and by the upstream stimulatory factor (USF) that recognizes a composite CRE/Ebox site in R1b. Interestingly, chronic cocaine exposure leads to an increase in phosphorylated CREB. In this proposal, we will test the role that CREB, ATF4, and USF play in controlling endogenous expression of R1a and R1b in the nucleus accumbens (NAc) (Aim 1). Then, we will the address whether R1a and R1b regulation in the NAc is affected by chronic baclofen treatment (Aim 2) and in a rat model of cocaine self-administration (Aim 3).