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的问题：仅在美国，估计2000年就有超过500万的可卡因使用者。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。GABABR1 （R1）和GABABR2 （R2）两个亚基的抑制和表达被认为是受体功能所必需的。R1亚型（R1a和R1b）的表达受R1基因中替代启动子的控制。启动子受到CREB家族成员和上游刺激因子（USF）的不同调控，后者识别R1b中的复合CRE/Ebox位点。有趣的是，长期接触可卡因会导致磷酸化的CREB增加。在本提案中，我们将测试CREB， ATF4和USF在控制伏隔核（NAc）中R1a和R1b内源性表达中的作用（Aim 1）。然后，我们将探讨慢性巴氯芬治疗（Aim 2）和可卡因自我给药大鼠模型（Aim 3）是否影响NAc中R1a和R1b的调节。

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).