Striatal RGS4 Interacts with mGluR5 Signaling in Relapse to Cocaine-seeking

纹状体 RGS4 与 mGluR5 信号相互作用导致可卡因寻求复发

基本信息

批准号：
8027727
负责人：
Marek Schwendt
金额：
$ 17.88万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-02-15 至 2013-01-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Cocaine dependence remains a substantial public health problem in the United States today. There is a wide and well-documented range of adverse health, psychological and social problems associated with chronic use of cocaine. However, in spite of two decades of intense research, effective pharmacotherapies for the treatment of addiction have not been identified. One of the key challenges in the successful treatment of cocaine addiction is decreasing the vulnerability of relapse to drug-taking which persists even after long periods of abstinence. Animal models have provided evidence that drug-seeking behavior arises from persistent neuroadaptations in mesolimbic dopaminergic circuitry during acquisition and cortico-striatal glutamatergic circuitry during relapse. Accordingly, the ventral striatum has been identified as a critical element of the neurocircuitry underlying drug and cue-induced reinstatement of cocaine-seeking after extinction training. However, recent evidence indicates that the habitual or compulsive quality of persistent drug-seeking in abstinent animals which do not undergo extinction training depends on the dorsal striatum (dSTR). Activity of metabotropic glutamate receptors (mGluRs) located in the ventral striatum is thought to be important for regulating cocaine-seeking behavior and cortico-striatal plasticity. Whether mGluRs in the dSTR are involved in relapse to cocaine-seeking after abstinence is not known. Our previous studies have shown that expression of the protein termed regulator of G-protein signaling 4 (RGS4) in the dSTR is regulated by acute or chronic noncontingent exposure to psychostimulants. RGS4 is a known potent negative regulator of G?i- and G?q- coupled receptors, including mGluR1/5 receptors. Cocaine self-administration followed by prolonged abstinence resulted in a decrease of RGS4 gene expression. Re-exposure to a cocaine-paired context, which resulted in robust cocaine-seeking, normalized the reduced expression of RGS4 gene expression in the dSTR. In addition, we have demonstrated that RGS4 protein in the dSTR directly associates with mGluR5-signalling assembly. Therefore, we hypothesize that changes in RGS4 levels result in altered mGluR5-mediated cellular signaling in the dSTR that contributes to increased vulnerability to relapse after abstinence. This hypothesis will be tested by addressing the following SPECIFIC AIMS: 1) To characterize changes in membrane- and mGluR5-associated RGS4 protein in the dSTR occurring with abstinence from cocaine self- administration and after relapse to cocaine-seeking. 2) To investigate the effects of RGS4 overexpression in the dSTR on relapse to cocaine-seeking after abstinence 3) To determine the effects of RGS4 overexpression on mGluR5-mediated cellular signaling in the dSTR during relapse to cocaine-seeking after abstinence. Completion of these aims will help to fill fundamental gaps in our understanding of the intracellular mechanisms underlying relapse to cocaine-seeking behavior and potentially lead to new pharmacotherapies for the treatment of addiction. PUBLIC HEALTH RELEVANCE: Cocaine addiction remains a substantial public health problem in the United States today. It is widely recognized that high risk of relapse even after long periods of abstinence represents one of the key challenges in successful treatment of cocaine addiction. This project proposal, entitled "Striatal RGS4 Interacts with mGluR5 Signaling in Relapse to Cocaine-seeking" is aimed to study neurobiological correlates of enduring vulnerability to relapse utilizing animal model with high face validity for human cocaine addiction.

描述（由申请人提供）：可卡因的依赖仍然是当今美国的实质性公共卫生问题。与可卡因的长期使用有关，有广泛且有据可查的不良健康，心理和社会问题。然而，尽管进行了二十年的深入研究，但尚未确定有效治疗成瘾的药物治疗。成功治疗可卡因成瘾的关键挑战之一是减少了毒品复发的脆弱性，即使经过长时间的禁欲，这种复发仍然存在。动物模型提供了证据表明，寻求药物的行为是由在复发期间采集和皮质 - 纹状体谷氨酸能回路期间中脱甲贝型多巴胺能回路的持续神经适应引起的。因此，腹侧纹状体已被确定为灭绝训练后的神经通行物的关键元素和提示引起的可卡因寻求可卡因的恢复。但是，最近的证据表明，在避免的动物中，持续的毒品寻求药物的习惯或强迫性质量不进行灭绝训练取决于背纹状体（DSTR）。位于腹侧纹状体中的代谢型谷氨酸受体（MGLURS）的活性被认为对于调节可卡因寻求可卡因行为和皮质纹状体可塑性很重要。尚不清楚DSTR中的mglurs是否参与了戒酒后寻求可卡因的复发。我们先前的研究表明，DSTR中称为G蛋白信号4（RGS4）的蛋白质调节剂的表达受到急性或慢性非转化性暴露于心理刺激剂的调节。 RGS4是G？i-和g？Q-偶联受体的已知有效调节剂，包括MGLUR1/5受体。可卡因自我给药，然后延长节制，导致RGS4基因表达降低。重新暴露于可卡因生的环境，从而导致可卡因寻求可卡因，使DSTR中RGS4基因表达的表达降低。此外，我们已经证明了DSTR中的RGS4蛋白与mglur5-签名组件直接相关。因此，我们假设RGS4水平的变化会导致DSTR中MGLUR5介导的细胞信号的改变，这导致戒酒后脆弱性增加。该假设将通过解决以下具体目的来检验：1）表征DSTR中与可卡因自我给药以及复发到可卡因寻求可卡因后的戒酒中，与膜和MGLUR5相关的RGS4蛋白的变化。 2）研究DSTR中RGS4过表达对禁欲后的可卡因寻求可卡因的影响，以确定RGS4过表达对MGLUR5介导的细胞信号的影响DSTR在禁欲后复发至可卡因探测期间的DSTR中的DSTR。这些目的的完成将有助于填补我们对寻求可卡因行为的基础内机制的理解，并有可能导致新的药物治疗来治疗成瘾。公共卫生相关性：可卡因成瘾仍然是当今美国的实质性公共卫生问题。人们普遍认为，即使经过长时间的禁欲，复发的高风险也代表了成功治疗可卡因成瘾的主要挑战之一。该项目建议，标题为“纹状体RGS4与MGLUR5信号相互作用，以复发到可卡因寻求可卡因”的目的是研究使用具有高面部有效性的人类可卡因成瘾的动物模型的持久脆弱性的神经生物学相关性。