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

描述（由申请人提供）：可卡因依赖在今天的美国仍然是一个重大的公共卫生问题。与长期使用可卡因有关的一系列不良健康、心理和社会问题广泛而有据可查。然而，尽管经过了二十年的深入研究，治疗成瘾的有效药物疗法仍未被发现。成功治疗可卡因成瘾的关键挑战之一是减少重新吸毒的可能性，这种情况即使在长期戒断后仍然存在。动物模型提供的证据表明，药物寻求行为源于获取期间中边缘多巴胺能回路和复发期间皮质纹状体谷氨酸能回路的持续神经适应。因此，腹侧纹状体已被确定为药物和线索诱导的戒毒训练后可卡因寻求恢复的神经回路的关键因素。然而，最近的证据表明，在没有接受灭绝训练的禁欲动物中，持续寻求药物的习惯性或强迫性质量取决于背纹状体（dSTR）。位于腹侧纹状体的代谢性谷氨酸受体（mGluRs）的活性被认为是调节可卡因寻求行为和皮质纹状体可塑性的重要因素。dSTR中的mglur是否与戒断后的可卡因寻求复发有关尚不清楚。我们之前的研究表明，dSTR中称为g蛋白信号传导调节因子4 （RGS4）的蛋白表达受到急性或慢性非偶然暴露于精神兴奋剂的调节。RGS4是已知的G？i-和G？q偶联受体，包括mGluR1/5受体。自我给药后长期戒断导致RGS4基因表达降低。再次暴露于可卡因配对的环境中，导致强烈的可卡因寻求，使dSTR中RGS4基因表达的减少正常化。此外，我们已经证明dSTR中的RGS4蛋白直接与mglur5信号组装相关。因此，我们假设RGS4水平的变化导致dSTR中mglur5介导的细胞信号通路改变，从而增加了戒断后复发的易变性。这一假设将通过解决以下特定目的来验证：1)表征在戒断可卡因自我给药和重新寻求可卡因后dSTR中膜和mglur5相关RGS4蛋白的变化。2)研究dSTR中RGS4过表达对戒毒后可卡因寻求复发的影响3)研究RGS4过表达对戒毒后可卡因寻求复发时dSTR中mglur5介导的细胞信号传导的影响。完成这些目标将有助于填补我们对可卡因寻求行为复发的细胞内机制的理解的基本空白，并可能导致治疗成瘾的新药物疗法。

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.