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

描述（由申请人提供）：可卡因依赖仍然是当今美国的一个重大公共卫生问题。有大量证据表明，长期使用可卡因会造成一系列不良的健康、心理和社会问题。然而，尽管进行了二十年的深入研究，但尚未确定治疗成瘾的有效药物疗法。成功治疗可卡因成瘾的关键挑战之一是减少吸毒复吸的脆弱性，这种脆弱性即使在长期戒断之后仍然存在。动物模型提供的证据表明，觅药行为源于获得过程中中脑边缘多巴胺能回路和复发过程中皮质-纹状体多巴胺能回路的持续神经适应。因此，腹侧纹状体已被确定为一个关键的元素的神经回路的基础药物和线索诱导恢复可卡因寻求后灭绝训练。然而，最近的证据表明，习惯性或强迫性的持续药物寻求在禁欲的动物，不经历灭绝训练取决于背侧纹状体（dSTR）。位于腹侧纹状体的代谢型谷氨酸受体（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mGluRs是否与戒断后可卡因寻求复发有关尚不清楚。我们以前的研究表明，蛋白质的表达被称为调节G蛋白信号传导4（RGS 4）在dSTR的急性或慢性非偶然暴露于精神兴奋剂的调节。RGS 4是已知的G？i和G？q-偶联受体，包括mGluR 1/5受体。考马斯亮蓝自我管理，然后延长禁欲导致RGS 4基因表达的减少。重新暴露于可卡因配对的环境，这导致了强烈的可卡因寻求，使dSTR中RGS 4基因表达的降低表达正常化。此外，我们已经证明，RGS 4蛋白在dSTR直接关联与mGluR 5信号组装。因此，我们假设RGS 4水平的变化导致dSTR中mGluR 5介导的细胞信号传导改变，这导致戒断后复发的脆弱性增加。将通过解决以下特定目的来检验该假设：1）表征在可卡因自我给药戒断和可卡因寻求复发后发生的dSTR中膜和mGluR 5相关RGS 4蛋白的变化。2)研究dSTR中RGS 4过表达对戒断后可卡因寻求复发的影响3）确定在戒断后可卡因寻求复发期间RGS 4过表达对dSTR中mGluR 5介导的细胞信号传导的影响。这些目标的完成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根本空白，并可能导致新的药物治疗成瘾。 公共卫生相关性：可卡因成瘾仍然是当今美国的一个重大公共卫生问题。人们普遍认识到，即使在长期戒断之后，复发的风险也很高，这是成功治疗可卡因成瘾的关键挑战之一。这项名为“纹状体RGS 4与mGluR 5信号在可卡因成瘾复发中的相互作用”的项目提案旨在利用人类可卡因成瘾的高表面有效性动物模型研究持久易复发性的神经生物学相关性。

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.