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

描述(申请人提供)：可卡因依赖在今天的美国仍然是一个严重的公共卫生问题。与长期使用可卡因有关的各种不良健康、心理和社会问题广泛且有充分的文件记载。然而，尽管进行了20年的密集研究，仍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降低吸毒复发的脆弱性，即使在长期戒毒之后，吸毒问题仍然存在。动物模型提供的证据表明，药物寻求行为源于中脑边缘多巴胺能回路在获得时的持续神经适应，以及皮质-纹状体谷氨酸能回路在复发时的持续神经适应。因此，腹侧纹状体被认为是药物和线索诱导的戒毒训练后恢复寻找可卡因的神经回路的关键元件。然而，最近的证据表明，在没有进行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取决于背侧纹状体(DSTR)。位于腹侧纹状体的代谢性谷氨酸受体(MGluRs)的活性被认为对调节可卡因寻找行为和皮质-纹状体可塑性具有重要作用。Dstr中的mGluRs是否与戒断后复发寻找可卡因有关尚不清楚。我们以前的研究表明，DSTR中被称为G蛋白信号转导调节因子4(RGS4)的蛋白的表达受精神刺激剂的急性或长期非偶然暴露的调节。RGS4是已知的G？I-和G？Q偶联受体，包括mGluR1/5受体的有效负性调节因子。可卡因自身给药后持续戒断导致RGS4基因表达下降。再次暴露于与可卡因配对的环境中，导致强烈的可卡因寻求，使DSTR中RGS4基因表达的降低正常化。此外，我们还证明了DSTR中的RGS4蛋白与mGluR5信号组装直接相关。因此，我们假设RGS4水平的变化导致dstr中mGluR5介导的细胞信号的改变，从而增加了戒断后复发的易感性。这一假说将通过解决以下具体目标来验证：1)表征DSTR中与膜和mGluR5相关的RGS4蛋白的变化，这些变化发生在戒断可卡因自我给药和复发到寻求可卡因之后。2)研究RGS4在dstr中的过表达对戒断后寻找可卡因复吸的影响；3)研究RGS4过表达对dstr中mGluR5介导的细胞信号转导的影响。这些目标的完成将有助于填补我们对复发到寻求可卡因行为的细胞内机制的理解的根本空白，并可能导致治疗成瘾的新药物疗法。 与公共健康相关：可卡因成瘾在今天的美国仍然是一个严重的公共健康问题。人们普遍认识到，即使在长期戒毒之后，复发的高风险也是成功治疗可卡因成瘾的关键挑战之一。该项目名为“纹状体RGS4与mGluR5信号在寻求可卡因的复吸中的相互作用”，旨在利用具有高表面效度的人类可卡因成瘾动物模型研究复吸耐受性与神经生物学的相关性。

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.