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:
- 金额:$ 17.88万
- 依托单位:
- 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
- 来源:
- 关键词:AbstinenceAcuteAddressAnimal ModelAnimalsBehaviorChronicCocaineCocaine DependenceCorpus striatum structureCuesDataDorsalDrug AddictionElementsExposure toExtinction (Psychology)FaceGTP-Binding Protein RegulatorsGene ExpressionGlutamatesHumanLeadMediatingMembraneMental HealthMessenger RNAMetabotropic Glutamate ReceptorsNeurobiologyPharmaceutical PreparationsPharmacotherapyProteinsPublic HealthRattusRelapseResearchRoleSelf AdministrationSignal TransductionSocial ProblemsTestingTrainingUnited StatesVentral Striatumaddictioncocaine usedesigndrug seeking behaviorhigh riskneuroadaptationoverexpressionpostsynapticpresynapticprotein expressionpsychostimulantpublic health relevancereceptorreceptor coupling
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):可卡因依赖仍然是当今美国的一个重大公共卫生问题。长期使用可卡因会导致一系列广泛且有据可查的不良健康、心理和社会问题。然而,尽管经过二十年的深入研究,治疗成瘾的有效药物疗法尚未确定。成功治疗可卡因成瘾的关键挑战之一是降低吸毒复发的可能性,即使在长期戒毒后,这种情况仍然存在。动物模型提供的证据表明,药物寻求行为是由获取期间中脑边缘多巴胺能回路和复发期间皮质纹状体谷氨酸回路中持续的神经适应引起的。因此,腹侧纹状体已被确定为药物和线索诱导的消除训练后可卡因寻求恢复的神经回路的关键元件。然而,最近的证据表明,未接受灭绝训练的戒断动物持续寻求药物的习惯性或强迫性取决于背侧纹状体(dSTR)。位于腹侧纹状体的代谢型谷氨酸受体(mGluR)的活性被认为对于调节可卡因寻求行为和皮质纹状体可塑性很重要。 dSTR 中的 mGluR 是否与戒除可卡因后复发有关尚不清楚。我们之前的研究表明,dSTR 中名为 G 蛋白信号调节因子 4 (RGS4) 的蛋白质的表达受到急性或慢性非偶然接触精神兴奋剂的调节。 RGS4 是已知的 Gαi 和 Gαq 偶联受体(包括 mGluR1/5 受体)的有效负调节因子。自我注射可卡因并长期戒断会导致 RGS4 基因表达下降。重新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,我们还证明 dSTR 中的 RGS4 蛋白与 mGluR5 信号传导组装直接相关。因此,我们假设 RGS4 水平的变化导致 dSTR 中 mGluR5 介导的细胞信号传导发生改变,从而导致戒烟后复发的可能性增加。该假设将通过解决以下具体目标进行检验:1) 表征在戒断可卡因自我施用和复发后重新寻求可卡因后,dSTR 中膜和 mGluR5 相关 RGS4 蛋白的变化。 2) 研究 dSTR 中 RGS4 过表达对戒断后可卡因寻求复发的影响 3) 确定戒断后可卡因寻求复发期间 RGS4 过表达对 dSTR 中 mGluR5 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理解的根本空白,并可能导致治疗成瘾的新药物疗法。
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。人们普遍认为,即使在长期戒断后,复发的高风险也是成功治疗可卡因成瘾的关键挑战之一。该项目提案题为“纹状体 RGS4 与 mGluR5 信号在可卡因寻求复发中相互作用”,旨在利用人类可卡因成瘾具有高表面效度的动物模型,研究持久脆弱性复发的神经生物学相关性。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The Effects of Extended-Access Cocaine Self-Administration on Working Memory Performance, Reversal Learning and Incubation of Cocaine-Seeking in Adult Male Rats.
延长可卡因自我给药对成年雄性大鼠工作记忆表现、逆转学习和可卡因寻求孵化的影响。
- DOI:10.13188/2330-2178.1000035
- 发表时间:2017
- 期刊:
- 影响因子:0
- 作者:Gobin,Christina;Schwendt,Marek
- 通讯作者:Schwendt,Marek
Chronic methamphetamine self-administration dysregulates 5-HT2A and mGlu2 receptor expression in the rat prefrontal and perirhinal cortex: Comparison to chronic phencyclidine and MK-801.
- DOI:10.1016/j.pbb.2018.09.007
- 发表时间:2018-12
- 期刊:
- 影响因子:0
- 作者:Hámor PU;Šírová J;Páleníček T;Zaniewska M;Bubeníková-Valešová V;Schwendt M
- 通讯作者:Schwendt M
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Marek Schwendt其他文献
Marek Schwendt的其他文献
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{{ truncateString('Marek Schwendt', 18)}}的其他基金
A novel model of oxycodone seeking that considers sex and stress susceptibility
一种考虑性别和压力敏感性的羟考酮寻求新模型
- 批准号:
10399874 - 财政年份:2021
- 资助金额:
$ 17.88万 - 项目类别:
A novel model of oxycodone seeking that considers sex and stress susceptibility.
一种考虑性别和压力敏感性的羟考酮寻求新模型。
- 批准号:
10183214 - 财政年份:2020
- 资助金额:
$ 17.88万 - 项目类别:
A novel model of oxycodone seeking that considers sex and stress susceptibility.
一种考虑性别和压力敏感性的羟考酮寻求新模型。
- 批准号:
10057442 - 财政年份:2020
- 资助金额:
$ 17.88万 - 项目类别:
Developing novel tools for targeting mGlu2(3) receptors in methamphetamine addiction.
开发针对甲基苯丙胺成瘾中的 mGlu2(3) 受体的新工具。
- 批准号:
9806929 - 财政年份:2019
- 资助金额:
$ 17.88万 - 项目类别:
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
- 批准号:
7788579 - 财政年份:2010
- 资助金额:
$ 17.88万 - 项目类别:
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