Caveolins, Striatal Toxicity and Methamphetamine Addiction

小窝蛋白、纹状体毒性和甲基苯丙胺成瘾

• 批准号: 9348473
• 负责人: Chitra D Mandyam
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9348473
• 关键词: Adaptive Behaviors; Address; Age; Animal Model; Animals; Behavior; Behavioral; Belief; Brain; Caring; Caveolins; Characteristics; Cholesterol; Chronic; Corpus striatum structure; Dopamine D1 Receptor; Dorsal; Drug Addiction; Event; Extracellular Signal Regulated Kinases; Genetic; Genetic Techniques; Goals; Hyperactive behavior; Impairment; Intake; Knowledge; Lead; MAPK3 gene; Mediating; Membrane Lipids; Membrane Microdomains; Methamphetamine; Methamphetamine dependence; Mitogen-Activated Protein Kinases; Modeling; Molecular; Motivation; Neurobiology; Neurons; Pathology; Pattern; Pharmacology; Phenotype; Play; Pre-Clinical Model; Publishing; Rattus; Receptor Signaling; Reinforcement Schedule; Relapse; Reporting; Research; Rewards; Rodent Model; Role; Saline; Scaffolding Protein; Self Administration; Self-Administered; Signal Transduction; Sphingolipids; Subfamily lentivirinae; Sucrose; Techniques; Testing; Therapeutic Intervention; Toxic effect; Veterans; Work; addiction; behavioral response; caveolin 1; cholesterol-binding protein; clinically relevant; drug seeking behavior; experience; functional disability; methamphetamine effect; overexpression; prevent; protein expression; receptor expression; repaired; substance abuse treatment

Summary Dopamine D1 receptors (D1Rs) in the dorsal striatum are hypothesized to play a major role in methamphetamine (Meth) addiction, and self-administration paradigms of Meth intake (clinically relevant models of Meth addiction) have reported that Meth self-administration increases D1R expression in the striatum and systemic D1R blockade decreases responding to Meth and reduces Meth seeking. Systemic D1 receptor antagonism in Meth experienced animals also prevented some aspects of maladaptive alterations; e.g. Meth-induced hyperphosphorylation of ERK1/2 in the striatum and Meth reward, indicating that enhancement of ERK1/2 by Meth is an intracellular signal transduction mechanism contributing to the maladaptive plasticity associated with reinforcing effects of Meth. These studies suggest that progressive increases in the intake of Meth over extended access schedules of reinforcement may lead to persistent neurobiological alterations in the striatum through aberrant increases in D1R expression and ERK1/2 activity. Therefore, the proposal will determine whether D1Rs and ERK1/2 activity in the dorsal striatum plays a role in establishing compulsive-like self-administration in animals experiencing Meth over extended access schedules of reinforcement. New evidence demonstrates that D1R signaling occurs in discrete plasmalemmal microdomains termed membrane/lipid rafts. Lipid rafts are enriched in cholesterol- and sphingolipid and the cholesterol binding and scaffolding protein caveolin-1 (Cav-1). Cav-1 is important in regulating D1R signaling, turnover and function. Therefore, we also seek to determine whether Cav-1 in D1R expressing neurons plays a role in mediating the maladaptive behavioral responses in compulsive Meth taking and seeking in Meth addicted animals. We will test these hypotheses using well-established rodent models of compulsive-like Meth self-administration and state-of-the-art genetic and pharmacological techniques to determine the role of D1Rs, ERK1/2 activity and Cav-1 in Meth addiction. Understanding the cellular and molecular mechanisms underlying Meth addiction in the dorsal striatum in animal models that demonstrate compulsive-like behavior has tremendous potential for identifying therapeutic interventions for reducing Meth addiction and maladaptive patterns of Meth seeking.

概括 假设背纹状体中的多巴胺D1受体（D1RS）被认为在 甲基苯丙胺（甲基苯丙胺）成瘾和甲基甲基甲基甲基甲基甲基甲基苯丙胺范围（临床相关） 甲基成瘾模型）报告说，甲基化的自我给药会增加D1R的表达 纹状体和全身性D1R阻滞减少了对甲基甲基苯丙胺的反应并减少寻求甲基甲基苯丙胺。系统性D1 冰毒经历的动物中的受体拮抗作用也阻止了适应不良改变的某些方面。 例如甲基菌诱导的ERK1/2在纹状体和甲基奖励中的热磷酸化，表明 通过METH增强ERK1/2是一种细胞内信号转导机制，有助于 与甲基苯丙胺的增强作用相关的不良适应性可塑性。这些研究表明渐进式 甲基甲基苯丙胺摄入的摄入量超过扩展的加固访问时间表可能会导致持续 通过异常增加D1R表达和ERK1/2活性，纹状体的神经生物学改变。 因此，该提案将确定背侧纹状体中的D1RS和ERK1/2活性在 在经历甲基甲基的动物中建立强迫性自我给药，以扩展访问时间表 加固。新证据表明，D1R信号传导发生在离散的浆膜中 微域称为膜/脂质筏。脂质筏富集在胆固醇和鞘脂中，并且 胆固醇结合和脚手架蛋白小窝蛋白1（CAV-1）。 CAV-1对于调节D1R信号传导很重要 营业额和功能。因此，我们还试图确定D1R中表达神经元中的CAV-1是否扮演 在强迫甲基甲基甲基苯丙胺中介导不良适应性行为反应中的作用 上瘾的动物。我们将使用公认的啮齿动物模型来检验这些假设 自我管理以及最先进的遗传和药理学技术来确定D1RS的作用， ERK1/2活性和甲基成瘾中的Cav-1。了解细胞和分子机制 动物模型中背纹状体中的甲基成瘾表现出强迫性行为的 识别减少甲基甲基苯甲酸甲酯和适应不良的治疗干预措施的巨大潜力 寻求甲基苯丙胺的模式。