Caveolins, Striatal Toxicity and Methamphetamine Addiction

总结 背侧纹状体中的多巴胺D1受体（D1 Rs）被假设在以下方面起主要作用： 甲基苯丙胺（Meth）成瘾和Meth摄入的自我给药模式（临床相关 Meth成瘾模型）已经报道了Meth自我给药增加了D1 R在 纹状体和全身性D1 R阻断降低了对甲基苯丙胺的反应并减少了甲基苯丙胺寻求。全身D1 受体拮抗剂在甲基经验的动物也防止了某些方面的适应不良的变化; 例如甲基苯丙胺诱导的纹状体ERK 1/2过度磷酸化和甲基苯丙胺奖赏，表明 METH增强ERK 1/2是一种细胞内信号转导机制， 适应不良的可塑性与甲基苯丙胺的强化作用有关。这些研究表明， 增加摄入量的甲基超过延长访问时间表的加强可能会导致持续的 通过D1 R表达和ERK 1/2活性异常增加引起的纹状体神经生物学改变。 因此，该提案将确定背侧纹状体中的D1 Rs和ERK 1/2活性是否在以下方面发挥作用： 在经历甲基苯丙胺的动物中建立强迫性自我给药， 的强化。新的证据表明，D1 R信号发生在离散的质膜， 称为膜/脂筏的微区。脂筏富含胆固醇和鞘脂， 胆固醇结合和支架蛋白Caveolin-1（Cav-1）。Cav-1在调节D1 R信号传导中是重要的， 营业额和功能。因此，我们也试图确定Cav-1在表达D1 R的神经元中是否起作用。 在介导强迫性甲基苯丙胺服用和寻求中的适应不良行为反应中的作用 上瘾的动物我们将使用完善的啮齿动物模型来测试这些假设， 自我给药和最先进的遗传和药理学技术来确定D1 R的作用， 冰毒成瘾中的ERK 1/2活性和Cav-1。了解细胞和分子机制， 在表现出强迫性行为的动物模型中， 确定治疗干预措施以减少甲基苯丙胺成瘾和适应不良的巨大潜力 寻找冰毒的模式

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.