5HT receptors, neuronal plasticity, and methamphetamine-induced place perference.

描述(申请人提供)：甲基苯丙胺(冰毒)是一种高度上瘾的精神兴奋剂。反复服用冰毒会引起神经适应，这种适应会在戒毒后很长一段时间内持续。这些适应有助于戒除吸毒者的强迫寻求药物和复发，当吸毒者面对与其吸毒有关的人、地点或事物时，这种现象尤其引人注目。这个项目的目的是研究5-HT2受体(5-HT2R)和相关的信号蛋白GSKSbeta，作为治疗冰毒滥用的可能的新药物靶点。冰毒诱导的大鼠条件性位置偏爱(CPP)将被用来有效地模拟人类药物使用的各个方面。由于成瘾治疗需要在成瘾后有效，我们计划评估已经表达冰毒诱导CPP的大鼠的治疗靶点。我们提供了米氮平逆转甲基化的初步数据，米氮平是一种对5-HT2受体具有高亲和力的抗抑郁药。这项授权的总体假设是，5-HT2拮抗剂将扰乱药物奖赏记忆的维持，并将补偿和/或逆转冰毒条件下大鼠引发的神经适应。提出了三个假设驱动的具体目标。目的I假设：系统地给冰毒条件大鼠注射5-HT2R拮抗剂和/或GSKSbeta抑制剂，将剂量依赖地减弱随后对冰毒配对环境的偏好。目的II假说：冰毒诱导的持续性CPP的减弱将与AMPA受体表面表达的增加和丝氨酸9位的GSKSbeta磷酸化水平有关。我们将使用一种新的交联法来确定AMPA受体运输的变化，并使用免疫印迹程序来检测GSKSbeta的磷酸化状态。目的III假说：甲基应激大鼠将增强AMPA介导的神经元在AMPAR表面表达升高的神经元的兴奋性(在AIM II中确定)。这将通过全细胞膜片钳电生理学进行评估。使用人类成瘾的啮齿动物模型提供了从事翻译研究的机会，这将扩大我们对冰毒成瘾的分子机制的理解，并提出一种新的成瘾治疗策略。这笔NRSA拨款还将为申请者提供令人兴奋的新的成瘾神经科学培训机会。总而言之，冰毒滥用在美国是一个严重的问题，目前还没有有效的治疗计划。这项提案的目标是帮助确定潜在的“防成瘾”药物，以支持冰毒成瘾的康复。

DESCRIPTION (provided by applicant): Methamphetamine (METH) is a highly addictive psychomotorstimulant. Repeated administration of METH elicits neuroadaptations that last long after drug-taking ceases. These adaptations contribute to compulsive drug-seeking and relapse in the withdrawn addict, phenomena that are particularly compelling when the addict is faced with people, places or things that were associated with their drug use. The purpose of this project is to investigate 5-HT2 receptors (5-HT2R) and an associated signaling protein, GSKSbeta, as possible new medication targets for METH abuse. METH-induced conditioned place preference (CPP) in rats will be used to efficiently model aspects of human drug use. As addiction therapy will need to be effective after one becomes addicted, we plan to evaluate the treatment targets in rats already expressing METH-induced CPP. We provide Preliminary Data where METH-conditioning can be reversed with mirtazapine, an antidepressant with high affinity for 5-HT2 receptors. The overall hypothesis for this grant is that 5-HT2 antagonists will disrupt the maintenance of the drug-reward memory and will compensate and/or reverse the neuroadaptations elicited in METH-conditioned rats. Three hypothesis-driven Specific Aims are proposed. Aim I Hypothesis: Systemic administration of 5-HT2R antagonists, and/or an inhibitor of GSKSbeta, to METH-conditioned rats will dose-dependently attenuate subsequent preference for the METH- paired context. Aim II Hypothesis: Attenuation of persistent METH-induced CPP will correlate with increased surface expression of AMPA receptors and levels of GSKSbeta phosphorylated at the serine 9 position. We will use a novel cross-linking assay to determine changes in AMPA receptor trafficking and immunoblot procedures to detect the phosphorylation state of GSKSbeta. Aim III Hypothesis: METH- conditioned rats will enhance AMPA-mediated excitability of neurons in those regions where AMPAR surface expression was elevated (determined in Aim II). This will be assessed by whole-cell patch clamp electrophysiology. Using a rodent model of human addiction provides opportunity to engage in translational research that will expand our understanding of the molecular mechanisms underlying METH addiction, and suggest a novel addiction treatment strategy. This NRSA grant will also allow the applicant exciting new training opportunities in the neuroscience of addiction. In summary, METH abuse is a serious problem in the United States, with no current effective treatment programs. The goal of this proposal is to help identify potential "anti-addiction" medications that will support recovery from METH addiction.