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

描述（由申请人提供）：甲基苯丙胺（METH）是一种高度成瘾的精神运动兴奋剂。重复使用METH会增强神经适应，这种适应在停止服药后会持续很长时间。这些适应性的改变促使戒断的吸毒者产生强迫性的寻求毒品和复吸，当吸毒者面对与其吸毒有关的人、地方或事物时，这种现象特别引人注目。该项目的目的是研究5-HT 2受体（5-HT 2 R）和相关的信号蛋白GSKSbeta，作为METH滥用的可能的新药物靶点。在大鼠中的METH诱导的条件性位置偏爱（CPP）将用于有效地模拟人类药物使用方面。由于成瘾治疗需要在成瘾后有效，我们计划在已经表达MET诱导的CPP的大鼠中评估治疗靶点。我们提供了初步数据，其中METH调节可以用米氮平逆转，米氮平是一种对5-HT 2受体具有高亲和力的抗抑郁药。这项研究的总体假设是，5-HT 2拮抗剂将破坏药物奖励记忆的维持，并将补偿和/或逆转在MET条件大鼠中引起的神经适应。提出了三个假设驱动的具体目标。目标I假设：向MET-条件化大鼠全身施用5-HT 2 R拮抗剂和/或GSKS β抑制剂将剂量依赖性地减弱随后对MET-配对环境的偏好。目标II假设：持续性MET诱导的CPP的减弱与AMPA受体的表面表达增加和丝氨酸9位磷酸化的GSKSbeta水平相关。我们将使用一种新的交联试验来确定AMPA受体运输和免疫印迹程序的变化，以检测GSKSbeta的磷酸化状态。目标三假设：METH-条件化大鼠将增强AMPA-介导的神经元兴奋性，在那些区域中AMPA表面表达升高（在Aim II中测定）。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参与转化研究的机会，这将扩大我们对METH成瘾的分子机制的理解，并提出一种新的成瘾治疗策略。这项NRSA拨款也将允许申请人在成瘾神经科学方面获得令人兴奋的新培训机会。总之，METH滥用在美国是一个严重的问题，目前没有有效的治疗方案。该提案的目标是帮助确定潜在的“抗成瘾”药物，以支持从METH成瘾中恢复。

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 These adaptations contribute to compulsive drug-seeking and relapse in the withdrawn addict, phenomena that are particularly compelling when the addict is faced with people, places or things that were associated with their drug use.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.