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

5HT 受体、神经元可塑性和甲基苯丙胺诱导的位置偏好。

基本信息

  • 批准号:
    7777356
  • 负责人:
  • 金额:
    $ 3.58万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-01-01 至 2011-12-31
  • 项目状态:
    已结题

项目摘要

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 These adaptations contribute to compulsive drug-seeking and relapse in the withdrawn addict, phenomena that are particularly compelling when the addict is faced with people, places or things that were associated with their drug use.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.
描述(由申请人提供):甲基苯丙胺(冰毒)是一种高度上瘾的精神运动兴奋剂。反复服用甲基苯丙胺会引起神经适应,这种适应在药物停止服用后持续很长时间。这些适应导致了戒断成瘾者的强迫性药物寻求和复发,当成瘾者面对与他们吸毒有关的人、地方或事物时,这种现象尤其引人注目。本项目的目的是研究5-HT2受体(5-HT2R)和相关的信号蛋白GSKSbeta,作为甲基安非他明滥用的可能的新药物靶点。冰毒诱导的大鼠条件位置偏好(CPP)将用于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才有效,我们计划在已经表达冰毒诱导的CPP的大鼠中评估治疗靶点。我们提供的初步数据表明,甲基甲醚调节可以用米氮平逆转,米氮平是一种对5-HT2受体具有高亲和力的抗抑郁药。这项资助的总体假设是,5-HT2拮抗剂将破坏药物奖励记忆的维持,并将补偿和/或逆转在冰毒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。假设:对冰毒条件下的大鼠全身给予5-HT2R拮抗剂和/或GSKSbeta抑制剂会剂量依赖性地减弱对冰毒配对环境的后续偏好。假设:甲基甲醚诱导的持续性CPP的衰减与AMPA受体表面表达的增加和GSKSbeta丝氨酸9位点磷酸化水平的升高有关。我们将使用一种新的交联试验来确定AMPA受体运输的变化,并使用免疫印迹方法来检测GSKSbeta的磷酸化状态。假设:冰毒条件下的大鼠在AMPAR表面表达升高的区域会增强ampa介导的神经元兴奋性(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参与转化研究的机会,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nssa资助也将为申请人提供令人兴奋的成瘾神经科学方面的新培训机会。总之,滥用冰毒在美国是一个严重的问题,目前没有有效的治疗方案。这项提议的目的是帮助确定潜在的“抗瘾”药物,这些药物将支持从冰毒成瘾中恢复过来。

项目成果

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Steven Michael Graves其他文献

Steven Michael Graves的其他文献

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{{ truncateString('Steven Michael Graves', 18)}}的其他基金

Methamphetamine, mitochondria, and neurodegeneration
甲基苯丙胺、线粒体和神经退行性疾病
  • 批准号:
    10554338
  • 财政年份:
    2021
  • 资助金额:
    $ 3.58万
  • 项目类别:
Methamphetamine, mitochondria, and neurodegeneration
甲基苯丙胺、线粒体和神经退行性疾病
  • 批准号:
    10382336
  • 财政年份:
    2021
  • 资助金额:
    $ 3.58万
  • 项目类别:
Methamphetamine, mitochondria, and neurodegeneration
甲基苯丙胺、线粒体和神经退行性疾病
  • 批准号:
    10209204
  • 财政年份:
    2021
  • 资助金额:
    $ 3.58万
  • 项目类别:
Chronic alcohol-induced mitochondrial oxidant stress and Alzheimer's related pathogenesis
慢性酒精诱导的线粒体氧化应激和阿尔茨海默病相关发病机制
  • 批准号:
    10436351
  • 财政年份:
    2020
  • 资助金额:
    $ 3.58万
  • 项目类别:
Chronic alcohol-induced mitochondrial oxidant stress and Alzheimer's related pathogenesis
慢性酒精诱导的线粒体氧化应激和阿尔茨海默病相关发病机制
  • 批准号:
    10659030
  • 财政年份:
    2020
  • 资助金额:
    $ 3.58万
  • 项目类别:
Chronic alcohol-induced mitochondrial oxidant stress and Alzheimer's related pathogenesis
慢性酒精诱导的线粒体氧化应激和阿尔茨海默病相关发病机制
  • 批准号:
    10264166
  • 财政年份:
    2020
  • 资助金额:
    $ 3.58万
  • 项目类别:
Methamphetamine and Parkinson's disease: converging mechanisms of pathogenesis
甲基苯丙胺和帕金森病:发病机制的融合
  • 批准号:
    9033364
  • 财政年份:
    2016
  • 资助金额:
    $ 3.58万
  • 项目类别:
Methamphetamine and Parkinson's disease: converging mechanisms of pathogenesis
甲基苯丙胺和帕金森病:发病机制的融合
  • 批准号:
    9258419
  • 财政年份:
    2016
  • 资助金额:
    $ 3.58万
  • 项目类别:
L-DOPA-induced dyskinesias and dysregulation of striatopallidal neurons
左旋多巴诱导的运动障碍和纹状体苍白球神经元失调
  • 批准号:
    8758664
  • 财政年份:
    2013
  • 资助金额:
    $ 3.58万
  • 项目类别:
L-DOPA-induced dyskinesias and dysregulation of striatopallidal neurons
左旋多巴诱导的运动障碍和纹状体苍白球神经元失调
  • 批准号:
    8596683
  • 财政年份:
    2013
  • 资助金额:
    $ 3.58万
  • 项目类别:

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