Time resolution of ethanol-induced neurotransmission

乙醇诱导的神经传递的时间分辨率

• 批准号: 6921517
• 负责人: JOANNA PERIS
• 金额: $ 30.46万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-12 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6921517
• 关键词: acamprosate; alcoholic beverage consumption; alcoholism /alcohol abuse; amygdala; behavioral /social science research tag; capillary electrophoresis; craving; dopamine; drug administration routes; drug withdrawal; electrolyte balance; ethanol; glutamates; ion channel blocker; laboratory rat; microdialysis; neural transmission; neuropharmacology; nucleus accumbens; reinforcer; relapse /recurrence; taurine; tetrodotoxin; acamprosate; alcoholic beverage consumption; alcoholism /alcohol abuse; amygdala; behavioral /social science research tag; capillary electrophoresis; craving; dopamine; drug administration routes; drug withdrawal; electrolyte balance; ethanol; glutamates; ion channel blocker; laboratory rat; microdialysis; neural transmission; neuropharmacology; nucleus accumbens; reinforcer; relapse /recurrence; taurine; tetrodotoxin

DESCRIPTION (provided by applicant): Ethanol is able to increase neuronal firing in the mesolimbic dopamine pathways associated with drug addiction. Repeated ethanol treatment can change the activity of these neurons and that of other related pathways such that stimuli associated with alcohol use can induce cravings and increase the probability of relapse to drinking. Acamprosate, a calcium homologue of taurine, has been shown to decrease craving and relapse in abstinent alcoholics, suggesting an action on neurotransmitter signaling in these areas. Preliminary data for the proposed experiments indicates that both injected and self-administered ethanol increase dopamine and taurine levels in the nucleus accumbens (Nac), the terminal area of the mesolimbic pathway. Interestingly, only self-administered ethanol (not injected ethanol) consistently results in an increase in glutamate release in Nac. We hypothesize that alterations in ethanol-induced increases in taurine levels in Nac may be a media in ism for inducing persistent alcohol cravings via an interaction with dopamine and glutamate efflux. This proposal describes a series of experiments that will characterize the mechanism for the ethanol-induced efflux of glutamate, taurine and dopamine in Nac and other limbic regions as well as determine the relationship between these neurotransmitters and changes in the "non-transmitter" amino acid environment caused by ethanol. Comparing the effect of a low dose of injected ethanol in na'ive and ethanoltrained rats will allow distinction of alterations in these relationships by the induction of self-administration (the first step in the process of alcohol addiction) as well as progression to more alcoholic-like behaviors. Using capillary electrophoresis coupled with laser-induced fluorescence detection, the effects of low doses of ethanol on the levels of at least 10 amino acids plus dopamine in brain regions important for mediating ethanol self-administration (Nac, central nucleus of the amygdala) and striatum as a control region, will be measured. The very high time resolution (in seconds) provided by this methodology will allow us to distinguish changes in neurotransmitter levels during anticipation of ethanol versus that caused pharmacologically by consuming ethanol. Since the anticipation of ethanol is a likely component of craving and relapse to alcohol, this approach will provide new information about the involvement of changes in neurotransmitter release in alcohol relapse so that more effective strategies can be developed for the successful treatment of ethanol abuse.

描述（由申请人提供）：乙醇能够增加与药物成瘾相关的中唇多巴胺途径中的神经元射击。重复的乙醇处理可以改变这些神经元的活性和其他相关途径的活性，即与酒精使用相关的刺激可以引起渴望并增加饮酒复发的可能性。牛磺酸的钙同源物阿克罗酸盐已被证明会减少戒烟的渴望和复发，这表明对这些区域的神经递质信号传导作用。提出的实验的初步数据表明，注射和自我管理的乙醇都会增加伏隔核（NAC）（NAC）的牛磺酸水平，这是中龙途径的末端面积。有趣的是，只有自我管理的乙醇（未注射乙醇）始终导致NAC中谷氨酸释放的增加。我们假设NAC中乙醇诱导的牛磺酸水平升高的改变可能是ISM中通过与多巴胺和谷氨酸外排相互作用引起持续酒精渴望的培养基。该提案描述了一系列实验，这些实验将表征NAC和其他边缘区域中乙醇引起的谷氨酸，牛磺酸和多巴胺的外排的机制，并确定这些神经递质的关系以及这些神经递质之间的关系以及“非透射剂”氨基酸环境引起的氨基酸环境的变化。比较低剂量的注射乙醇在Na'ive和乙醇训练的大鼠中的影响，将通过诱导自我给药（酒精成瘾过程的第一步）以及对更含酒精的行为的进展来区分这些关系的改变。使用毛细管电泳与激光诱导的荧光检测结合在一起，低剂量乙醇对至少10个氨基酸和多巴胺的水平的影响对于介导乙醇自我加入至关重要（NAC，NAC，NAC，NAC，amygdala的中央核）和纹状体和纹状体的对照区域，将是测量的。这种方法提供的非常高的时间分辨率（以秒为单位）将使我们能够在预期乙醇期间与通过食用乙醇引起的药理作用，从而区分神经递质水平的变化。由于对乙醇的预期很可能是渴望和对酒精复发的组成部分，因此这种方法将提供有关神经递质释放变化在酒精复发中的变化的新信息，因此可以制定更有效的策略来成功治疗乙醇滥用。