Ethanol and mesolimbic GABAergic neurons

乙醇和中脑边缘 GABA 能神经元

• 批准号: 7146489
• 负责人: JIANG-HONG YE
• 金额: $ 22.35万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7146489
• 关键词: action potentials; alcoholism /alcohol abuse; dopamine; drug addiction; ethanol; gamma aminobutyrate; interneurons; ion channel blocker; laboratory rat; limbic system; membrane channels; neural inhibition; neural transmission; neurochemistry; neuroregulation; neurotransmitter transport; potassium channel; psychopharmacology; tegmentum; tissue /cell culture; voltage /patch clamp

DESCRIPTION (provided by applicant): This is an exploratory (R21) grant to examine the role of GABAergic (GABA) neurons in alcohol addiction. The mesolimbic dopamine (DA) system, originating from the ventral tegmental area (VTA), is thought to mediate the reinforcing properties of drugs of abuse, including ethanol. How acute ethanol increases the activity of VTA-DA neurons has not been fully elucidated. The VTA-DA neurons are under the tonic inhibitory control of GAB A neurons. It is well established that some drugs of abuse, such as opioids, excite VTA-DA neurons by inhibiting the GAB A neurons-a mechanism of disinhibition. There is recent in vivo evidence that ethanol inhibits VTA-GABA neurons. Preliminary data indicate that ethanol inhibits VTA-GABA neurons. Importantly, ethanol inhibition of the GAB A neurons is more potent than the excitation of DA neurons. My long-term goal is to identify the cellular mechanisms of alcohol addiction. The objective of this application is to examine the mechanisms by which GAB A neurons mediate the effects of ethanol in the VTA. The central hypothesis is that acute ethanol increases VTA-DA release within the addiction circuit primarily through disinhibition, by suppression of the inhibitory tone of VTA-GABA neurons. The proposed work will combine patch-clamp electrophysiological techniques with pharmacological tests on VTA neurons of rats, either in acute brain slices or in acutely dissociated neurons. Specific aim 1 will test the hypothesis that ethanol inhibits VTA-GABA neurons: this will be done by examining the effects of ethanol on both the spontaneous firing of GABA neurons, and the spontaneous IPSCs (sIPSCs) recorded from DA neurons. Specific aim 2 will test the hypothesis that ethanol inhibition of GABAergic inhibitory tone is more potent than its direct excitatory effect on DA neurons by comparing ethanol's excitatory action on DA neurons with its inhibitory potency on GABA neurons, and by comparing the ethanol-induced increase in VTA-DA cell firing in the presence and absence of synaptic inputs. This aim will also explore whether the inhibition of GABA neurons affects the burst firing of DA neurons. Specific aim 3 will test the hypothesis that ethanol inhibits VTA-GABA inter-neurons by enhancing their K+ currents by comparing ethanol's potency on VTA-GABA cells in the absence and presence of K+ channel blocker(s). The results of this study will characterize a previously under-investigated effect of ethanol on VTA-GABA neurons, and its subsequent indirect effect on VTA-DA neurons. Such results will provide valuable information on novel mechanisms underlying the addictive properties of alcohol and a firm scientific foundation for future neurobiological studies.

描述（由申请人提供）：这是一项探索性（R21）资助，旨在研究GABA能（GABA）神经元在酒精成瘾中的作用。 起源于腹侧被盖区（VTA）的中脑边缘多巴胺（DA）系统被认为介导了滥用药物（包括乙醇）的强化特性。急性乙醇如何增加VTA-DA神经元的活性尚未完全阐明。VTA-DA神经元受GABA神经元的紧张性抑制控制。已经确定的是，某些滥用药物，如阿片类药物，通过抑制GABA神经元来兴奋腹侧被盖区-多巴胺能神经元，这是一种去抑制机制。最近有体内证据表明，乙醇抑制腹侧被盖区-GABA神经元。初步数据表明，乙醇抑制腹侧被盖区-GABA神经元。重要的是，乙醇对GABA神经元的抑制比DA神经元的兴奋更有效。我的长期目标是确定酒精成瘾的细胞机制。本申请的目的是检查GABA神经元介导VTA中乙醇作用的机制。中心假设是，急性乙醇增加VTA-DA释放成瘾回路内主要是通过解除抑制，抑制的VTA-GABA神经元的抑制音。这项工作将联合收割机膜片钳电生理技术与大鼠腹侧被盖区神经元的药理学试验相结合，无论是在急性脑片还是在急性分离的神经元中。具体目标1将检验乙醇抑制VTA-GABA神经元的假设：这将通过检查乙醇对GABA神经元自发放电和从DA神经元记录的自发IPSC（sIPSC）的影响来完成。 具体目标2将通过比较乙醇对DA神经元的兴奋作用与其对GABA神经元的抑制效力，并通过比较在存在和不存在突触输入的情况下乙醇诱导的VTA-DA细胞放电的增加，来检验乙醇抑制GABA能抑制性音调比其对DA神经元的直接兴奋作用更有效力的假设。本研究还将探讨抑制GABA神经元是否影响DA神经元的爆发放电。具体目标3将通过比较在不存在和存在K+通道阻断剂的情况下乙醇对VTA-GABA细胞的效力来检验乙醇通过增强其K+电流来抑制VTA-GABA中间神经元的假设。本研究的结果将表征先前未充分研究的乙醇对VTA-GABA神经元的影响，以及其随后对VTA-DA神经元的间接影响。这些结果将为酒精成瘾特性的新机制提供有价值的信息，并为未来的神经生物学研究奠定坚实的科学基础。