Electrophysiology of alcohol in extended amygdala

扩展杏仁核中酒精的电生理学

• 批准号: 6798621
• 负责人: GEORGE Robert SIGGINS
• 金额: $ 27.7万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-27 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6798621
• 关键词: GABA receptor; NMDA receptors; alcoholic beverage consumption; alcoholism /alcohol abuse; amygdala; behavioral /social science research tag; cooperative study; corticotropin releasing factor; craving; drug /alcohol abstinence; drug withdrawal; electrophysiology; ethanol; gene targeting; genetically modified animals; glutamate receptor; hormone receptor; laboratory mouse; membrane potentials; nucleus accumbens; opioid receptor; receptor expression; synapses; video microscopy; voltage /patch clamp

DESCRIPTION (provided by applicant): We have pursued electrophysiological studies of the role of synaptic transmitters, neuropeptides and their receptors in alcohol effects, with the rationale that these elements are the most sensitive sites of ethanol action. This project is based on behavioral findings that the nucleus accumbens (Nace) and extended amygdala are key areas in the reinforcing properties of abused drugs, and that these properties also may involve several transmitters (e.g., GABA, glutamate) and neuropeptides (e.g., CRF and opioids). The amygdala has been implicated in motivated behaviors and anxiety states, and it is hypothesized that these same neuropharmacological systems within the extended amygdala mediate the increases in ethanol self-administration that occur during withdrawal from chronic ethanol. Therefore, we propose several sets of experiments: 1) To begin in vitro brain slice studies of acute and chronic ethanol effects on membrane and synaptic properties of central amygdala (CeA) neurons and NAcc neurons in the mouse for comparison to our rat data, and to prepare for studies of murine genetic models. 2) To determine the role of CRF receptors, whose expression may be responsible for excessive alcohol consumption, by examining extended amygdala network and cellular functioning in brain slices taken from mice with knockouts for brain CRF-I receptors. 3) To determine the role of opiate receptors that could be responsible for excessive alcohol consumption, by examining extended amygdala network and cellular functioning in brain slices taken from rnice with knockouts for brain mu opiate and, later, delta opiate receptors. These studies will use amygdala and NAce brain slices and involve standard intracellular (current- and voltage-clamp) and "patch-slice" whole-cell clamp methods. The infrared DIC-videoniieroseopic method will be used to identify morphologically different cells types for comparison to electrophysiological and pharmacological properties. We will record evoked, pharmacologically-isolated monosynaptic currents or potentials, and spontaneous and miniature synaptic events, to test the specificity and site of action of ethanol effects. These studies should provide important new information on possible sequelac of ethanol intoxication at the cellular level, and, by comparisons of ethanol and peptide actions in control, ethanol-withdrawn, protracted abstinence, and knockout models, will also provide clues as to the cellular and ion channel correlates of ethanol dependence.

描述（由申请人提供）： 我们对突触的作用进行了电生理学研究 酒精效应中的递质、神经肽及其受体 理由是这些元素是乙醇作用最敏感的位点。 该项目基于伏隔核（Nace）的行为发现 和扩展的杏仁核是增强受虐待特性的关键区域 药物，并且这些特性也可能涉及多种发射器（例如， GABA、谷氨酸）和神经肽（例如 CRF 和阿片类药物）。杏仁核有 与动机行为和焦虑状态有关，并且 假设这些相同的神经药理学系统在扩展 杏仁核介导乙醇自我施用的增加 从长期乙醇戒断期间。因此，我们提出了几套 实验：1）开始急性和慢性的体外脑切片研究 乙醇对中央杏仁核 (CeA) 膜和突触特性的影响 小鼠神经元和 NAcc 神经元与我们的大鼠数据进行比较，并 为小鼠遗传模型的研究做好准备。 2）确定CRF的作用 受体，其表达可能与过量饮酒有关 通过检查扩展的杏仁核网络和细胞功能来消耗 取自大脑 CRF-I 受体敲除小鼠的脑切片。 3） 确定阿片受体的作用 过度饮酒，通过检查扩展的杏仁核网络和 取自小鼠脑切片的细胞功能，并敲除大脑 mu 阿片受体，后来是 delta 阿片受体。这些研究将使用杏仁核 和 NAce 脑切片并涉及标准细胞内（当前和 电压钳）和“贴片切片”全细胞钳方法。红外线 DIC-视频方法将用于形态学鉴定 不同细胞类型进行电生理比较 药理特性。我们将记录诱发的、药理学隔离的 单突触电流或电位，以及自发和微型突触 事件，以测试乙醇效应的特异性和作用位点。这些 研究应提供有关可能的后遗症的重要新信息 细胞水平的乙醇中毒，并且通过比较乙醇和 肽在对照、乙醇戒断、长期戒断和戒断中的作用 敲除模型，还将提供有关细胞和离子通道的线索 乙醇依赖性的相关性。