BRAIN SLICE ELECTROPHYSIOLOGY

脑切片电生理学

• 批准号: 6233815
• 负责人: GEORGE Robert SIGGINS
• 金额: $ 19.22万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-12-01 至 1997-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6233815
• 关键词: acetylcholine; action potentials; alcoholism /alcohol abuse; alcoholism antagonist; charge coupled device camera; digital imaging; dopamine; drug interactions; electrophysiology; ethanol; evoked potentials; gamma aminobutyrate; genetic strain; glutamates; hippocampus; infrared microscopy; laboratory rat; membrane potentials; microscopy; neural transmission; neuropharmacology; neurotransmitter metabolism; neurotransmitter receptor; nucleus accumbens; preference; reinforcer; serotonin; synapses; video recording system; voltage /patch clamp

This project will continue cellular studies of the role of synaptic transmitters in the intoxicating effects of ethanol, and initiate investigations on the cellular substrate of alcohol addiction. The rationale behind the first approach is the considerable literature showing the synapse to be the most sensitive site of ethanol action, and evidence for pronounced effects of intoxicating doses of ethanol on the functions of several transmitters. For example, our studies have revealed ethanol effects on cholinergic and somatostatinergic function, but not on GABAergic transmission. The second approach is based on behavioral findings with heroine, cocaine and alcohol, suggesting that the nucleus accumbens (NAcc) is a key area in the reinforcing properties of these drugs, and that these properties also may involve several transmitter candidates. We propose the following five sets of experiments: 1) continue and complete tests of ethanol effects on cholinergic and somatostatinergic function; 2) seek interactions between ethanol and several transmitter candidates in the NAcc, using new recording and cell identification methods to compare ethanol effects in different neuronal cell types; 3) test effects of the 'anti-alcoholism' drug Ca-AOTA (calcium-acetylhomotaurinate; AOTAL; acamprosate) on membrane properties and neurotransmission in hippocampal and NAcc neurons of naive and ethanol-withdrawn animals; 4) compare ethanol effects on NAcc neurons from the ethanol-preferring (P) and non-preferring (NP) rat strains developed by the Li-Lumeng group. These studies will use hippocampal and NAcc brain slices and involve standard intracellular (current- and voltage-clamp) and new "patchslice" whole-cell clamp methods. The powerful new infrared DIC-videomicroscopic method will be used to clearly distinguish morphologically different cells types for comparison of electrophysiological and pharmacological properties and to determine if the frequent negative electrophysiological findings of ethanol-transmitter interactions (e.g., ethanol-GABA) arise from cell sampling problems. Other transmitter candidates to be examined for ethanol interactions or mimicry include primarily glutamate, dopamine, and serotonin (5-HT), transmitters under study by other ARC units, although acetylcholine and somatostatin may be tested later. We believe these studies will not only provide important new information on possible sequelae of ethanol intoxication at the cellular level, but, by virtue of comparisons of ethanol and Ca-AOTA actions in normal, P and NP rats, may also provide clues as to the cellular and ion channel correlates of ethanol dependence.

该项目将继续对突触作用进行细胞研究 乙醇中毒作用的递质，并启动 酒精成瘾的细胞基质的研究。 这 第一种方法背后的基本原理是大量文献 显示突触是乙醇作用最敏感的位点，并且 有证据表明，致醉剂量的乙醇对人体有显着影响 几个发射器的功能。 例如，我们的研究有 揭示了乙醇对胆碱能和生长抑素能功能的影响， 但不适用于 GABAergic 传输。 第二种方法基于 海洛因、可卡因和酒精的行为发现表明 伏隔核 (NAcc) 是增强特性的关键区域 这些药物的特性，并且这些特性也可能涉及几个 发射机候选人。 我们提出以下五套 实验：1）继续并完成乙醇对人体影响的测试 胆碱能和生长抑素能功能； 2）寻求之间的相互作用 乙醇和 NAcc 中的几个候选发射器，使用新的 比较乙醇效应的记录和细胞识别方法 不同的神经元细胞类型； 3）测试“解酒”效果 药物 Ca-AOTA（乙酰高牛磺酸钙；AOTAL；阿坎酸） 海马和 NAcc 神经元的膜特性和神经传递 幼稚动物和乙醇戒断动物； 4) 比较乙醇对 来自乙醇偏好 (P) 和非偏好 (NP) 大鼠的 NAcc 神经元 由Li-Lumeng小组开发的菌株。 这些研究将使用 海马和 NAcc 脑切片并涉及标准细胞内 （电流和电压钳）和新的“patchslice”全细胞钳 方法。 强大的新型红外 DIC-视频显微方法将 用于清楚地区分形态上不同的细胞类型 电生理学和药理学特性的比较 确定是否经常出现阴性电生理结果 乙醇-递质相互作用（例如乙醇-GABA）由细胞产生 抽样问题。 其他待检查的发射机候选者 乙醇相互作用或模仿主要包括谷氨酸、多巴胺、 和血清素 (5-HT)，其他 ARC 单位正在研究的递质， 尽管乙酰胆碱和生长抑素可能稍后进行测试。 我们相信 这些研究不仅将提供有关可能的重要新信息 乙醇中毒在细胞水平上的后遗症，但是，凭借 正常大鼠、P 大鼠和 NP 大鼠中乙醇和 Ca-AOTA 作用的比较可能 还提供了细胞和离子通道相关性的线索 乙醇依赖。