BRAIN SLICE ELECTROPHYSIOLOGY

这个项目将继续研究突触的作用， 乙醇的致醉作用中的递质，并启动 研究酒精成瘾的细胞基质。 的 第一种方法背后的基本原理是大量的文献 显示突触是乙醇作用的最敏感部位， 有证据表明，中毒剂量的乙醇对 多个发射机的功能。 例如，我们的研究 揭示了乙醇对胆碱能和生长抑素能功能的影响， 但对γ-氨基丁酸能的传播没有影响 第二种方法基于 海洛因、可卡因和酒精的行为研究结果表明， 晶核（NAcc）是增强性能的关键区域 这些药物，这些属性也可能涉及几个 候选发射机。 我们建议以下五套 实验：1）继续并完成乙醇对 胆碱能和生长抑素能功能; 2）寻求 乙醇和几个候选发射器在NAcc，使用新的 记录和细胞鉴定方法，以比较乙醇对 不同的神经元细胞类型; 3）测试“抗酒精中毒”的效果 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 的幼稚和乙醇撤回的动物; 4）比较乙醇对 来自乙醇偏好（P）和非乙醇偏好（NP）大鼠的NAcc神经元 由李鲁蒙集团开发的菌株。 这些研究将使用 海马和NAcc脑切片，并涉及标准的细胞内 （电流和电压钳）和新的“膜片”全细胞钳 方法. 强大的新红外DIC-视频显微镜方法将是 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， 确定是否频繁的负面电生理结果， 乙醇-递质相互作用（例如，乙醇-GABA）从细胞中产生 抽样问题。 其他待检验的候选发射机 乙醇相互作用或模仿主要包括谷氨酸，多巴胺， 和5-羟色胺（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以稍后测试。 我们认为 这些研究不仅将提供重要的新信息， 酒精中毒的后遗症在细胞水平上，但是，凭借 比较乙醇和Ca-AOTA在正常、P和NP大鼠中的作用， 还提供了细胞和离子通道相关的线索， 酒精依赖

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AOTAL; acamprosate) on membrane properties and neurotransmission in hippocampal and NAcc neurons of naive and ethanol-withdrawn animals; 4) compare ethanol effects on NAcc neurons from the ethanol-preferring (P) and non-preferring (NP) rat strains developed by the Li-Lumeng group.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.