NEURONAL AND NEUROTRANSMITTER ACTIONS OF ETHANOL

这项建议将探讨神经元和神经递质的机制 乙醇（ET）中毒和戒断（ETX）的影响。 ET可以作用于几个脑区域，包括下丘（IC）和下丘脑。 脑桥网状结构（PRF），以产生其影响。 反弹 这些领域的活动可能对ETX有重要贡献。 一个重要 ETX综合征的潜在危险特征是全身强直性- 阵挛性癫痫 在大鼠ETX中观察到的癫痫发作包括自发性癫痫发作， 和听源性癫痫发作（AGS）。 目前的证据表明，ET可能 增强GABA的作用，降低兴奋性氨基酸的作用 （EAA）。 ETX可能由EAA兴奋的反弹增加引起， 减少GABA对这些通路的抑制。 拟议的研究将 通过记录单个信号来检查ET作用的神经机制。 行为动物的神经元反应模式和显微注射试剂 影响GABA和EAA对IC和PRF的作用。 初步研究 表明将EAA拮抗剂微量注射到IC中，PRF将阻断 内毒素抽搐 初步的单一单位记录研究表明， 自由活动大鼠IC和PRF神经元的听觉反应性 在中毒时下降，在ETX时反应过度。 一 在高强度下，PRF神经元的听觉反应急剧上升， 见过 这些变化可能涉及ET介导的GABA和/或 EAA控制神经元反应的作用。 因此，我们建议 比较离子导入氨基酸的效果 神经递质对IC神经元的动物之前，期间和之后 慢性ET给药，观察ET引起的变化。 IC和 PRF对于遗传性癫痫表现出的AGS的启动至关重要- 倾向率（GEPRs）。 最近的工作描绘了神经元和 GEPRs中AGS的神经递质机制可能与 内毒素治疗时癫痫发作 抑制缺陷和异常神经元放电 在GEPR的IC和PRF中观察到了模式， AGS易感性，我们的初步实验表明，类似的 机制也可以在ETX期间起作用。 GABA和EAA的变化 在GEPRs中也观察到IC中的作用，这些机制是通过 类似于在ETX期间发生的变化。 因此，这项建议旨在 扩展我们对单单位记录和聚焦的初步研究 ET给药前和给药期间以及ETX给药期间的微量输注研究 提高我们对重大公共卫生问题的认识， 过度使用ET。

This proposal will investigate neuronal and neurotransmitter mechanisms underlying the effects of ethanol (ET) intoxication and withdrawal (ETX). ET may act at several brain regions, including inferior colliculus (IC) and pontine reticular formation (PRF), to produce its effects. Rebound activity in these areas may contribute importantly to ETX. An important and potentially dangerous feature of the ETX syndrome is generalized tonic- clonic seizures. The seizures observed in ETX of rats include spontaneous and audiogenic seizures (AGS). Current evidence indicates that ET may enhance GABA's action and decrease the action of excitant amino acids (EAAs). ETX may result from rebound increases in EAA excitation and decreases in GABA inhibition in these pathways. The proposed studies will examine neural mechanisms involved in ET's actions by recording single neuron response patterns in behaving animals and by microinjecting agents affecting GABA and EAA action into IC and PRF. Preliminary studies indicate that microinjection of EAA antagonists, into IC an PRF will block ETX seizures. Preliminary single unit recording studies indicate that auditory responsiveness in IC and PRF neurons in freely moving rats declines during intoxication and hyperresponsiveness during ETX. A dramatic rise in the auditory responses of PRF neurons at high intensity is seen. These changes may involve ET-mediated alterations in GABA and /or EAA actions that govern neuronal responses. Therefore, we propose to compare the effects of iontophoretically applied amino acid neurotransmitters onto IC neurons in animals before, during and after chronic ET administration to observe for ET-induced changes. The IC and PRF are vital for the initiation of AGS exhibited by genetically epilepsy- prone rate (GEPRs). Recent work has delineated neuronal and neurotransmitter mechanisms in AGS in GEPRs which may be relevant to seizures during ETX. Inhibition deficits and abnormal neuronal firing patterns have been observed in IC and PRF of GEPRs which is associated with AGS susceptibility, and our preliminary experiments suggest that similar mechanisms may also be operative during ETX. Alterations in GABA and EAA action in the IC are also observed in GEPRs, and these mechanisms by be similar to changes that occur during ETX. Thus, this proposal seeks to extend our preliminary studies on single unit recording and focal microinfusion studies before and during ET administration and during ETX to improve our understanding of the important public health problem produced by the excessive ET use.