NEURONAL AND NEUROTRANSMITTER ACTIONS OF ETHANOL

这项提案将研究神经元和神经递质机制。 乙醇(ET)中毒和戒断(ETX)的潜在影响。 ET可作用于多个脑区，包括下丘(IC)和 桥脑网状结构(PRF)，以产生其影响。反弹 这些领域的活动可能会对ETX做出重要贡献。一个重要的 ETX综合征的潜在危险特征是全身性补药- 克隆性癫痫发作。在大鼠ETX中观察到的癫痫发作包括自发的 和听源性癫痫(AGS)。目前的证据表明，ET可能 增强GABA的作用，减少兴奋性氨基酸的作用 (EaaS)。ETX可能是EAA激发和EAA的反弹增加所致 减少这些途径中的GABA抑制。拟议的研究将 通过记录单次记录来研究ET活动中涉及的神经机制 行为动物和微量注射药物的神经元反应模式 影响GABA和EAA对IC和PRF的作用。初步研究 表明向IC内微量注射EAA拮抗剂和PRF将阻断 ETX癫痫发作。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 在中毒期间下降，在ETX期间出现高反应性。一个 高强度的PRF神经元的听觉反应显著增加 看到了。这些变化可能涉及ET介导的GABA和/或 支配神经元反应的EAA作用。因此，我们建议 比较离子导入应用氨基酸的效果 动物前、中、后中脑内核神经元的神经递质 长期给予ET，观察ET诱导的变化。集成电路和 PRF对于遗传性癫痫所表现出的AGS的启动至关重要- 俯卧率(GEPR)。最近的工作描绘了神经元和 GEPR中AGS的神经递质机制可能与 ETX期间癫痫发作。抑制缺陷与神经元异常放电 在GPRs的IC和PRF中观察到了与 AGS易感性，我们的初步实验表明类似 机制也可能在ETX期间运行。GABA和EAA的变化 在GPR中也观察到IC中的作用，BE也观察到这些机制 类似于ETX期间发生的变化。因此，这项提案旨在 扩展我们对单一单元记录和聚焦的初步研究 ET给药前、给药中及ETX期间微量输注的研究 提高对重大公共卫生问题的认识 由于ET的过度使用。

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.