GABAERGIC ADAPTATION IN ETHANOL TOLERANCE AND DEPENDENCE

功能耐受和身体依赖被认为涉及 中枢神经系统(CNS)的适应性变化作为对 延长了酒精引起的抑郁。对这些机制的理解 已被认为对发展 酒精中毒的理性治疗。实验证据支持 由抑制剂介导的神经传递增加的假说 递质，伽马氨基丁酸(GABA)，在一定程度上负责 乙醇诱导的中枢神经系统抑制。相反，也有可能 乙醇持续治疗引起代偿性GABA能 缺乏活力才能发展。这一行动的后果被认为是 是双重的。功能耐受性是由于能力减弱造成的。 乙醇来激活GABA能传递。身体上的依赖和 与酒精戒断相关的中枢神经系统，由于 GABA能引起的中枢神经系统兴奋抑制活性失衡 在没有乙醇的情况下活性低下。本提案将试图 从三个方面评价这一假说的功能效度。 第一，从药理上激活GABA能的作用 将对长期酒精治疗期间的神经传递进行研究。如果 假设是正确的，那么对乙醇和身体的功能耐受性 应该加速依赖。二、长期药理作用 GABA能传递的激活应导致功能耐受 并导致类似于酒精戒断的迹象，如果假设 是正确的。最后，单边激活引起的旋转行为 GABA激动剂对黑质GABA受体的影响将用于 评估单剂量或多剂量乙醇对 突触后GABA受体的功能能力。这些结果将 确定GABA受体是否发生了功能上的重大变化， 如果这些都与急性和慢性影响相一致 乙醇对中枢神经系统兴奋性的影响。

Functional tolerance and physical dependence are thought to involve adaptive changes in the central nervous system (CNS) as compensation for prolonged ethanol-induced depression. An understanding of these mechanisms has been considered to have important implications for the development of a rational therapy of alcoholism. Experimental evidence supports the hypothesis that increased neurotransmission mediated by the inhibitor transmitter, gamma-aminobutyric acid (GABA), is responsible in part for ethanol-induced CNS depression. Conversely, it is also likely that continuous treatment with ethanol causes a compensatory GABAergic hypoactivity to develop. The consequences of this action are believed to be two-fold. Functional tolerance would result from a diminished ability of ethanol to activate GABAergic transmission. Physical dependence and ethanol withdrawal-related, CNS, hyperexcitability would occur due to an imbalance in CNS excitatory-inhibitory activity caused by GABAergic hypodactivity in the absence of ethanol. The present proposal will attempt to evaluate the functional validity oif this hypothesis in three ways. First, the effect of pharacologically activating GABAergic neurotransmission during long-term ethanol treatment will be studied. If the hypothesis is correct then functional tolerance to ethanol and physical dependence should be accelerated. Second, long-term pharmacological activation of GABAergic transmission should result in functional tolerance to ethanol and cause signs similar to ethanol withdrawal if the hypothesis is correct. Finally, rotational behavior caused by unilateral activation of substantia nigra GABA receptors by GABA agonists will be used to evaluate the effects of a single or multiple doses of ethanol on the functional capacity of postsynaptic GABA receptors. These results will determine wehther functionally significant changes in GABA receptors occur, and if these are consistent with both the acute and chronic effecs of ethanol on CNS excitability.