GABA RECEPTOR MECHANISMS IN ALCOHOL REINFORCEMENT

越来越多的证据表明GABAA-苯二氮卓类（BDZ）受体参与EtOH自我给药的调节。 本提案的目的是确定GABAA-BDZ神经传递介导EtOH强化的特定神经生物学底物。 为了实现这一目标，将使用选择性繁殖的高酒精饮酒（HAD）1和2大鼠品系。 待检验的主要假设是两个延伸杏仁核位点中的GABAA-BDZ神经解剖回路[例如，杏仁核的中央核、终纹的床核]，部分地介导有助于EtOH的增强性质的潜在神经解剖学底物的激活。 首先，剂量-效应和时间过程研究将检查在杏仁核的中央核和终纹的床核中位点特异性显微注射高亲和力BDZ反向激动剂、BDZ拮抗剂和GABAA拮抗剂SR 95531以使用预定的控制响应（即，操作方法）。 假设具有相似结合亲和力的反向激动剂和拮抗剂应与EtOH拮抗剂同样有效。 有效的拮抗剂（即，EtOH维持的反应的反向激动剂）应该被竞争性BDZ拮抗剂拮抗，因为它们的抑制应该通过对GABAA复合物的BDZ组分的直接作用来介导。 其次，为了系统地评价抑制EtOH激发反应的药物的选择性，将采用4阶段行为分析。 假设代理（例如，反向激动剂，BDZ拮抗剂，SR 95531），其特异性地影响EtOH的增强方面，不应改变具有类似增强功效的替代性增强剂的响应（即，糖精），或类似的摄入后热量特性（即，蔗糖）。最后，假设GABAA-BDZ位点的相互作用可以调节维持EtOH寻求行为的单胺能神经元的功能。 这些研究有助于科学地理解GABAA-BDZ受体复合物在调节EtOH寻求行为中的作用。

There is increasing evidence that GABAA-benzodiazepine (BDZ) receptors are involved in the regulation of EtOH-self- administration. The goal of this proposal is to identify specific neurobiological substrates of GABAA-BDZ neurotransmission which mediate EtOH reinforcement. To accomplish this goal, the selectively bred high alcohol drinking (HAD) 1 and 2 rat lines will be used. The main hypothesis to be tested is that GABAA-BDZ neuroanatomical circuits in two extended amygdala loci [e.g., central nucleus of the amygdala, bed nucleus of the stria terminalis], mediate in part, activation of underlying neuroanatomical substrates contributing to the reinforcing properties of EtOH. First, dose-effect and time course studies will examine the capacity of site-specific microinjections of high affinity BDZ inverse agonists, a BDZ antagonist and the GABAA antagonist SR 95531 in the central nucleus of the amygdala and bed nucleus of the stria terminalis to attenuate EtOH intake using scheduled controlled responding (i.e., operant methodology). It is hypothesized that inverse agonists and antagonists with similar binding affinity should be equally effective as EtOH antagonists. Effective antagonists (i.e., inverse agonists) of EtOH-maintained responding should be antagonized by competitive BDZ antagonist, since their suppression should be mediated by a direct action at the BDZ component of the GABAA complex. Second, to systematically evaluate the selectivity of the agents to suppress EtOH-motivated responding, a 4-stage behavioral analysis will be employed. It is hypothesized that agents (e.g., inverse agonists, BDZ antagonist, SR 95531) which specifically affect the reinforcing aspects of EtOH should not alter responding of alternative reinforcers with similar reinforcing efficacy (i.e., saccharin), or similar post-ingestional caloric properties (i.e., sucrose). Finally, it is hypothesized that interactions at GABAA-BDZ sites may modulate the function of monoaminergic neurons sustaining EtOH-seeking behaviors. These studies should contribute to a scientific understanding of the role of GABAA-BDZ receptor complex plays in regulating EtOH seeking behavior.