GABA RECEPTOR MECHANISMS IN ALCOHOL REINFORCEMENT

越来越多的证据表明GABAA-苯二氮卓(BDZ)受体参与乙醇自我给药的调节。这项建议的目的是确定介导乙醇强化的GABAA-BDZ神经传递的特定神经生物学底物。为了实现这一目标，将使用选择性培育的高酒精饮酒(HAD)1和2大鼠品系。有待检验的主要假设是，杏仁核两个延伸部位[如杏仁中央核、终纹床核]上的GABAA-BDZ神经解剖回路，在一定程度上介导了潜在神经解剖底物的激活，有助于乙醇的增强特性。首先，量效和时程研究将考察在杏仁中央核和终纹床核的部位特异性注射高亲和力BDZ反向激动剂、BDZ拮抗剂和GABA A拮抗剂SR 95531的能力，以减少乙醇摄取的程序控制反应(即操作法)。假设具有相似结合亲和力的反向激动剂和拮抗剂应该与乙醇拮抗剂同样有效。有效的乙醇维持反应的拮抗剂(即反向激动剂)应该被竞争性的BDZ拮抗剂拮抗，因为它们的抑制应该通过GABAA复合体的BDZ组分的直接作用来介导。其次，为了系统地评价这些药物抑制乙醇激发的反应的选择性，将采用四阶段行为分析。假设特定影响乙醇增强方面的药物(例如反向激动剂、BDZ拮抗剂、SR 95531)不应改变具有类似增强效果(即糖精)或类似摄入后热量特性(即蔗糖)的替代增强剂的反应。最后，假设GABAA-BDZ位点的相互作用可能调节维持乙醇寻找行为的单胺能神经元的功能。这些研究将有助于科学地理解GABAA-BDZ受体复合体在调节乙醇寻找行为中所起的作用。

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.