GABA RECEPTOR MECHANISMS IN ALCOHOL REINFORCEMENT

越来越多的证据表明gabaa -苯二氮卓（BDZ）受体参与了etoh自我给药的调节。本研究的目的是确定GABAA-BDZ神经传递中介导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用（HAD） 1和2大鼠系。待验证的主要假设是，GABAA-BDZ神经解剖回路在两个扩展的杏仁核位点（例如，杏仁核中央核，终纹床核）中，部分介导底层神经解剖底物的激活，从而促进EtOH的增强特性。首先，剂量效应和时间过程研究将检验在杏仁核中央核和终纹床核中使用预定控制反应（即操作方法）微量注射高亲和力BDZ逆激动剂、BDZ拮抗剂和GABAA拮抗剂SR 95531的能力。假设具有相似结合亲和力的逆激动剂和拮抗剂应该与EtOH拮抗剂同样有效。etoh维持应答的有效拮抗剂（即逆激动剂）应该被竞争性BDZ拮抗剂拮抗，因为它们的抑制应该通过GABAA复合物的BDZ组分的直接作用来介导。其次，为了系统地评估代理人抑制etoh动机反应的选择性，将采用四阶段行为分析。据推测，特异性影响EtOH强化方面的药物（如逆激动剂、BDZ拮抗剂、SR 95531）不应改变具有类似强化效果的替代强化剂（如糖精）或类似的摄入后热量特性（如蔗糖）的反应。最后，假设GABAA-BDZ位点的相互作用可能调节单胺能神经元维持eth寻求行为的功能。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.