BENZODIAZEPINE ACTIONS ON ALCOHOL REINFORCEMENT

描述：(改编自申请者摘要)总体目标 本提案旨在鉴定并系统检测苯二氮(BDZ)。 减弱乙醇增强作用的受体配体 (Etoh)。为了实现这一目标，高饮酒(HAD)大鼠和 将采用无水乙醇加固措施。定量受体 放射自显影(QAR)也将用于确定结合亲和力 中枢神经系统(CNS)部位的有效BDZ配体的数量相关 行为影响的大小。要检验的主要假说 某些BDZ反向激动剂和拮抗剂配体是否可以 选择性地减弱乙醇强化的措施；这可能与 它们在安定敏感(DS)时结合，在安定时结合程度较小 GABAA-BDZ受体不敏感(DI)构象。初始剂量效应 时间进程研究将检验药物减弱乙醇的能力。 使用操作法进行摄取。据推测，具有高水平的特工 对DS位点的亲和力将是有效的乙醇拮抗剂；然而，试剂 在DS和DI位置都有高亲和力，应该会产生更强大的 长期的对抗。在第二系列实验中， 脑电刺激奖赏(BSR)将在幼稚的HAD和 低度饮酒(LAD)大鼠。口头(或有)Etoh的作用 还将测试给药与胃内给药(IG)的比较 给HAD大鼠(非偶然性)输液。此外，HAD和LAD大鼠将 比较非或有乙醇对BSR的敏感度 行政管理。据推测，有老鼠会有更低的证据 与LAD大鼠相比，BSR的反应阈值和反应率更高 天真和顺从的非偶然的Etoh。临时Etoh政府是 预计会对BSR产生更积极(兴奋)的作用 在HAD大鼠中的非偶然路线。高效抗乙醇制剂的研究进展 使用最佳Etoh BSR门限路由将在HAD中执行 老鼠。使用QAR，第三系列实验将检验这两种抑制 以及作为乙醇拮抗剂有效的药物的时程曲线 CNS站点。据推测，高效的乙醇拮抗剂应该 有证据表明DS和DI位点有更强的结合可能调节乙醇脱氢酶 加强，这些部位的相互作用可能在一定程度上起调节作用 (间接影响)神经解剖底物的激活 有助于乙醇的增强性能。它更远了 假设行为和约束性时间进程配置文件不会 保持平行。这些研究应该会促进我们对 GABAA-BDZ受体复合体在介导乙醇增强中发挥作用，并可能 导致酒精滥用和酒精中毒治疗方法的发展。

DESCRIPTION: (Adapted from the APPLICANTS ABSTRACT) The overall goal of this proposal is to identify and systematically examine benzodiazepine (BDZ) receptor ligands which attenuate the reinforcing properties of ethanol (ETOH). To accomplish this goal, the high alcohol drinking (HAD) rat and measures of ETOH reinforcement will be used. Quantitative receptor autoradiography (QAR) will also be used to determine if the binding affinity of effective BDZ ligands at central nervous system (CNS) sites correlates with the magnitude of behavioral effects. The main hypothesis to be tested is whether certain BDZ inverse agonist and antagonist ligands can selectively attenuate measures of ETOH reinforcement; this may be related to their binding at diazepam sensitive (DS), and to a lesser degree at diazepam insensitive (DI) conformations of GABAA-BDZ receptors. Initial dose-effect and time course studies will examine the ability of agents to attenuate ETOH intake using operant methodology. It is hypothesized that agents with high affinity for DS sites will be effective ETOH antagonists; however, agents with high affinity at both DS and DI sites should produce more potent and prolonged antagonism. In a second series of experiments, the threshold for electrical brain stimulation reward (BSR) will be compared in naive HAD and low alcohol drinking (LAD) rats. The role of oral (contingent) ETOH administration will also be tested for comparison with intra gastric (IG) (noncontingent) infusions in HAD rats. In addition, HAD and LAD rats will be compared for sensitivity to BSR following noncontingent ETOH administration. It is hypothesized that HAD rats will evidence a lower threshold and higher rate of responding for BSR compared with LAD rats under naive and following noncontingent ETOH. Contingent ETOH administration is expected to yield a more positive (euphoric) action on BSR compared with the noncontingent route in HAD rats. Studies of effective anti-ETOH agents using the optimal ETOH BSR threshold route will then be conducted in HAD rats. Using QAR, a third series of experiments will examine both inhibition and time course profiles of agents found effective as ETOH antagonists at CNS sites. It is hypothesized that highly effective ETOH antagonists should evidence greater binding at DS and DI sites hypothesized to mediate ETOH reinforcement, and that interactions at these sites may mediate in part (indirectly influence) activation of underlying neuroanatomical substrates contributing to the reinforcing properties of ETOH. It is further hypothesized that the behavioral and binding time course profiles will not be parallel. These studies should advance our understanding of the role the GABAA-BDZ receptor complex plays in mediating ETOH reinforcement, and may lead to the development of treatments for alcohol abuse and alcoholism.