BENZODIAZEPINE ACTIONS ON ALCOHOL REINFORCEMENT

描述：（改编自申请人摘要） 本研究旨在鉴别和系统检测苯二氮卓类药物（BDZ）， 削弱乙醇增强性能的受体配体 （ETOH）。 为了实现这一目标，高酒精饮酒（HAD）大鼠和 将采用ETOH加固措施。 定量感受器 还将使用放射自显影（QAR）来确定结合亲和力 中枢神经系统（CNS）部位有效BDZ配体的数量与 行为影响的大小。 待检验的主要假设 某些BDZ反向激动剂和拮抗剂配体是否可以 选择性地减弱ETOH强化措施;这可能与 它们与地西泮敏感（DS）结合，与地西泮结合程度较低 GABAA-BDZ受体的不敏感（DI）构象。 初始剂量效应 时间进程研究将检验药剂减弱ETOH的能力 使用操作方法的摄入量。 据推测，具有高浓度的药物 对DS位点的亲和力将是有效的ETOH拮抗剂;然而， 在DS和DI位点都具有高亲和力， 长期对抗 在第二系列实验中， 脑电刺激奖励（BSR）将在幼稚HAD中进行比较， 低酒精饮酒（LAD）大鼠。 口服（应急）ETOH的作用 还将测试给药以与胃内（IG） （非偶然）输注HAD大鼠。 此外，HAD和LAD大鼠将 比较非偶然ETOH后BSR的敏感性 局 假设HAD大鼠将表现出较低的 与LAD大鼠相比， 初始和非偶然性ETOH。 应急ETOH管理是 预期对BSR产生更积极的（欣快）作用， HAD大鼠的非偶然途径。 有效抗ETOH药物的研究 使用最佳ETOH BSR阈值路由将在HAD中进行 大鼠 使用QAR，第三个系列的实验将检查两种抑制 和时程曲线的药物发现有效的ETOH拮抗剂， CNS部位。 据推测，高效ETOH拮抗剂应 证据表明DS和DI部位的结合更强，假设介导ETOH 这些位点的相互作用可能部分介导了 （间接影响）潜在神经解剖基质的激活 有助于ETOH的增强性能。 进一步 假设行为和约束时间过程曲线不会 是平行的。 这些研究应该促进我们对 GABAA-BDZ受体复合物在介导ETOH强化中起作用，并且可能 导致酒精滥用和酒精中毒治疗的发展。

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.