GABAa Receptor Subunits in Alcohol Reinforcement

GABAa 受体亚基在酒精强化中的作用

• 批准号: 6745072
• 负责人: Harry L June
• 金额: $ 22.92万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6745072
• 关键词: GABA receptor; alcoholism /alcohol abuse; ethanol; genetically modified animals; hippocampus; laboratory mouse; laboratory rat; microinjections; neuropharmacology; psychological reinforcement; receptor binding; receptor expression; receptor sensitivity; substance abuse related behavior

DESCRIPTION (provided by applicant): The goal of this proposal is to evaluate the role of the alphal and alpha5 GABAA receptor subunits in EtOH reinforcement. To accomplish this, the high alcohol drinking (HAD) rat lines, the alphal knock out (KO) mice and their wild type counter part (WT) will be used. The first hypothesis to be tested is whether postsynaptic alpha1 receptors in the ventral pallidum (VP) of HAD rats contribute to the reinforcing properties of EtOH. Site-specific microinjection of selective alphal antagonists in the VP will be evaluated for their capacity to attenuate EtOH-maintained responding. It is hypothesized that the alphal antagonist will selectively decrease EtOH responding since the alphal subunit is present in very high levels throughout the VP. The second hypothesis will evaluate the degree to which complete deletion of the alphal subtype modulates acquisition of alcohol-seeking behaviors using the KO and WT mice. It is hypothesized that the KO mice will initiate alcohol-maintained responding because alcohol reward has been shown to be regulated by multiple neurotransmitter systems; however, the drinking in the KO mice is predicted to be significantly lower than the WT. Moreover, we hypothesize that the magnitude of reduction with alphal antagonists in the KOs will be less than that seen in the WT because the KOs will be devoid of a functional alphal subunit. The third specific aim will test the hypothesis that enhanced alphal binding selectivity, longer lived in vivo and more water soluble ligands will result in a more optimal alcohol antagonist. Finally, the fourth hypothesis will assess whether alpha5 receptors in the hippocampus (CA1 and CA3) modulate putative GABAergic EtOH reward substrates (e.g., nucleus accumbens, basal amygdala, bed nucleus of the stria terminalis). To accomplish this, microinjection of selective alpha5 inverse agonists in the hippocampus to attenuate EtOH-maintained responding will be evaluated. We hypothesized that the alpha5 ligands will selectively decrease EtOH responding in the hippocampus since the alpha5 containing receptors are primarily localized in the hippocampus. In contrast, the selective alpha5 ligands infused in the VP will not alter EtOH responding, since this locus is completely devoid of alpha5 subunits, and the ligands have a very low affinity for the alphal receptor subtype. These studies should further our understanding of the GABAA receptor mechanisms in EtOH-seeking behavior and may possibly identify agents which may have potential in reducing alcohol drinking in humans.

描述（由申请人提供）：该提案的目的是评估 α5GABAA受体亚基在ETOH中的作用 加强。为此，高饮酒（有）老鼠线， α敲除（KO）小鼠及其野生型柜台（wt）将是 用过的。要检验的第一个假设是突触后α1是否 大鼠的腹侧胸膜（VP）中的受体有助于 ETOH的增强特性。选择性的特定于现场的显微注射 VP中的α拮抗剂将评估其衰减的能力 ETOH维护的响应。假设α拮抗剂将 由于α亚基存在于 在整个副总裁中非常高。第二个假设将评估 alphal子类型的完全删除的程度调节采集 使用KO和WT小鼠寻求酒精行为的行为。假设 KO小鼠将发起维持饮酒的响应，因为酒精奖励 已显示由多个神经递质系统调节；然而， 预计KO小鼠中的饮酒明显低于WT。 此外，我们假设α的减少幅度 KOS中的拮抗剂将小于WT中的拮抗剂，因为KOS 将没有功能性α亚基。第三个特定目标将测试 增强α结合选择性，体内寿命更长的假设 更多的水溶性配体将导致更优化的酒精 对手。最后，第四个假设将评估α5受体是否 在海马（CA1和CA3）中 底物（例如，伏隔核，基底杏仁核，纹状体的床核 终端）。为此，选择性alpha5反向显微注射 海马中的激动剂减弱ETOH维护的反应将是 评估。我们假设α5配体将有选择地减少 由于含有α5受体的eTOH在海马中反应 主要位于海马。相反，选择性alpha5 在VP中注入的配体不会改变EtOH的响应，因为此基因座是 完全没有α5亚基，配体的亲和力非常低 对于α受体亚型。这些研究应该进一步理解 寻求Etoh的行为中的GABAA受体机制，可能可能是 确定可能在减少饮酒潜力的代理 人类。