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）：本提案的目标是评估 α 1和α 5 GABAA受体亚单位在EtOH中的作用 加固.为了实现这一点，高酒精饮用（HAD）大鼠系， 将用免疫球蛋白敲除（KO）小鼠及其野生型对应部分（WT） 采用第一个要检验的假设是突触后α 1 HAD大鼠腹侧苍白球（VP）中的受体参与了HAD大鼠的 EtOH的增强性能。位点特异性显微注射 将评价VP中的β-受体拮抗剂减弱 EtOH维持反应。据推测，神经元拮抗剂将 选择性降低EtOH响应，因为β-半乳糖醛酸亚基存在于 在整个VP中非常高的水平。第二个假设将评估 完全缺失的α 1亚型调节获得的程度 对KO和WT小鼠的酒精寻求行为进行了研究。它是假设 KO小鼠将启动酒精维持反应，因为酒精奖励 已显示受多种神经递质系统调节;然而， 预测KO小鼠的饮水量显著低于WT小鼠。 此外，我们假设， 科斯中的拮抗剂将少于WT中观察到的拮抗剂，因为科斯 将缺乏功能性的细胞亚基。第三个具体目标将测试 假设增强的细胞结合选择性，在体内存活时间更长， 水溶性配体越多， 拮抗剂最后，第四个假设将评估α 5受体是否 在海马（CA 1和CA 3）调节假定的GABA能EtOH奖励 衬底（例如，杏仁基底核，纹状体床核 terminalis）。为了实现这一点，显微注射选择性α 5逆 在海马中的激动剂，以减弱EtOH维持的反应， 评估。我们假设α 5配体会选择性地减少 EtOH在海马体中的反应，因为含有α 5的受体是 主要位于海马体相比之下，选择性α 5 VP中注入的配体不会改变EtOH反应，因为该位点是 完全没有α 5亚基，并且配体具有非常低的亲和力 对于神经元受体亚型这些研究应该进一步加深我们的理解 GABAA受体机制的EtOH寻求行为，可能 确定可能具有减少饮酒潜力的药物， 人类