GABAa Receptor Subunits in Alcohol Reinforcement

描述(由申请人提供)：本提案的目标是评估 Alphal和Alpha5 GABAA受体亚基在乙醇脱氢酶中的作用 增援。为了做到这一点，高酒精饮酒(HAD)大鼠系， 字母基因敲除(KO)小鼠和它们的野生型对应部分(WT)将被 使用。第一个要检验的假设是突触后字母1 HAD大鼠腹侧苍白球(Vp)受体参与 乙醇的增强性能。选择性部位特异性微量注射 将评估VP中的字母拮抗剂的衰减能力 Etoh-维持回应。据推测，阿尔法对手将 选择性地减少乙醇反应，因为字母亚单位存在于 整个副总裁的级别都很高。第二个假设将评估 字母亚型的完全删除对习得的调节程度 用KO和WT小鼠研究寻找酒精的行为。据推测， KO小鼠将启动酒精维持的反应，因为酒精奖励 已被证明受多个神经递质系统的调节；然而， 据预测，KO小鼠的饮酒量明显低于WT小鼠。 此外，我们假设用Alphal减少的幅度 KO中的对手将少于WT中的对手，因为KO 将缺乏一个功能性的字母亚单位。第三个具体目标将测试 增强阿尔法结合选择性的假说在体内存活更长时间 更多的水溶性配体将产生更理想的酒精 对抗者。最后，第四种假设将评估alpha5受体是否 在海马区(CA1和CA3)调节GABA能乙醇奖赏 底物(如伏隔核、杏仁基底核、纹状床核 终生)。为了做到这一点，微量注射选择性Alpha5相反 海马体中减弱乙醇维持反应的激动剂将是 已评估。我们假设Alpha5配体将选择性地减少 在海马区的乙醇反应，因为含有α5的受体是 主要定位于海马体。相比之下，选择性字母5 在VP中注入的配体不会改变乙醇反应，因为这个基因座是 完全没有α5亚基，而且配体的亲和力很低 对于字母受体亚型。这些研究应该会加深我们的理解 GABAA受体在寻找乙醇行为中的机制，并可能 找出可能在减少饮酒方面有潜力的药物 人类。

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.