GABA-A Subunit Specificity of Ethanol-Related Behavior

描述(由申请人提供)：GABA-A受体被认为介导了酒精的几种作用。GABA-A受体是五聚体配体门控离子通道。目前，已经发现了七种不同的受体亚基类别(α1-6、β1-3、伽马1-3、Rho 1-3、Delta、epsilon、theta)，某些亚基的存在可以对受体药理学产生深远的影响。事实上，数据表明，α受体亚基介导镇静、健忘和一些抗惊厥作用，而α2受体亚基介导苯二氮卓类药物的抗焦虑作用。此外，药理学数据表明，α5亚基介导了酒精的增强特性。在目前的方案中，我们的目标是研究GABA-A的酒精敏感性 α2和α5受体亚单位缺失突变小鼠。我们预测，这些零突变将导致酒精敏感性的亚基特异性变化。我们假设，alpha2基因的缺失将导致对酒精缓解焦虑作用的敏感度降低，而alpha5基因的零突变将导致对酒精增强特性的敏感度降低。我们希望这些数据将有助于旨在确定潜在的酒精中毒药物治疗策略的研究。

DESCRIPTION (provided by applicant): GABA-A receptors are thought to mediate several effects of alcohol. GABA-A receptors are pentameric ligand-gated ion channels. Currently, seven different receptor subunit classes have been discovered (alpha 1-6, beta 1-3, gamma 1-3, rho 1-3, delta, epsilon, theta), and the presence of certain subunits can have profound effects on receptor pharmacology. Indeed, data has shown that whereas alphal-receptor subunits mediate the sedative, amnestic, and some anticonvulsant effects, alpha2 receptor subunits mediate the anxiolytic effects ofbenzodiazepines. Moreover, pharmacological data suggests that alpha5 subunits mediate alcohol's reinforcing properties. In the current proposal, we aim to investigate the alcohol sensitivity of GABA-A alpha2- and alpha5-receptor subunit null mutant mice. We predict that these null mutations will result in subunit specific changes in alcohol sensitivity. We hypothesize that deletion of the alpha2 gene will result in reduced sensitivity to alcohol's anxiolytic effects, whereas null mutation of the alpha5 gene will result in reduced sensitivity to alcohol's reinforcing properties. It is our hope that these data will aid in research aimed at identifying potential pharmacological treatment strategies for alcoholism.