CONTRIBUTION OF GABA-A RECEPTOR SUBTYPES TO THE SUBJECTIVE EFFECTS OF ETHANOL

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。酒精的滥用是由药物的多重影响控制的，包括它的主观影响。酒精通过GABA受体增强γ -氨基丁酸（GABA）神经传递的能力被认为是其对动物主观影响的重要机制。GABA-A受体是一种五聚体，由至少五个不同家族的亚基组成，包括α， β和γ亚基。我们的实验室专注于使用不同GABA-A - α亚基的选择性配体作为药理学工具，探索这些受体亚型在酒精主观效应中的作用。松鼠猴被训练在固定比例的食物递送时间表下区分酒精和生理盐水。在测试条件下，酒精引起药物杠杆反应的剂量依赖性增加，达到超过80%的平均最大值。同样，alpha1 GABA-A激动剂唑吡坦、扎来普隆和CL218,872， alpha2/3 GABA-A激动剂JC-510， alpha5 GABA-A激动剂QH-ii-066和panadiplon部分到完全再现了酒精的作用。然而，当与酒精联合使用时，α 1 GABA-A拮抗剂BCCT未能减弱酒精的主观影响。BCCT也没有明显改变唑吡坦和扎来普隆的酒精样作用。相比之下，使用α 5 GABA-A逆激动剂L-655,708进行预处理，剂量依赖性地减弱了酒精的主观效应以及QH-ii-066的类酒精效应。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Abuse of alcohol is controlled by multiple effects of the drug, including its subjective effects. Alcohol's ability to enhance gamma-aminobutyric acid (GABA) neurotransmission via GABA-A receptors has been implicated as an important mechanism underlying its subjective effects in animals. The GABA-A receptor is a pentamer consisting of subunits from at least five different families including alpha, beta, and gamma subunits. Our laboratory has focused on the use of ligands selective for different GABA-A alpha subunits as pharmacological tools to explore the role of these receptor subtypes in the subjective effects of alcohol. Squirrel monkeys were trained to discriminate alcohol from saline under a fixed-ratio schedule of food delivery. Under test conditions, alcohol engendered a dose-dependent increase in drug-lever responding, reaching an average maximum of greater than 80 per cent. Similarly, the alpha1 GABA-A agonists zolpidem, zaleplon and CL218,872, the alpha2/3 GABA-A agonist JC-510, and the alpha5 GABA-A agonists QH-ii-066 and panadiplon partially-to-fully reproduced the alcohol's effects. However, when combined with alcohol, the alpha1 GABA-A antagonist BCCT failed to attenuate the subjective effects of alcohol. BCCT also did not alter appreciably the alcohol-like effects of zolpidem and zaleplon. In contrast, pretreatment with the alpha5 GABA-A inverse agonist L-655,708 dose-dependently attenuated the subjective effects of alcohol as well as the alcohol-like effects of QH-ii-066.