GABA-A RECEPTOR SUBTYPES MEDIATING SUBJECTIVE EFFECTS OF BENZODIAZEPINES

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。最近的报道表明，α-1/GABA-A受体可能在介导常规苯二氮卓类(BZS)以及BZ类化合物对含有特定GABA-A亚单位受体的选择性刺激效应中起关键作用。L-838,417是一种BZ位点的配体，在含有GABAA受体的α2、α3和α5亚基具有部分激动剂作用，但在含有GABAA受体的α1亚基具有拮抗剂作用。这一子项目评估了L-838,417的辨别刺激效应，以确定GABA-A受体的α-2、α-3和α-5亚单位对传统BZ激动剂的内感效应的贡献程度。在固定比例的食物强化方案下，训练松鼠猴从车辆中辨别L-838,417。在实验条件下，L-838,417可引起剂量依赖性的药物水平反应增加，但对应答率没有任何影响。传统的非选择性BZ激动剂，如三唑仑、安定和劳拉西潘，可完全替代L-838,417(药物水平反应80%-100%)。令人惊讶的是，对α-1/GABA-A受体具有选择性亲和力的化合物，包括唑吡坦、扎莱普隆和CL218872，在不改变应答率的剂量下产生了大约80%的药物水平反应。

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. Recent reports suggest that the alpha-1/GABA-A receptor may play a key role in mediating the discriminative stimulus effects of conventional benzodiazepines (BZs) as well as BZ-type compounds selective for specific GABA-A subunit-containing receptors. L-838,417 is a BZ-site ligand with partial agonist efficacy at alpha-2, alpha-3, and alpha-5-subunit containing GABA-A receptors, but is an antagonist at alpha-1 subunit-containing GABA-A receptors. This subproject evaluated the discriminative stimulus effects of L-838,417 in order to determine the extent to which the alpha-2, alpha-3, and alpha-5 subunits of the GABA-A receptor contribute to the interoceptive effects of conventional BZ agonists. Squirrel monkeys were trained to discriminate L-838,417 from vehicle under a fixed-ratio schedule of food reinforcement. Under test conditions, L-838,417 engendered dose-dependent increases in drug lever responding without any effect on rates of responding. Conventional non-selective BZ agonists, e.g., triazolam, diazepam, and lorazepam, engendered full substitution for L-838,417 (80-100 per cent drug-lever responding). Surprisingly, compounds with selective affinity for alpha-1/GABA-A receptors, including zolpidem, zaleplon, and CL218872, engendered approximately 80 per cent of drug-lever responding at doses that did not alter response rates.