GABA-A RECEPTOR SUBTYPES MEDIATING SUBJECTIVE EFFECTS OF BENZODIAZEPINES

GABA-A 受体亚型介导苯二氮卓类药物的主观效应

• 批准号: 7349555
• 负责人: STEPHANIE C LICATA
• 金额: $ 2.8万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7349555
• 关键词: GABA; RECEPTOR; SUBTYPES; MEDIATING; SUBJECTIVE

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.

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。最近的报道表明，α -1/GABA-A受体可能在介导传统苯二氮卓类药物（BZs）以及bz型化合物对特定GABA-A亚基受体的选择性刺激作用中起关键作用。L-838,417是一种bz位点配体，对含有GABA-A受体的α -2、α -3和α -5亚基具有部分激动剂作用，但对含有GABA-A受体的α -1亚基具有拮抗剂作用。本子项目评估了L-838,417的鉴别刺激作用，以确定GABA-A受体的α -2、α -3和α -5亚基在多大程度上参与了传统BZ激动剂的内感受性作用。在固定比例的食物强化计划下，训练松鼠猴区分L-838,417与车辆。在测试条件下，L-838,417产生药物水平反应的剂量依赖性增加，而对反应率没有任何影响。传统的非选择性BZ激动剂，如三唑仑、地西泮和劳拉西泮，可以完全替代L-838,417（80% - 100%的药物水平反应）。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、扎来普隆和CL218872，在不改变反应率的剂量下，产生了大约80%的药物水平反应。