Harvard Medical School, New England Primate Research Center, One Pine Hill Drive, P.O. Box 9102, Southborough, MA 01772-9102, USA.
Psychopharmacology (Berl). 2011 May;215(2):311-9. doi: 10.1007/s00213-010-2142-y. Epub 2010 Dec 30.
Experimental evidence suggests that the differential behavioral effects of benzodiazepines depend on their relative actions at γ-aminobutyric acid type A (GABA(A)) receptors that contain either an α1, α2, α3, or α5 subunit.
The present study was aimed at understanding the role of α3 subunit-containing GABA(A) (α3GABA(A)) receptors by examining the behavioral pharmacology of TP003 (4,2'-difluoro-5'-[8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-a]pyridine-3-yl]biphenyl-2-carbonitrile), which shows functional selectivity for α3GABA(A) receptors.
First, a conflict procedure was used to assess the anxiolytic-like effects of TP003 and a representative clinically available benzodiazepine. TP003 was also administered before daily periods of sucrose pellet availability to evaluate potential hyperphagic effects. In separate experiments, observable behavioral effects were used to assess the motor and sedative effects of TP003.
Administration of TP003 produced robust anti-conflict effects without the rate-decreasing effects that were observed with the representative benzodiazepine. Unlike the reported effects of benzodiazepines, TP003 did not enhance palatable food consumption. However, increases in observable sleep-associated posture were induced by TP003, as were decreases in some species-typical behaviors (vocalization, locomotion, and environment-directed behaviors). When evaluated for its ability to induce a procumbent posture, TP003 failed to produce an effect.
Based on conflict and observation tests in monkeys, our results suggest that TP003 may have anxiolytic properties but lack ataxic, hyperphagic, and pronounced sedative effects characteristic of classical benzodiazepines. TP003 did induce myorelaxant-like effects and had relatively mild sedative effects. Collectively, these results suggest that α3GABA(A) receptors play an important role in the anxiolytic-like and motor effects of benzodiazepine-type drugs.
实验证据表明，苯二氮䓬类药物的不同行为效应取决于它们在包含 α1、α2、α3 或 α5 亚基的γ-氨基丁酸 A 型（GABA(A))受体上的相对作用。
本研究旨在通过检查 TP003（4,2'-二氟-5'-[8-氟-7-(1-羟基-1-甲基乙基）咪唑并[1,2-a]吡啶-3-基]联苯-2-甲腈）的行为药理学来了解包含 α3 亚基的 GABA(A)（α3GABA(A)) 受体的作用，TP003 对 α3GABA(A) 受体具有功能选择性。
首先，使用冲突程序评估 TP003 和一种代表性的临床可用苯二氮䓬类药物的抗焦虑样作用。TP003 还在每日提供蔗糖丸期间给药，以评估潜在的食欲亢进作用。在单独的实验中，观察到的行为效应用于评估 TP003 的运动和镇静作用。
TP003 给药产生了强大的抗冲突作用，而没有观察到代表性苯二氮䓬类药物引起的降低速度的作用。与苯二氮䓬类药物的报道作用不同，TP003 不会增强美味食物的消耗。然而，TP003 诱导了可观察到的与睡眠相关的姿势增加，同时减少了一些物种特有的行为（发声、运动和环境导向行为）。当评估其诱导俯卧姿势的能力时，TP003 没有产生作用。
基于猴子的冲突和观察测试，我们的结果表明，TP003 可能具有抗焦虑特性，但缺乏经典苯二氮䓬类药物所具有的共济失调、食欲亢进和明显的镇静作用。TP003 确实诱导了类松弛作用，并具有相对温和的镇静作用。总的来说，这些结果表明，α3GABA(A) 受体在苯二氮䓬类药物的抗焦虑样和运动效应中发挥重要作用。
