Harvard Medical School, New England Primate Research Center, One Pine Hill Drive, Southborough, MA 01772-9102, USA.
Neuropharmacology. 2010 Feb;58(2):357-64. doi: 10.1016/j.neuropharm.2009.10.004. Epub 2009 Oct 22.
Previous reports suggest that gamma-aminobutyric acid type A (GABA(A)) receptors containing alpha1 subunits may play a pivotal role in mediating the discriminative stimulus effects of benzodiazepines (BZs). L-838,417 (7-tert-Butyl-3-(2,5-difluoro-phenyl)-6-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-[1,2,4]triazolo[4,3-b]pyridazine) is a GABA(A) receptor modulator with intrinsic efficacy in vitro at alpha2, alpha3, and alpha5 subunit-containing GABA(A) receptors, and little demonstrable intrinsic efficacy in vitro at alpha1 subunit-containing GABA(A) receptors. The present study evaluated the discriminative stimulus effects of L-838,417 in order to determine the extent to which the alpha2, alpha3, and alpha5 subunit-containing GABA(A) receptors contribute to the interoceptive effects of BZ-type drugs. Squirrel monkeys (Saimiri sciureus) were trained to discriminate L-838,417 (0.3 mg/kg, i.v.) from vehicle under a 5-response fixed-ratio schedule of food reinforcement. Under test conditions, L-838,417 administration resulted in dose-dependent increases in drug-lever responding that were antagonized by the BZ-site antagonist, flumazenil. Administration of non-selective BZs, compounds with 10-fold greater affinity for alpha1 subunit-containing GABA(A) receptors compared to alpha2, alpha3, and alpha5 subunit-containing GABA(A) receptors, barbiturates and ethanol (which modulate the GABA(A) receptor via a non-BZ site), all resulted in a majority of responses on the L-838,417-paired lever (65-100% drug-lever responding). betaCCT, an antagonist that binds with 20-fold greater affinity for alpha1 subunit-containing GABA(A) receptors relative to alpha2, alpha3, and alpha5-containing GABA(A) receptors, had no significant effect on the discriminative stimulus effects of L-838,417 or the L-838,417-like effects of diazepam or zolpidem. These data suggest that efficacy at alpha2, alpha3, and/or alpha5 subunit-containing GABA(A) receptors likely are sufficient for engendering BZ-like discriminative stimulus effects.
先前的报告表明，含有 alpha1 亚基的γ-氨基丁酸 A 型（GABA(A)) 受体可能在介导苯二氮䓬类药物（BZs）的辨别刺激效应中发挥关键作用。L-838,417（7-叔丁基-3-(2,5-二氟-苯基）-6-(2-甲基-2H-[1,2,4]三唑-3-基甲氧基）-[1,2,4]三唑并[4,3-b]吡啶）是一种 GABA(A) 受体调节剂，在含有 alpha2、alpha3 和 alpha5 亚基的 GABA(A) 受体中具有内在效力，而在含有 alpha1 亚基的 GABA(A) 受体中几乎没有可证明的内在效力。本研究评估了 L-838,417 的辨别刺激效应，以确定含有 alpha2、alpha3 和 alpha5 亚基的 GABA(A) 受体在 BZ 型药物的内感受效应中所起的作用程度。训练松鼠猴（Saimiri sciureus）根据食物强化的 5 次应答固定比率时间表，辨别 L-838,417（0.3mg/kg，静脉内）与载体。在测试条件下，L-838,417 的给药导致药物杠杆反应的剂量依赖性增加，这种增加被 BZ 位拮抗剂氟马西尼拮抗。非选择性 BZs、与 alpha1 亚基相比对 alpha2、alpha3 和 alpha5 亚基含有 GABA(A) 受体具有 10 倍亲和力的化合物、巴比妥类药物和乙醇（通过非 BZ 位调节 GABA(A)受体），都导致大多数反应出现在 L-838,417 配对杠杆上（65-100%药物杠杆反应）。βCCT 是一种拮抗剂，与 alpha2、alpha3 和 alpha5 亚基含有 GABA(A) 受体相比，对 alpha1 亚基含有 GABA(A) 受体的亲和力高 20 倍，对 L-838,417 的辨别刺激效应或 L-838,417 样效应的地西泮或唑吡坦无显著影响。这些数据表明，alpha2、alpha3 和/或 alpha5 亚基含有 GABA(A) 受体的效力足以产生 BZ 样辨别刺激效应。
