Koek Wouter, Flores Lauren R, Carter Lawrence P, Lamb R J, Chen Weibin, Wu Huifang, Coop Andrew, France Charles P
Departments of Psychiatry and Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900, USA.
J Pharmacol Exp Ther. 2004 Mar;308(3):904-11. doi: 10.1124/jpet.103.056093. Epub 2004 Jan 12.
gamma-Hydroxybutyrate (GHB) is an emerging drug of abuse with multiple mechanisms of action. This study is part of an effort to examine the role of GHB, GABA(A), and GABA(B) receptors in the discriminative stimulus (DS) effects of GHB. In pigeons trained to discriminate 100 mg/kg GHB from saline, GHB and its precursors gamma-butyrolactone and 1,4-butanediol produced 80 to 100% GHB-appropriate responding, whereas other compounds such as morphine, naltrexone, cocaine, and haloperidol produced no more than 34%. Compounds interacting with GABA receptors produced different maximal levels of GHB-appropriate responding. For example, the GABA(A) agonist muscimol produced 3%; the GABA(A)-positive modulators diazepam, pentobarbital, and ethanol, and the GABA(B) agonist baclofen produced levels ranging from 54 to 73%; and the benzodiazepine antagonist flumazenil and inverse agonist Ro 15-4513 (ethyl 8-azido-6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-alpha]-[1,4]-benzodiazepine-3-carboxylate) both produced 96%. The putative GHB receptor antagonist (2E)-(5-hydroxy-5,7,8,9-tetrahydro-6H-benzo[a][7]annulen-6-ylidene ethanoic acid (NCS-382) produced 70% GHB-appropriate responding. The GABA(B) antagonist (3-aminopropyl)(diethoxymethyl)phosphinic acid (CGP 35348) completely blocked the GHB-like DS effects of NCS-382 and baclofen at a dose of 56 mg/kg. CGP 35348 also blocked the DS effects of GHB, but incompletely and only at a dose of 560 mg/kg. Together, these results are consistent with a role for diazepam-sensitive and -insensitive GABA(A) and GABA(B) receptors in the DS effects of GHB. Together with previous findings, the present results suggest that diazepam-insensitive GABA(A) receptors are more prominently involved in the DS effects of GHB in pigeons than in rats, whereas GABA(B) receptors are less prominently involved. Exploring the role of GHB receptors with NCS-382 is hampered by its GABA(B) receptor-mediated, GHB-like agonist activity.
γ-羟基丁酸（GHB）是一种新型滥用药物，具有多种作用机制。本研究是探讨GHB、GABA(A)和GABA(B)受体在GHB辨别刺激（DS）效应中作用的一部分。在训练用于区分100mg/kg GHB和生理盐水的鸽子中，GHB及其前体γ-丁内酯和1,4-丁二醇产生了80%至100%的GHB适宜反应，而吗啡、纳曲酮、可卡因和氟哌啶醇等其他化合物产生的反应不超过34%。与GABA受体相互作用的化合物产生了不同水平的GHB适宜反应最大值。例如，GABA(A)激动剂蝇蕈醇产生了3%的反应；GABA(A)阳性调节剂地西泮、戊巴比妥和乙醇，以及GABA(B)激动剂巴氯芬产生的反应水平在54%至73%之间；苯二氮䓬拮抗剂氟马西尼和反向激动剂Ro 15-4513（8-叠氮基-6,7-二氢-5-甲基-6-氧代-4H-咪唑并[1,5-α][1,4]苯并二氮䓬-3-羧酸乙酯）均产生了96%的反应。推定的GHB受体拮抗剂(2E)-(5-羟基-5,7,8,9-四氢-6H-苯并[a][7]环壬烯-6-亚基)乙酸（NCS-382）产生了70%的GHB适宜反应。GABA(B)拮抗剂(3-氨丙基)(二乙氧基甲基)次膦酸（CGP 35348）在56mg/kg剂量时完全阻断了NCS-382和巴氯芬的GHB样DS效应。CGP 35348也阻断了GHB的DS效应，但仅在560mg/kg剂量时不完全阻断。总之，这些结果与地西泮敏感和不敏感的GABA(A)和GABA(B)受体在GHB的DS效应中的作用一致。与先前的研究结果一起，目前的结果表明，地西泮不敏感的GABA(A)受体在鸽子中比在大鼠中更显著地参与GHB的DS效应，而GABA(B)受体的参与则不那么显著。用NCS-382探索GHB受体的作用受到其GABA(B)受体介导的GHB样激动剂活性的阻碍。
