Abstract

γ-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 γ-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-α]-[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.