RT Journal Article
SR Electronic
T1 Discriminative Stimulus Effects of γ-Hydroxybutyrate in Pigeons: Role of Diazepam-Sensitive and -Insensitive GABA<sub>A</sub> and GABA<sub>B</sub> Receptors
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 904
OP 911
DO 10.1124/jpet.103.056093
VO 308
IS 3
A1 Wouter Koek
A1 Lauren R. Flores
A1 Lawrence P. Carter
A1 R. J. Lamb
A1 Weibin Chen
A1 Huifang Wu
A1 Andrew Coop
A1 Charles P. France
YR 2004
UL http://jpet.aspetjournals.org/content/308/3/904.abstract
AB 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, GABAA, and GABAB 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 GABAA agonist muscimol produced 3%; the GABAA-positive modulators diazepam, pentobarbital, and ethanol, and the GABAB 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 GABAB 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 GABAA and GABAB receptors in the DS effects of GHB. Together with previous findings, the present results suggest that diazepam-insensitive GABAA receptors are more prominently involved in the DS effects of GHB in pigeons than in rats, whereas GABAB receptors are less prominently involved. Exploring the role of GHB receptors with NCS-382 is hampered by its GABAB receptor-mediated, GHB-like agonist activity. The American Society for Pharmacology and Experimental Therapeutics