The role of GABAB receptors in the discriminative stimulus effects of gamma-hydroxybutyrate in rats: time course and antagonism studies

Abstract

gamma-Hydroxybutyrate (GHB) is a neurotransmitter in brain and an emerging drug of abuse, although its mechanism of action is poorly understood. This study characterized the role of GABA(A), GABA(B), and other receptors in the discriminative stimulus effects of GHB. Eight rats reliably discriminated 200 mg/kg GHB from saline after a median of 35 (range: 23-41) training sessions. GHB, a metabolic precursor 1,4-butanediol (1,4-BDL), and the GABA(B) agonist (+/-)baclofen all occasioned greater than 83% responding on the GHB lever. The onset of action was similar for GHB and 1,4-BDL; however, 1,4-BDL exhibited a longer duration of action than GHB. The GHB precursor gamma-butyrolactone, the benzodiazepine diazepam, the neuroactive steroid pregnanolone, the opioid agonist morphine, and the N-methyl-d-aspartate antagonist ketamine elicited substantial GHB-appropriate responding, although none occasioned greater than 66% drug-lever responding. The barbiturate pentobarbital and the GABA(A) receptor agonist muscimol did not occasion greater than 17% drug-lever responding at any dose tested. The benzodiazepine antagonist flumazenil attenuated GHB-lever responding occasioned by diazepam, but not GHB. The GABA(B) receptor antagonist CGP 35348 antagonized GHB-lever responding occasioned by baclofen or GHB. Small doses of the purported GHB receptor antagonist (2E)-(5-hydroxy-5,7,8,9-tetrahydro-6H-benzo[a][7]annulen-6-ylidene ethanoic acid (NCS-382) attenuated partially the effects of GHB, whereas larger doses of NCS-382 alone occasioned partial GHB-lever responding. These results implicate GABA(B) mechanisms in the discriminative stimulus effects of GHB and further suggest that the effects of 1,4-BDL under these conditions result from its conversion to GHB. That NCS-382 shares effects with GHB could explain the lack of antagonism reported for NCS-382 in some studies.