The Role of GABA_B Receptors in the Discriminative Stimulus Effects of γ-Hydroxybutyrate in Rats: Time Course and Antagonism Studies

Abstract

␥-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 (Ϯ)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 ␥-butyrolactone, the benzodiazepine diazepam, the neuroactive steroid pregnanolone, the opioid agonist morphine, and the Nmethyl-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 GHBlever 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.

Cataleptic effects of γ-hydroxybutyrate (GHB) and baclofen in mice: mediation by GABAB receptors, but differential enhancement by N-methyl-d-aspartate (NMDA) receptor antagonists

“…At present, there appears to be little evidence for a role for GHB receptors in the in vivo effects of GHB (Wong et al 2004). Instead, many studies suggest that GABA B receptors are particularly important for various behavioral effects of GHB, including discriminative stimulus effects (e.g., Winter 1981, Colombo et al 1998, Carter et al 2003, decreased operant responding (Goodwin et al 2005), and directly observable effects such as hypolocomotion (Kaupmann et al 2003), catalepsy (Carter et al 2005), ataxia (Goodwin et al 2005), and loss of righting (Carai et al 2001). Consistent with the involvement of GABA B receptors, all of these effects of GHB are produced also by the prototypical GABA B receptor agonist baclofen (Carter et al 2003(Carter et al , 2005.…”

Discriminative Stimulus Effects of γ-Hydroxybutyrate in Pigeons: Role of Diazepam-Sensitive and -Insensitive GABAA and GABAB Receptors

“…Overlap in the actions of GHB and positive GABA A receptor modulators such as diazepam suggests a possible role for GABA A systems (Colombo et al, 1998;Carter et al, 2003). Thus, GHB is likely to have multiple mechanisms of action.…”

“…Rats can discriminate GHB from saline (Winter, 1981;Colombo et al, 1995aColombo et al, ,b, 1998Metcalf et al, 2001;Carter et al, 2003), and its effects seem to be selective because pharmacologically unrelated drugs (e.g., phencyclidine and ketamine) do not occasion GHBappropriate responding (Winter, 1981;Carter et al, 2003). Also, GHB does not occasion drug-appropriate responding in discriminations that use training drugs pharmacologically unrelated to GHB (Beardsley et al, 1996;Woolverton et al, 1999).…”

“…antagonized by the GABA B receptor antagonist CGP 35348 (Colombo et al, 1998;Carter et al, 2003). Overlap in the actions of GHB and positive GABA A receptor modulators such as diazepam suggests a possible role for GABA A systems (Colombo et al, 1998;Carter et al, 2003).…”

Presynaptic Modulation of Spontaneous Inhibitory Postsynaptic Currents by Gamma-hydroxybutyrate in the Substantia Nigra Pars Compacta

“…This result suggests that the depressant effect of GHB shown in this study, which leaves out GHB effects on the GABA B receptor, is mediated by the activation of the GHB receptor. In this regard, it should be mentioned that the selectivity and specificity of NCS-382 for the GHB receptor is still a matter of debate, as some laboratories have reported divergent results regarding this issue (Metcalf et al, 2001;Carter et al, 2003;Gould et al, 2003;Lamb et al, 2003).…”