Effects of -Hydroxybutyrate (GHB) on Schedule-Controlled Responding in Rats: Role of GHB and GABAB Receptors

-Hydroxybutyrate (GHB), a metabolite of -aminobutyric acid (GABA), is an increasingly popular drug of abuse and was recently approved for the treatment of narcolepsy (Xyrem). GHB and GABA receptors have been implicated in mediating effects of GHB; however, the relative importance of each of these receptors is unclear. This study evaluated the effects of selective antagonists in combination with GHB and related compounds on schedule-controlled responding. Eight male Sprague-Dawley rats responded under a fixed-ratio schedule of food presentation. Cumulative dose-effect curves were generated and ED50 values calculated to evaluate the relative potency at decreasing responding. The rank-order potency was as follows: diazepam baclofen -butyrolactone (GBL) 1,4-butanediol (1,4-BDL) GHB. All compounds decreased responding 20 min after administration. The duration of action of diazepam, GHB, and GBL was shorter than that of 1,4-BDL and baclofen. p-3-Aminopropyl-p-diethoxymethyl phosphinic acid (CGP 35348) antagonized the rate-decreasing effects of baclofen and not GHB; flumazenil antagonized the effects of diazepam and not GHB. The GHB receptor antagonist (2E)-(5-hydroxy5,7,8,9-tetrahydro-6H-benzo[a][7]annulen-6-ylidene ethanoic acid (NCS-382) did not attenuate the rate-decreasing effects of GHB, baclofen, or diazepam; larger doses of NCS-382 further decreased rate of responding when given in combination with each of these compounds. These studies show that GBL, 1,4-BDL, and GHB differ significantly in potency and duration of action. The ability of CGP 35348 to antagonize the rate-decreasing effects of baclofen may be limited by the involvement of multiple GABAB receptor subtypes and the lack of antagonism of GHB by NCS382 may be due to its own GHB-like effects. -Hydroxybutyrate (GHB) is an endogenous metabolite of -aminobutyric acid (GABA) and a putative neurotransmitter (Roth and Giarman, 1970; Maitre, 1997). GHB binds to GABAB receptors (Mathivet et al., 1997; Lingenhoehl et al., 1999) and specific GHB sites (Benavides et al., 1982; Snead and Liu, 1984; Mehta et al., 2001) in the brain. GHB-specific binding sites (as labeled by [H]NCS-382) are believed to be G protein-coupled receptors (Snead, 2000). In addition to binding at GHB and GABAB receptors, GHB is metabolized to GABA (Roth and Giarman, 1969), which may act at GABAA, GABAB, and GABAC receptors. Administration of GHB can induce sedation, amnesia, ataxia, catalepsy, absence seizures, coma, and death (Snead and Liu, 1993; Nicholson and Balster, 2001); however, the relative importance of GHB receptors and GABA receptors in mediating these effects is unclear. GHB is an emerging drug of abuse (Nicholson and Balster, 2001; Mason and Kerns, 2002); thus, a GHB antagonist could be clinically useful for treating GHB over-