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

-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 GABAA, GABAB, 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 GABAB 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 -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 GABAA 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 GABAB receptor antagonist CGP 35348 antagonized GHBlever responding occasioned by baclofen or GHB. Small doses of the purported GHB receptor antagonist (2E)-(5-hydroxy5,7,8,9-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 GABAB 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. -Hydroxybutyrate (GHB) is a neurotransmitter in brain and an emerging drug of abuse (Roth and Giarman, 1966; Doherty et al., 1978). Widespread abuse of GHB was first reported in 1990 and has increased in recent years as evidenced by a dramatic increase in the number of patients treated for GHB intoxication (Bernasconi et al., 1999; Nicholson and Balster, 2001; Mason and Kerns, 2002). Exogenously administered GHB can induce amnesia, sedation, absence seizures, coma, and death (Roth and Suhr, 1970; Snead and Liu, 1993). GHB has been used clinically as an anesthetic, to treat alcoholism, and has been recently approved by the Food and Drug Administration for the treatment of narcolepsy (Mason and Kerns, 2002). Although GHB is widely abused, its pharmacological profile differs from other drugs of abuse. GHB does not substitute for the discriminative stimulus effects of heroin, phencyclidine (PCP), ethanol, d-amphetamine, pentobarbital, or triazolam (Beardsley et al., 1996; Woolverton et al., 1999; Metcalf et al., 2001). Conditioned place preference has been reported for GHB in rats; however, many more exposures to GHB were required to induce preference as compared with other drugs of abuse (Martellotta et al., 1997). Drug-naı̈ve mice self-administer GHB (Martellotta et al., 1998), whereas rhesus monkeys trained to self-administer either methohexital or PCP do not (Beardsley et al., 1996; Woolverton et al.,