Gamma-hydroxybutyrate (GHB) is an endogenous substance that binds to specific GHB receptors where it is thought to act as a neurotransmitter/neuromodulator. GHB is used therapeutically, to treat the sleep disorder narcolepsy and to treat alcoholism, and recreationally, as a """"""""club drug"""""""". However, neither the physiological role of GHB, nor the mechanisms for its therapeutic actions and its abuse are understood. This stems in part from the complex pharmacology of GHB, which is thought to act at GABAs and at GHB receptors. To advance our knowledge of the mechanisms underlying the therapeutic utility of GHB and its abuse, research under this grant has used drug discrimination procedures to develop more selective behavioral assays for studying the neuropharmacology of GHB. Using these assays, we obtained further evidence that, instead of GHB receptors, GABAB receptors are prominently involved in the discriminative stimulus effects of GHB. Also, although GHB shares many effects with the prototypical GABAB agonist baclofen, we obtained further evidence that their effects are not identical and perhaps not mediated by the same GABAB mechanisms. Whereas baclofen directly activates GABAs receptors, both GABAB receptor activation and modulation could conceivably be involved in the effects of GHB. There is currently much interest in GABAe receptor positive modulators, because modulation may offer advantages over direct activation of receptors, as exemplified by the benzodiazepines at GABAA receptors. This competing renewal is aimed at further examining similarities and differences between the discriminative stimulus effects of GHB, baclofen, and recently described GABAs positive modulators by studying i) whether GABAe receptor positive modulators produce or enhance GHB- and baclofen-like discriminative stimulus effects (SPECIFIC AIM I), and 2) by further characterizing the discriminative stimulus effects of GABAB receptor positive modulators as training drugs (SPECIFIC AIM II). Based on evidence that GHB may interact synergistically with other club drugs (i.e., the NMDA antagonist ketamine), the present application will also characterize interactions between NMDA antagonists and GHB and related compounds, as well as GABA-ergic compounds (SPECIFIC AIM III). This will increase our understanding of the interactions between the glutamatergic system, which is thought to play an important role in modulating/mediating effects of drugs of abuse, and the GABAB systems involved in the behavioral effects of GHB. The contributions of these studies extend beyond substance abuse to how GABAB mechanisms might contribute to the therapeutic actions of GHB, a systematic characterization of the behavioral effects of GABAB positive modulators, and analysis of interactions between GABAB and glutamatergic systems. Increased knowledge about the activation and modulation of GABAB systems will help to develop effective approaches to treating sleep-, drug abuse-, and other CNS disorders.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
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Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
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Wetherington, Cora Lee
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University of Texas Health Science Center San Antonio
Schools of Medicine
San Antonio
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Koek, Wouter; Cheng, Kejun; Rice, Kenner C (2013) Discriminative stimulus effects of the GABAB receptor-positive modulator rac-BHFF: comparison with GABAB receptor agonists and drugs of abuse. J Pharmacol Exp Ther 344:553-60
Hensler, Julie G; Advani, Tushar; Burke, Teresa F et al. (2012) GABAB receptor-positive modulators: brain region-dependent effects. J Pharmacol Exp Ther 340:19-26
Koek, Wouter; France, Charles P; Cheng, Kejun et al. (2012) Effects of the GABAB receptor-positive modulators CGP7930 and rac-BHFF in baclofen- and ?-hydroxybutyrate-discriminating pigeons. J Pharmacol Exp Ther 341:369-76
Koek, Wouter; France, Charles P; Cheng, Kejun et al. (2010) GABAB receptor-positive modulators: enhancement of GABAB receptor agonist effects in vivo. J Pharmacol Exp Ther 335:163-71
Carter, Lawrence P; Koek, Wouter; France, Charles P (2009) Behavioral analyses of GHB: receptor mechanisms. Pharmacol Ther 121:100-14
Koek, Wouter; Mercer, Susan L; Coop, Andrew et al. (2009) Behavioral effects of gamma-hydroxybutyrate, its precursor gamma-butyrolactone, and GABA(B) receptor agonists: time course and differential antagonism by the GABA(B) receptor antagonist 3-aminopropyl(diethoxymethyl)phosphinic acid (CGP35348). J Pharmacol Exp Ther 330:876-83
Koek, Wouter; France, Charles P (2008) Cataleptic effects of gamma-hydroxybutyrate (GHB) and baclofen in mice: mediation by GABA(B) receptors, but differential enhancement by N-methyl-d-aspartate (NMDA) receptor antagonists. Psychopharmacology (Berl) 199:191-8
Koek, Wouter; Khanal, Mandar; France, Charles P (2007) Synergistic interactions between 'club drugs': gamma-hydroxybutyrate and phencyclidine enhance each other's discriminative stimulus effects. Behav Pharmacol 18:807-10
Koek, Wouter; Mercer, Susan L; Coop, Andrew (2007) Cataleptic effects of gamma-hydroxybutyrate (GHB), its precursor gamma-butyrolactone (GBL), and GABAB receptor agonists in mice: differential antagonism by the GABAB receptor antagonist CGP35348. Psychopharmacology (Berl) 192:407-14
Carter, Lawrence P; Chen, Weibin; Coop, Andrew et al. (2006) Discriminative stimulus effects of GHB and GABA(B) agonists are differentially attenuated by CGP35348. Eur J Pharmacol 538:85-93

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