Recreational use of gamma-hydroxybutyrate (GHB) is increasing dramatically. The pharmacological mechanisms by which GHB produces its abuse-related effects are poorly understood. GHB abuse is likely related to its subjective effects, and subjective effects of drugs in humans can often be predicted from drug discrimination experiments in animals. The discriminative stimulus effects of GHB are likely to be multidimensional and to involve several different receptor mechanisms. Some of these mechanisms may be unique to GHB (i.e., those involving specific GHB receptors), whereas others may be in common with other compounds (i.e., those involving GABAA and GABAB receptors). The studies proposed here will examine the involvement of these mechanisms in the discriminative stimulus effects of GHB under various conditions. Studies under Specific Aim I examine the ability of positive GABAA modulators and agonists at GABAA, GABAB and GHB receptors to substitute for GHB, and the ability of negative GABAA modulators and antagonists at GABAA, GABAB and GHB receptors to attenuate the discriminative stimulus effects of GHB. These substitution and antagonism studies are conducted under conditions involving different training doses of GHB, because the training dose often affects the pharmacological selectivity of the discrimination. Not only the training dose, but also the alterative training condition can affect the pharmacological selectivity, as shown by drug-drug discrimination studies. Studies under Specific Aim II attempt to increase the pharmacological selectivity of the discriminative stimulus effects of GHB by training to discriminate GHB not only from saline, but also from other drugs that share receptor mechanisms with GHB. It is hypothesized that 1) GABAA, GABAB, and GHB receptors each are involved in the discriminative stimulus of GHB, 2) when a low training dose is used the role of GABAA receptors is more prominent, and when a high training dose is used the discrimination will primarily involve GABAB and GHB receptors, and 3) when a high dose of GHB can be discriminated from a GABAB agonist, its discriminative stimulus effects will involve only GHB receptors. By identifying the role of specific receptors in abuse-related effects of GHB, future studies may be better able to develop specific, pharmacologically targeted therapies for GHB abuse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
1R01DA015692-01
Application #
6557748
Study Section
Special Emphasis Panel (ZRG1-IFCN-4 (08))
Program Officer
Wetherington, Cora Lee
Project Start
2003-04-01
Project End
2006-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
1
Fiscal Year
2003
Total Cost
$219,000
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Psychiatry
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
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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