Effect of GABA Agonists and GABA-A Receptor Modulators on Cocaine- and Food-Maintained Responding and Cocaine Discrimination in Rats (original) (raw)
Research ArticleBEHAVIORAL PHARMACOLOGY
Journal of Pharmacology and Experimental Therapeutics November 2005, 315 (2) 858-871; DOI: https://doi.org/10.1124/jpet.105.086033
Abstract
Recent studies indicate that GABAergic ligands modulate abuse-related effects of cocaine. The goal of this study was to evaluate the effects of a mechanistically diverse group of GABAergic ligands on the discriminative stimulus and reinforcing effects of cocaine in rats. One group of rats was trained to discriminate 5.6 mg/kg cocaine from saline in a two-lever, food-reinforced, drug discrimination procedure. In two other groups, responding was maintained by cocaine (0–3.2 mg/kg/injection) or liquid food (0–100%) under a fixed ratio 5 schedule. Six GABA agonists were tested: the GABA-A receptor agonist muscimol, the GABA-B receptor agonist baclofen, the GABA transaminase inhibitor γ-vinyl-GABA (GVG), and three GABA-A receptor modulators (the barbiturate pentobarbital, the high-efficacy benzodiazepine midazolam, and the low-efficacy benzodiazepine enazenil). When tested alone, none of the compounds substituted fully for the discriminative stimulus effects of cocaine. As acute pretreatments, select doses of midazolam and pentobarbital produced 2.2- to 3.6-fold rightward shifts in the cocaine dose-effect function. In contrast, muscimol, baclofen, GVG, and enazenil failed to alter the discriminative stimulus effects of cocaine. In assays of cocaine- and food-maintained responding, midazolam and pentobarbital decreased cocaine self-administration at doses 9.6- and 3.3-fold lower, respectively, than those that decreased food-maintained responding. In contrast, muscimol, baclofen, and GVG decreased cocaine self-administration at doses that also decreased food-maintained responding. Enazenil failed to alter cocaine self-administration. Together with previous studies, these data suggest that among mechanistically diverse GABA agonists, high-efficacy GABA-A modulators may be the most effective for modifying the abuse-related effects of cocaine.
Footnotes
This work was supported by National Institute on Drug Abuse Grants T32-DA07252, R29-DA12142, P01-DA14528, R01-DA11949, R01-DA02519, and K05-DA00101, and the Zaffaroni Foundation.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.105.086033.
ABBREVIATIONS: VTA, ventral tegmental area; FR, fixed ratio; TO, time out; GVG, γ-vinyl-GABA; ANOVA, analysis of variance; SCH 39166, (-)-trans_-6,7,7_a,8,9,13_b_-hexahydro-3-chloro-2-hydroxy-_N_-methyl-5_H_-benzo[_d_]naptho-(2,1-b)azepine.
- Received March 9, 2005.
- Accepted July 18, 2005.
The American Society for Pharmacology and Experimental Therapeutics
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