The irreversible gamma-aminobutyric acid (GABA) transaminase inhibitor gamma-vinyl-GABA blocks cocaine self-administration in rats.
gamma-Vinyl gamma-aminobutyric acid (GABA) (GVG) is an irreversible inhibitor of GABA transaminase, the primary enzyme involved in GABA metabolism. Acute administration of GVG increases brain GABA levels and blocks cocaine-induced locomotor activity, cocaine-induced lowering of brain stimulation reward thresholds, and cocaine-induced conditioned place preference. To further evaluate the effects of GVG on cocaine-induced reward, we examined its effects on cocaine self-administration in male Wistar rats on fixed ratio 5 and progressive ratio schedules of reinforcement. Additionally, the effects of GVG on operant responding for a food reward were examined on the same two schedules to determine whether the effects of GVG were specific to cocaine reward or generalized to other types of reward. GVG dose dependently decreased responding for cocaine on both schedules of reinforcement, suggesting that GVG attenuated the reward value of the cocaine. Responding for food was also decreased by GVG, suggesting that the effects of increased GABA levels induced by GVG may have a general effect on central reward systems. Data from this and other studies indicate that GVG does not induce motor impairment, decrease spontaneous locomotor activity, or induce catalepsy. Taken together, these data suggest that increases in GABAergic activity induced by GVG have an attenuating effect on centrally mediated reward systems and that the GABA system may be a useful target in the development of new therapeutic strategies for cocaine addiction.
Laboratory of Behavioral Pharmacology, Department of Pharmacology, Boston University School of Medicine, Boston, Massachusetts. sk53@is7.nyu.edu
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Kushner
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Dewey
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Kornetsky
D000612:4-Aminobutyrate Transaminase / Q000037:antagonists & inhibitors*; D000818:Animals; D003042:Cocaine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D005502:Food; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012055:Reinforcement Schedule; D012201:Reward; D012646:Self Administration; D020888:Vigabatrin; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
D004791:Enzyme Inhibitors; D005680:gamma-Aminobutyric Acid; D000612:4-Aminobutyrate Transaminase; D020888:Vigabatrin; D003042:Cocaine