GABA(B) receptor agonists reduce operant ethanol self-administration and enhance ethanol sedation in C57BL/6J mice.
BACKGROUND
A growing number of studies suggest that gamma-aminobutyric acid type-B (GABA(B)) receptor agonists reduce alcohol use and craving.


OBJECTIVE
This study was designed to further clarify behavioral mechanism(s) by which GABA(B) agonists may decrease alcohol reinforcement.


METHODS
Male C57BL/6 J mice were trained to lever press on a concurrent schedule of ethanol (10% v/v) and water reinforcement during 16-h overnight sessions. Effects of the GABA(B) agonist baclofen (0-17 mg/kg, IP) or SKF 97541 (0-1 mg/kg, IP) were examined on parameters of self-administration. Subsequently, potential motor inhibition and interaction with ethanol-induced sedation by GABA(B) agonists was examined in ethanol naive and self-administering mice.


RESULTS
Baclofen (10 mg/kg) and SKF 97541 (0.3 mg/kg) reduced ethanol-reinforced responding. In a locomotor activity test, these doses of the GABA(B) agonists inhibited locomotion in the ethanol-experienced mice and in a group of ethanol-inexperienced mice; locomotor suppression was greater in the ethanol-inexperienced mice. These doses of the GABA(B) agonists also potentiated the sedative effects of ethanol (4 g/kg) and converted a nonsedative dose of ethanol (2 g/kg) into a fully sedative dose. GABA(B) agonist enhancement of the sedative effects of ethanol was less pronounced in ethanol self-administering mice, suggesting cross-tolerance at the low dose of ethanol.


CONCLUSIONS
GABA(B) agonists decrease the reinforcing effects of ethanol at doses that inhibit locomotor activity and potentiate the sedative hypnotic effects of ethanol. These nonspecific effects of GABA(B) agonists were reduced in alcohol experienced mice, suggesting cross-tolerance to the inhibitory properties of GABA(B) positive modulation. These data question the safety of prescribing GABA(B) agonists to alcoholics since these drugs may potentiate ethanol's sedative/hypnotic effects during relapse.
Besheer
Joyce
J
Bowles Center for Alcohol Studies, Department of Psychiatry, Thurston-Bowles Building, University of North Carolina at Chapel Hill, CB#7178, Chapel Hill, NC 27599, USA. jbesheer@med.unc.edu
Lepoutre
Veronique
V
Hodge
Clyde W
CW
D000704:Analysis of Variance; D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D003216:Conditioning, Operant / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D000431:Ethanol / Q000494:pharmacology*; D018755:GABA Agonists / Q000494:pharmacology*; D058786:GABA-B Receptor Agonists; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009943:Organophosphorus Compounds / Q000494:pharmacology; D018080:Receptors, GABA-B / Q000502:physiology*; D012018:Reflex / Q000187:drug effects; D012646:Self Administration
D018755:GABA Agonists; D058786:GABA-B Receptor Agonists; D006993:Hypnotics and Sedatives; D009943:Organophosphorus Compounds; D018080:Receptors, GABA-B; C068457:3-aminopropyl(methyl)phosphinic acid; D000431:Ethanol; D001418:Baclofen