GABAB receptor agonists reduce operant ethanol self-administration and enhance ethanol sedation in C57BL/6J mice
A growing number of studies suggest that γ-aminobutyric acid type-B (GABAB) receptor agonists reduce alcohol use and craving.
This study was designed to further clarify behavioral mechanism(s) by which GABAB agonists may decrease alcohol reinforcement.
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 GABAB 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 GABAB agonists was examined in ethanol naive and self-administering mice.
Baclofen (10 mg/kg) and SKF 97541 (0.3 mg/kg) reduced ethanol-reinforced responding. In a locomotor activity test, these doses of the GABAB 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 GABAB 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. GABAB 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.
GABAB 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 GABAB agonists were reduced in alcohol experienced mice, suggesting cross-tolerance to the inhibitory properties of GABAB positive modulation. These data question the safety of prescribing GABAB agonists to alcoholics since these drugs may potentiate ethanol’s sedative/hypnotic effects during relapse.
KeywordsAlcohol self-administration Reinforcement Mice GABAB agonist Baclofen SKF 97514 Locomotor activity Sedation
This work was supported by grants AA09981 and AA011605 to C.W.H. from the National Institute on Alcohol Abuse and Alcoholism and by the Bowles Center for Alcohol Studies.
- Broadbent J, Harless WE (1999) Differential effects of GABA(A) and GABA(B) agonists on sensitization to the locomotor stimulant effects of ethanol in DBA/2J mice. Psychopharmacology 141:197–205Google Scholar
- Faigle JW, Keberle H (1972) The chemistry of lioresal. Postgrad Med J Suppl 5:9–13Google Scholar
- Mead AJ, Little HJ (1995) Do GABAB receptors have a role in causing behavioural hyperexcitability, both during ethanol withdrawal and in naive mice? Psychopharmacology 117:232–239Google Scholar
- Samson HH (1987) Initiation of ethanol-maintained behavior: a comparison of animal models and their implication to human drinking. In: Thompson T, Dews PB, Barrett JE (eds) Adv Behav Pharmacol, vol 6. Neurobehavioral Pharmacology. Lawrence Erlbaum, Hillsdale, NJ, pp 221–248Google Scholar