The gamma-aminobutyric acid-B receptor agonist baclofen attenuates responding for ethanol in ethanol-dependent rats.
BACKGROUND
Gamma-aminobutyric acid-B (GABA(B)) receptor agonists have been shown to suppress operant self-administration of ethanol in nondependent rats. However, little work has focused on the effects of GABA(B) receptor agonists on self-administration of ethanol in dependent animals.


METHODS
In the present experiment, the GABA(B) receptor agonist baclofen was tested for the ability to modulate both fixed- (FR) and progressive-ratio (PR) responding for ethanol in rats while nondependent and subsequently after ethanol dependence induction. Following the acquisition and stabilization of baseline operant ethanol self-administration and after dependence induction, baclofen [0.0, 0.5, 1, 2, and 4 mg/kg, intraperitoneal (IP)] was tested on FR-1 responding for ethanol. The ability of baclofen (2.0 mg/kg) to affect responding under a PR schedule of reinforcement was also evaluated. Dependence was induced in the animals by subjecting them to a 1-month intermittent vapor-exposure period in which animals were exposed to ethanol vapor for 14 h/d. Following the 1-month period, the vapor-exposed animals resumed FR-1 and PR baclofen drug testing (doses as described above) in the operant chambers at a time point corresponding to the animals being 6 hours into withdrawal (i.e., 6 hours after the ethanol vapor had been discontinued for that day).


RESULTS
Baclofen (0.0, 0.5, 1, 2, and 4 mg/kg, IP) dose-dependently decreased ethanol self-administration in both nondependent and dependent rats on a FR schedule of reinforcement. However, the dose of baclofen that significantly reduced responding for ethanol was shifted to the left in the ethanol vapor-exposed animals, indicating an increased sensitivity to baclofen in animals that were chronically exposed to ethanol. When tested using a PR schedule of reinforcement, there was a significant increase in the breakpoint for the vapor-exposed animals (i.e., the animals were willing to work more in a dependent state). Baclofen (2.0 mg/kg, IP) suppressed intake for both nondependent and dependent animals.


CONCLUSIONS
Ethanol dependence produced increased self-administration of ethanol as reflected in increased ethanol intake and increased responding on a PR schedule of reinforcement. As baclofen suppressed ethanol self-administration and showed evidence of increased potency in dependent animals, the present experiment suggests that the GABA(B) receptor could be a potential pharmacotherapeutic target for the treatment of chronic alcoholism.
Walker
Brendan M
BM
Molecular and Integrative Neurosciences Department, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA. bwalker@scripps.edu
Koob
George F
GF
D000437:Alcoholism / Q000523:psychology*; D000818:Animals; D001418:Baclofen / Q000494:pharmacology*; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects; D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000494:pharmacology*; D018755:GABA Agonists / Q000494:pharmacology*; D008297:Male; D051381:Rats; D018080:Receptors, GABA-B / Q000187:drug effects*; D012055:Reinforcement Schedule
D002492:Central Nervous System Depressants; D018755:GABA Agonists; D018080:Receptors, GABA-B; D000431:Ethanol; D001418:Baclofen