The γ‐Aminobutyric Acid‐B Receptor Agonist Baclofen Attenuates Responding for Ethanol in Ethanol‐Dependent Rats

Abstract

Background: γ‐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.