The gamma-aminobutyric acid-B receptor agonist baclofen attenuates responding for ethanol in ethanol-dependent rats

Abstract

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.

Fig. 1

Mean (±SEM) lever-presses during the acquisition of ethanol and water operant self-administration, which clearly display a separation between ethanol and water responding as well as a maintained stability in responding.

Fig. 2

Mean (+SEM) breakpoints for ethanol over 18 sessions.

Fig. 3

Mean (+SEM) lever-presses for ethanol and water following baclofen (0.0, 0.5, 1, 2, and 4 mg/kg) challenge in nondependent and ethanol-dependent states (^{# #}p<0.01 when comparing the vapor-naïve and vapor-exposed conditions; *p<0.05 and **p<0.01 when compared with the appropriate vapor-naïve or vapor-exposed vehicle control).

Fig. 4

Mean (+SEM) ethanol consumption (g/kg) following baclofen (0.0, 0.5, 1, 2, and 4 mg/kg) challenge in nondependent and ethanol-dependent states (^{# #}p<0.01 when comparing the vapor-naïve and vapor-exposed vehicle conditions; *p<0.05 and **p<0.01 when compared with the appropriate vapor-naïve or vapor-exposed vehicle control).

Fig. 5

Mean (+SEM) breakpoints for ethanol with and without baclofen pretreatment while in nondependent and ethanol-dependent states (**p<0.01 for main effect of vapor exposure on ethanol self-administration; ^{# #}p<0.01 for main effect of baclofen on progressive-ratio breakpoints).

Fig. 6

Mean (+SEM) cumulative responses for ethanol with and without baclofen pretreatment while in nondependent and ethanol-dependent states (***p<0.001 for main effect of vapor-exposure; ^#p<0.05 for main effect of baclofen on cumulative responding).

Fig. 7

Mean cumulative responses for ethanol over the 180-minute progressive-ratio session while in nondependent and ethanol-dependent states. Ethanol-dependent animals worked longer and harder to obtain ethanol than when in their nondependent state.