Baclofen blocks yohimbine-induced increases in ethanol-reinforced responding in rats

Chronic or repeated stress increases alcohol consumption. The GABA-B agonist baclofen decreases alcohol consumption and may be most effective for individuals with comorbid anxiety/stress disorders. The present study sought to determine if baclofen blocks stress-induced increases in ethanol self-administration as modeled by repeated yohimbine injections in rats. Rats were trained to respond for 15% w/v ethanol in operant chambers using a method that applies neither water deprivation nor saccharin/sucrose fading. Following training, the rats received 6 injections of 1.25 mg/kg yohimbine were given immediately prior to the operant sessions during a 2-week time period. Subsequently, some rats were pair-matched to receive either 1.25 mg/kg yohimbine or saline in the presence of 0.3, 1, and 3 mg/kg baclofen prior to sessions. Acquisition of ethanol self-administration was poor. Pretreatment with yohimbine consistently increased responding across repeated injections. Yohimbine's effect on ethanol intake unexpectedly diverged from the effect on responding as the rats failed to consume all reinforcers earned. Smaller doses of baclofen paired with saline injections had no effect on ethanol responding; only 3 mg/kg baclofen reduced ethanol self-administration. The smallest baclofen dose of 0.3 mg/kg failed to block the yohimbine-induced increase in self-administration. The large baclofen dose of 3 mg/kg continued to suppress ethanol self-administration when given with yohimbine. Baclofen 1 mg/kg blocked the effect of yohimbine even though it had no effect when given in the absence of yohimbine. Exposure to high ethanol concentrations may induce self-administration only in certain conditions. The dissociation between responding and intake suggests that repeated yohimbine injections may initiate other behavioral or physiological mechanisms that confound its effects as a pharmacological stressor. Furthermore, an optimal baclofen dose range may specifically protect against stress-induced alcohol self-administration, highlighting a specific contribution of GABA-B receptors and a potential therapeutic efficacy of GABA-B agonists at a non-sedating dose.