Sex-dependent effects of yohimbine and prior ethanol-induced flavor aversion learning on ethanol intake and cortisol levels.

Stress is a major factor in alcohol drinking, but its effects may depend on sex and prior experience with ethanol's aversive consequences. This study examined whether yohimbine-induced pharmacological stress modifies ethanol-induced flavor aversion learning (FAL), voluntary ethanol intake, and plasma cortisol in male and female Wistar rats. Rats received vehicle or yohimbine, and a subset was first exposed to an ethanol-induced FAL procedure (intraperitoneal ethanol, 1.5 g/kg). Animals pre-exposed and not pre-exposed to FAL then underwent a 12-day two-bottle voluntary ethanol procedure with escalating concentrations (2%, 4%, 8%, 10%). Intake was analyzed across concentration phases and during an a priori high-concentration phase (8%-10%). Plasma cortisol was measured at the end of the experiment. FAL was acquired across groups, although its temporal expression varied with sex and yohimbine. During voluntary drinking, intake increased with concentration and was higher in females. Intake depended on the interaction among concentration, sex, prior FAL, and yohimbine. The clearest pattern emerged at high concentrations: under vehicle, females pre-exposed to FAL showed lower intake than non-pre-exposed females, a difference absent under yohimbine; within pre-exposed females, yohimbine increased intake. This pattern was not observed in males, although vehicle-treated pre-exposed males showed increased intake at 10%. Yohimbine increased plasma cortisol overall, and females showed higher cortisol than males, but cortisol did not fully parallel the intake pattern. Prior aversive ethanol experience and pharmacological stress interact in a sex-dependent manner to shape voluntary ethanol intake, with the clearest impact in females.