Enhancement of cue-induced reinstatement of cocaine-seeking in rats by yohimbine: sex differences and the role of the estrous cycle

Abstract

Rationale Previous studies have shown that female rats exhibit enhanced cocaine-seeking across several phases of the addiction cycle when compared to males. Drug-seeking in females is also estrous cycle dependent and inversely associated with plasma progesterone. Although sex and estrous cycle-dependent differences have been reported in the reinstatement of cocaine-seeking triggered by cocaine injections or drug-paired cues, it is not yet known what role the estrous cycle may have on stress-induced reinstatement, either alone or in combination with drug-paired cues. Objectives Here, we examined male and female rats for reinstatement of extinguished cocaine-seeking produced by cocaine-paired cues or the stress-activating drug, yohimbine. Methods Male and female Sprague–Dawley rats self-administered intravenous cocaine (0.5 mg/kg/infusion) paired with a light + tone stimulus for 10–14 days. Lever responding was then allowed to extinguish, with subsequent reinstatement testing occurring 30 min following an injection of yohimbine (1.25 or 2.5 mg/kg, intraperitoneal) or vehicle either in the presence or absence of the conditioned stimulus. Results While males and females showed similar cue- and yohimbine-induced reinstatement (3–4 times over “No Cue”-vehicle responding), combining these stimuli resulted in a robust enhancement in cocaine-seeking in both groups, with a greater increase in females (10–12 vs. 14–15 times over “No Cue”-vehicle responding for the males and females, respectively). When examined as a function of the estrous cycle, females in proestrus demonstrated higher levels of responding during yohimbine + cues reinstatement. Conclusions This cycle-dependent enhanced sensitivity to stress enhancement of cocaine-paired cues may generalize to greater relapse susceptibility under stressful conditions.