Influence of sex and estrous cyclicity on conditioned cue-induced reinstatement of cocaine-seeking behavior in rats

Rationale: Sex differences have been reported in physiological and behavioral responses to cocaine, but it is unclear whether sex differences exist in conditioned-cued relapse to cocaine seeking after prolonged abstinence. Furthermore, the role of estrous cyclicity in conditioned-cued relapse has not been investigated. Objective: We assessed the influence of sex and estrous cyclicity on conditioned-cued reinstatement of drug-seeking behavior in Sprague - Dawley rats. Methods: Rats were trained to self-administer intravenous cocaine ( unconditioned stimulus, US; 0.25, 0.4, 0.5, 0.6, or 1.0 mg/kg per infusion) paired with light+ tone conditioned stimuli (CSs) and were subsequently tested for the ability of the CSs to reinstate extinguished cocaine seeking (i.e., nonreinforced lever responding). Results: Females exhibited more responding on the cocaine-paired lever during self-administration and extinction than males. Subsequently, males exhibited equally robust conditioned-cued reinstatement of extinguished drug-seeking behavior independent of cocaine training dose. Males and females trained on 0.4 - 0.6 mg/kg cocaine reinstated to a similar extent. However, females trained on the lowest dose ( 0.25 mg/kg) exhibited less reinstatement than males, and the source of this effect was the absence of reinstatement in estrous females. In addition, independent of estrous state, females trained on the highest dose ( 1.0 mg/kg) exhibited less reinstatement than males. Conclusions: While males and females are equally responsive to cocaine-paired CSs when the conditions for CS - US association are optimal, females appear to attribute less motivational significance to the CS when it presumably acquires weaker motivational salience because of ( a) a low cocaine dose or (b) weaker CS - US contiguity due to the prolonged effects of a high cocaine dose.