Protracted time-dependent increases in cocaine-seeking behavior during cocaine withdrawal in female relative to male rats

Rationale Female rats display higher sensitivity to cocaine relative to males under a variety of conditions. Time-dependent increases in cocaine-seeking behavior (as measured by nonreinforced operant responses) during cocaine withdrawal have been reported in male, but not female, rats. Objectives The present study determines sex and estrous cycle influences on time-dependent changes in cocaine-seeking behavior. Materials and methods Male and female Sprague-Dawley rats were reinforced for “active lever” responses by a cocaine infusion (0.50 mg/kg/infusion, i.v., fixed ratio schedule of reinforcement, FR1) followed by a 20-s time-out when reinforcement was not delivered. Infusions were paired with a light + tone conditioned stimulus. Next, rats underwent cocaine withdrawal for 1, 14, 60, or 180 days before testing cocaine-seeking behavior. Each rat was tested for extinction of operant responding, conditioned-cued reinstatement, and cocaine-primed (10 mg/kg, i.p.) reinstatement. Results Both males and females displayed a time-dependent increase in cocaine-seeking behavior (active lever presses) under extinction of operant responding and conditioned-cued reinstatement conditions after 60 days of cocaine withdrawal. Moreover, cocaine-seeking behavior during extinction of operant responding in females, but not males, remained elevated at 180 days of cocaine withdrawal. Furthermore, females tested during estrus exhibited higher cocaine-seeking behavior under both extinction of operant responding and cocaine-primed reinstatement conditions relative to other rats independent of the duration of cocaine withdrawal. Conclusions The effects of reproductive cycle and withdrawal duration on cocaine-seeking behavior are additive and time-dependent increases in cocaine-seeking behavior are more enduring in females than in male rats.