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  • Title: Protracted time-dependent increases in cocaine-seeking behavior during cocaine withdrawal in female relative to male rats.
    Author: Kerstetter KA, Aguilar VR, Parrish AB, Kippin TE.
    Journal: Psychopharmacology (Berl); 2008 May; 198(1):63-75. PubMed ID: 18265959.
    Abstract:
    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.
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