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

Psychopharmacology (Berl). 2008 May;198(1):63-75. doi: 10.1007/s00213-008-1089-8. Epub 2008 Feb 12.


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.

MeSH terms

  • Animals
  • Cocaine / adverse effects*
  • Cocaine-Related Disorders / psychology*
  • Conditioning, Operant
  • Cues
  • Estrous Cycle / physiology
  • Female
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Reinforcement Schedule
  • Self Administration
  • Sex Characteristics
  • Substance Withdrawal Syndrome / psychology*
  • Time Factors


  • Cocaine