Incubation of Cocaine Craving After Intermittent-Access Self-administration: Sex Differences and Estrous Cycle

Biol Psychiatry. 2019 Jun 1;85(11):915-924. doi: 10.1016/j.biopsych.2019.01.015. Epub 2019 Jan 29.


Background: Studies using continuous-access drug self-administration showed that cocaine seeking increases during abstinence (incubation of cocaine craving). Recently, studies using intermittent-access self-administration showed increased motivation to self-administer and seek cocaine. We examined whether intermittent cocaine self-administration would potentiate incubation of craving in male and female rats and examined the estrous cycle's role in this incubation.

Methods: In experiment 1, male and female rats self-administered cocaine either continuously (8 hours/day) or intermittently (5 minutes ON, 25 minutes OFF × 16) for 12 days, followed by relapse tests after 2 or 29 days. In experiments 2 and 3, female rats self-administered cocaine intermittently for six, 12, or 18 sessions. In experiment 4, female rats self-administered cocaine continuously followed by relapse tests after 2 or 29 days. In experiments 3 and 4, the estrous cycle was measured using a vaginal smear test.

Results: Incubation of cocaine craving was observed in both sexes after either intermittent or continuous drug self-administration. Independent of access condition and abstinence day, cocaine seeking was higher in female rats than in male rats. In both sexes, cocaine seeking on both abstinence days was higher after intermittent drug access than after continuous drug access. In female rats, incubation of craving after either intermittent or continuous drug access was significantly higher during estrus than during non-estrus; for intermittent drug access, this effect was independent of the training duration.

Conclusions: In both sexes, intermittent cocaine access caused time-independent increases in drug seeking during abstinence. In female rats, the time-dependent increase in drug seeking (incubation) is critically dependent on the estrous cycle phase.

Keywords: Cocaine self-administration; Estrous cycle; Incubation of craving; Intermittent access; Relapse; Sex differences.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Cocaine / pharmacology*
  • Craving / drug effects*
  • Craving / physiology*
  • Estrous Cycle / physiology*
  • Extinction, Psychological
  • Female
  • Male
  • Rats
  • Self Administration / methods
  • Sex Characteristics*
  • Time Factors


  • Cocaine