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

      Abstract

      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

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      Linked Article

      • Sex and Hormonal Status Influence the Persistence of Addiction in Animal Models
        Biological PsychiatryVol. 85Issue 11
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          In this issue of Biological Psychiatry, Nicolas et al. (1) add to a growing literature demonstrating the importance of sex and gonadal hormones in the development of substance use disorders. Their study focused on the incubation of cocaine craving in male versus female rats tested at different estrous cycle phases. Overall, they showed that estrous cyclicity significantly altered cocaine craving (or seeking) after a drug-free period. From a translational perspective, these incubation of craving and self-administration procedures model several key features of human substance use.
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