Elsevier

Biological Psychiatry

Volume 85, Issue 11, 1 June 2019, Pages 915-924
Biological Psychiatry

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

https://doi.org/10.1016/j.biopsych.2019.01.015Get rights and content

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.

Section snippets

Methods and Materials

For information on subjects, see the Supplement.

Cocaine Self-administration

During the acquisition phase in sessions 1 to 4 (2 hours/day continuous access) there were no sex differences in the number of infusions, the frequency of infusions (infusions/min), and active and inactive lever presses (Figure 1B–E). Results showed that escalation of cocaine intake of days was observed under both access conditions, that total daily drug intake and the number of active lever presses were higher in the continuous-access condition, that infusion rate per minute and the number of

Discussion

We examined the effect of intermittent cocaine self-administration on incubation of cocaine craving in male and female rats. There are four main findings in our study. First, incubation of cocaine craving during abstinence was observed after intermittent-access drug self-administration, extending previous reports using the classical continuous-access training procedure 9, 13, 63. Second, in both male and female rats and independent of the abstinence day, intermittent-access cocaine

Acknowledgments and Disclosures

The research was supported by the Intramural Research Program of National Institute on Drug Abuse (to SI and YS) and a fellowship from the National Institute on Drug Abuse–French Institute of Health and Medical Research program (to CN).

CN, TIR, AP, SM, AH, and Z-BY carried out the experiments; CN and TIR performed data analysis. CN, MMC, AH, YS, and SI designed the study. CN, YS, and SI wrote the manuscript. All authors critically reviewed the content and approved the final version before

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