TY - JOUR T1 - Effects of Sex and Estrous Cycle on the Time-Course of Incubation of Cue-Induced Craving Following Extended-Access Cocaine Self-Administration JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0054-21.2021 SP - ENEURO.0054-21.2021 AU - Claire M. Corbett AU - Emily Dunn AU - Jessica A. Loweth Y1 - 2021/07/21 UR - http://www.eneuro.org/content/early/2021/07/21/ENEURO.0054-21.2021.abstract N2 - Cocaine addiction is a devastating public health epidemic that continues to grow. Studies focused on identifying biological factors influencing cocaine craving and relapse vulnerability are necessary in order to promote abstinence in recovering drug users. Sex and ovarian hormones are known to influence cocaine addiction liability and relapse vulnerability in both humans and rodents. Previous studies have investigated sex differences in the time-dependent intensification or “incubation” of cue-induced cocaine craving that occurs during withdrawal from extended-access cocaine self-administration and have identified changes across the rat reproductive cycle (estrous cycle). Female rats in the estrus stage of the cycle (Estrus Females), the phase during which ovulation occurs, show an increase in the magnitude of incubated cue-induced cocaine craving compared to females in all other phases of the estrous cycle (Non-Estrus Females). Here we extend these findings by assessing incubated craving across the estrous cycle during earlier (withdrawal day 1 and 15) and later withdrawal periods (withdrawal day 48). We found that this increase in the magnitude of incubated craving during estrus (Estrus Females) is present on withdrawal day 15 but not withdrawal day 1 and further increases by withdrawal day 48. No difference in the magnitude of incubated craving was observed between Males and Non-Estrus Females. Our data indicate that the effects of hormonal fluctuations on cue-induced cocaine craving intensify during the first month and a half of withdrawal, showing an interaction between abstinence length, estrous cycle fluctuations, and cocaine craving.SIGNIFICANCE STATEMENTCocaine addiction is a chronic, relapsing condition. Females have been historically understudied in preclinical research studies but understanding how biological factors like sex and ovarian hormones influence relapse vulnerability is critical in our understanding of how to reduce craving and promote abstinence in recovering users of both sexes. Here we characterized changes in the intensification or “incubation” of cue-induced cocaine craving during earlier and later withdrawal from extended-access cocaine self-administration between male and female rats and across the estrous cycle. Our results indicate an interaction between estrous cycle fluctuations and time-dependent changes in the underlying craving state and lay the foundation for future studies focused on investigating cellular mechanisms driving sex differences in relapse vulnerability. ER -