High incidence of estrous cycle irregularities in heterogeneous stock (HS) rats is associated with footshock-resistant cocaine intake

Hormonal fluctuations throughout the estrous cycle are hypothesized to influence drug-related behaviors. Preclinical models show that some cocaine-related behaviors are influenced by the estrous cycle. However, the extent to which the estrous cycle modulates cocaine self-administration in outbred heterogeneous stock (HS) rats is unknown. We aimed to examine the relationship between estrous phases and cocaine self-administration behavior in HS rats using an operant model of extended access to cocaine self-administration. We assessed the escalation of intake, breaking point, and resistance to foot shock. Using vaginal swabbing and lavage techniques, we characterized the relationship between estrous phase and cocaine behaviors. We then comprehensively evaluated estrous cycling patterns in young adult and adult HS rats, comparing them with Wistar rats. Estrous phase showed no association with cocaine self-administration in HS rats. 82% of female HS rats exhibited irregular estrous cycling with variability to the phase length, even in the absence of drug exposure, a phenomenon not observed in the Wistar strain. Females with irregular cycling showed greater footshock-resistant cocaine intake. This study provides the first evidence that most female HS rats exhibit irregular estrous cycling. In HS rats, the estrous phase per se has no major influence on cocaine self-administration, whereas cycling irregularity was associated with specific addiction-related behaviors, including footshock-resistant intake. As HS rats gain popularity in behavioral and genome-wide studies, understanding these cycle disruptions is crucial as they may reveal genetic links into cycling variability and individual differences to aspects of cocaine use.