Effects of fentanyl on acute locomotor activity, behavioral sensitization, and contextual reward in female and male rats

Background: Although fentanyl has gained widespread prominence, there remains a lack of knowledge on this opioid synthetic agonist, particularly related to sex effects. Therefore, we conducted behavioral tests in female and male rats to measure drug abuse-related responses to fentanyl hypothesizing sex-specific responses. Methods: Using female and male rats, we measured the effects of acute or repeated administration of fentanyl (20 mu g/kg) on locomotor activity (LMA) and behavioral sensitization in an open field test. We further measured contextual-reward and associated locomotor activity during training in a conditioned place preference (CPP) paradigm using a low (4 mu g/kg) or high (16 mu g/kg) dose of fentanyl. Vaginal lavage samples were collected from female rats in the CPP study, and the estrous phase was determined based on the cytological characterization. Results: Female, but not male, rats showed elevated LMA in response to acute fentanyl and behavioral sensitization to repeated administration of fentanyl. Fentanyl produced significant CPP in both sexes, but it was more potent in males. Finally, our secondary investigation of the estrous cycle on fentanyl-CPP suggests that non-estrus phases, likely reflecting high estradiol, may predict the degree of fentanyl preference in females. Conclusions: Fentanyl was more potent and/or effective to produce LMA and LMA sensitization in females but more potent to produce CPP in males. Furthermore, the role of sex in fentanyl responses varied across endpoints, and sex differences in LMA were not predictive of sex differences in CPP.

Automated summary

Female rats showed elevated locomotor activity in response to acute fentanyl and behavioral sensitization to repeated administration, while male rats exhibited a stronger conditioned place preference effect. Secondary investigation suggested that non-estrus phases in females may predict fentanyl preference.