Divergent behavioral responses in protracted opioid withdrawal in male and female C57BL/6J mice

• Published in: The European journal of neuroscience Vol. 51; no. 3; pp. 742 - 754
• Main Authors: Bravo, Isabel M., Luster, Brennon R., Flanigan, Meghan E., Perez, Patric J., Cogan, Elizabeth S., Schmidt, Karl T., McElligott, Zoe A.
• Format: Journal Article
• Language: English
• Published: France Wiley Subscription Services, Inc 01-02-2020
• Subjects: anxiety; Behavior; Divergence; Drug addiction; Drug withdrawal; Gender differences; Latency; locomotor activity; Morphine; Narcotics; opioid withdrawal; Opioids; Rodents; Sex differences; Social interaction; Thigmotaxis; anxiety; locomotor activity; opioid withdrawal; sex differences
• ISSN: 0953-816X; 1460-9568
• DOI: 10.1111/ejn.14580

Persons suffering from opioid use disorder (OUD) experience long‐lasting dysphoric symptoms well into extended periods of withdrawal. This protracted withdrawal syndrome is notably characterized by heightened anxiety and hyperkatifeia. Here, we investigated if an exacerbated withdrawal model of acute morphine dependence results in lasting behavioral adaptation 6 weeks into forced abstinence in C57BL/6J mice. We found that our exacerbated morphine withdrawal paradigm produced distinct alterations in behavior in elevated plus maze (EPM), open field, and social interaction tests in male and female mice. Following protracted withdrawal male mice showed enhanced exploration of the open arms of the EPM, reduced latency to enter the corner of the OF, and a social interaction deficit. In contrast, female mice showed enhanced thigmotaxis in the OF. In both sexes, protracted withdrawal enhanced locomotor behavior in response to subsequent morphine challenge, albeit at different doses. These findings will be relevant for future investigation examining the neural mechanisms underlying these behaviors and will aid in uncovering physiological sex differences in response to opioid withdrawal.
Six weeks following the exacerbated morphine withdrawal paradigm, sexually dimorphic behavioral adaptations were observed in elevated plus maze, open field, social interaction, and morphine challenge assays. These findings reveal sex differences in C57BL/6J mice in the long‐lasting dysphoric symptoms of protracted withdrawal syndrome, which is characterized by altered anxiety‐like behavior and hyperkatifeia.