Sex differences in the modulation of mouse nest building behavior by kappa opioid receptor signaling

• Published in: Neuropharmacology 2020-10, Vol.177, p.108254-108254, Article 108254
• Main Authors: Jacobson, Moriah L., Wulf, Hildegard A., Tsuda, Mumeko C., Browne, Caroline A., Lucki, Irwin
• Format: Article
• Language: English
• Subjects: Analgesics, Non-Narcotic - pharmacology; Analgesics, Opioid - pharmacology; Animals; Antidepressant; Aticaprant; Estrogen receptors; Female; JNJ-67953964; Kappa opioid receptors; Locomotion - drug effects; Locomotion - physiology; Male; Mice; Mice, Inbred C57BL; Narcotic Antagonists - pharmacology; Nesting; Nesting Behavior - drug effects; Nesting Behavior - physiology; Receptors, Opioid, kappa - agonists; Receptors, Opioid, kappa - antagonists & inhibitors; Receptors, Opioid, kappa - metabolism; Sex Characteristics; Sex differences; Signal Transduction - drug effects; Signal Transduction - physiology
• ISSN: 0028-3908; 1873-7064; 1873-7064
• DOI: 10.1016/j.neuropharm.2020.108254

Emerging evidence suggests that females are less sensitive than males to the effects of kappa opioid receptor (KOR) ligands across multiple behavioral measures. The effects of the KOR agonist U50,488 and the KOR antagonist aticaprant were assessed on nest building behavior, an ethologically relevant indicator of overall well-being and affect, in adult male and female C57BL/6J mice. Females required a higher dose of U50,488 to suppress nesting, and a higher dose of aticaprant to restore U50,488-induced impairment of nesting. Females also required a higher dose of aticaprant to decrease immobility scores in the forced swim test. Pretreatment with the estrogen receptor modulator tamoxifen, at a dose which blocked estrogen receptors, augmented the effect of U50,488 on nesting in female mice, suggesting that estrogen receptors play a key role in attenuating the effects of KOR ligands in female mice. Together, these results suggest that females are less sensitive to KOR mediation, requiring a higher dose to achieve comparable results to males. This behavioral sensitivity, as measured by nesting, may be mediated by estrogen receptors. Together these studies highlight the importance of comparing sex differences in response to KOR regulation on behaviors related to affective states. •Nest building behavior in mice is useful to investigate overall well-being.•Kappa opioid receptor (KOR) activation impairs nesting in both sexes.•Female mice require higher doses to induce KOR-mediated changes.•Estrogen receptors diminish KOR-mediated alterations in females.•The KOR antagonist aticaprant is effective on the FST in both sexes.