Sex and hormonal status influence the anxiolytic-like effect of oxytocin in mice

Khalin E Nisbett; Luis A Gonzalez; Marina Teruel; C Sue Carter; Leandro F Vendruscolo; Michael E Ragozzino; George F Koob

doi:10.1016/j.ynstr.2023.100567

Sex and hormonal status influence the anxiolytic-like effect of oxytocin in mice

Neurobiol Stress. 2023 Aug 26:26:100567. doi: 10.1016/j.ynstr.2023.100567. eCollection 2023 Sep.

Authors

Khalin E Nisbett^{1

2

3

4}, Luis A Gonzalez², Marina Teruel⁴, C Sue Carter^{5

6}, Leandro F Vendruscolo², Michael E Ragozzino⁴, George F Koob²

Affiliations

¹ Graduate Program in Neuroscience, Graduate College, University of Illinois Chicago, Chicago, IL 60607, USA.
² Neurobiology of Addiction Section, Integrative Neuroscience Research Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.
³ Stress and Addiction Neuroscience Unit, Integrative Neuroscience Research Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore, MD 21224, USA.
⁴ Department of Psychology, College of Liberal Arts and Sciences, University of Illinois Chicago, Chicago, IL 60607, USA.
⁵ Department of Psychology, University of Virginia, Charlottesville, VA 22903, USA.
⁶ Kinsey Institute, Indiana University, Bloomington, IN 47405, USA.

Abstract

Anxiety and depression are highly prevalent psychiatric disorders, affecting approximately 18% of the United States population. Evidence indicates that central oxytocin mediates social cognition, social bonding, and social anxiety. Although it is well-established that oxytocin ameliorates social deficits, less is known about the therapeutic effects of oxytocin in non-social contexts. We hypothesized that positive effects of oxytocin in social contexts are attributable to intrinsic effects of oxytocin on neural systems that are related to emotion regulation. The present study investigated the effect of intracerebroventricular (ICV) oxytocin administration (i.e., central action) on anxiety- and depression-like behavior in C57Bl/6J mice using non-social tests. Male and female mice received an ICV infusion of vehicle or oxytocin (100, 200, or 500 ng), then were tested in the elevated zero maze (for anxiety-like behavior) and the tail suspension test (for depression-like behavior). Oxytocin dose-dependently increased open zone occupancy and entries in the elevated zero maze and reduced immobility duration in the tail suspension test in both sexes. Oxytocin decreased anxiety and depression-like behavior in male and female mice. The observed effect of oxytocin on anxiolytic-like behavior appeared to be driven by the males. Given the smaller anxiolytic-like effect of oxytocin in the female mice and the established interaction between oxytocin and reproductive hormones (estrogen and progesterone), we also explored whether oxytocin sensitivity in females varies across estrous cycle phases and in ovariectomized females that were or were not supplemented with estrogen or progesterone. Oxytocin reduced anxiety-like behavior in female mice in proestrus/estrus, ovariectomized females (supplemented or not with estrogen or progesterone), but not females in metestrus/diestrus. Additionally, oxytocin reduced depression-like behavior in all groups tested with slight differences across the various hormonal statuses. These results suggest that the effect of oxytocin in depression- and anxiety-like behavior in mice can be influenced by sex and hormonal status.

Keywords: Anxiety; Depression; Estrous cycle; Oxytocin; Reproductive hormones; Sex differences.