Sex Differences in the Effects of a Kappa Opioid Receptor Antagonist in the Forced Swim Test

Abstract

There is growing evidence that kappa opioid receptor (KOR) antagonists could be a useful class of therapeutics for treating depression and anxiety. However, the overwhelming majority of preclinical investigations examining the behavioral effects of KOR antagonists have been in male rodents. Here, we examined the effects of the long-acting KOR antagonist nor-binaltophimine (norBNI) on immobility in the forced swim test in males and females of two different rodent species (C57Bl/6J and California mice). Consistent with previous reports, norBNI (10 mg/kg) decreased immobility in the forced swim test for male C57Bl/6J and California mice. Surprisingly, dose–response studies in female C57Bl/6J and California mice showed that norBNI did not reduce immobility. Pharmacokinetic analyses showed that metabolism and brain concentrations of norBNI were similar in male and female C57Bl/6J. In the nucleus accumbens of male but not female C57Bl/6J, norBNI increased phosphorylation of c-Jun N-terminal kinase (pJNK), a putative mechanism for norBNI action. However, no differences in pJNK were observed in male or female California mice. Together, these results suggest that immobility in the forced swim test is less dependent on endogenous KOR signaling in female rodents and highlight the importance of examining the effects of possible therapeutic agents in both males and females.

Repeated Administration of Norbinaltorphimine Produces Cumulative Kappa Opioid Receptor Inactivation

“…Female mice and rats have been reported to be less sensitive than males in their responses to kappa opioid agonists and antagonists (Russell et al, 2014; Abraham et al, 2018; Laman-Maharg et al, 2018; Williams and Trainor, 2018). These sex differences raise important questions about the utility of kappa antagonists in the treatment of stress-disorders in women.…”

The Role of Dynorphin and the Kappa Opioid Receptor in Schizophrenia and Major Depressive Disorder: A Translational Approach

“…Studies have shown that intracerebroventricular (ICV) infusion of either norBNI (Mague et al 2003;Pliakas et al 2001) or 5'-GNTI (Mague et al 2003) decreased immobility in the FST in a dose-dependent manner in rats. Additionally, systemic norBNI reduces immobility in the FST in mice (Falcon et al 2016;Laman-Maharg et al 2018;McLaughlin et al 2003) and rats (Reed et al 2012). Similarly, JDTic reduced immobility at higher dosages tested in the FST in rats; however, in this specific experiment, both norBNI and desipramine had no effect (Beardsley et al 2005).…”

“…Female rats have been shown to be less sensitive than male rats to the depressive-like effects of KOR agonists (Russell et al 2014) and female guinea pigs are less sensitive than male guinea pigs to the effects on pain (Wang et al 2011). One experiment found that the antidepressant effects of norBNI on the FST in two different strains of male mice were not found in females (Laman-Maharg et al 2018). Interestingly, one PET imaging study of naltrexone in humans reported a higher KOR availability in men than in women (Vijay et al 2016).…”

Activation of kappa opioid receptors in the dorsal raphe have sex dependent effects on social behavior in California mice

“…In a place aversion assay, females form place aversions to a lower dose of the KOR agonist U50,488 than males [38, 39]. However, in a forced swim test norBNI reduced immobility in males but not females [40], consistent with other studies suggesting that males may be more sensitive KOR than females [41, 42]. Previous work showed that activation of KOR within the DRN induced anxiety- and depression-like behavior, so we expected that similar responses in stress naïve mice.…”