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

Abigail Laman-Maharg,Rebecca Hao,Vanessa A Minie,Mikaela D Zufelt,Alexia V Williams,Stephanie Ramos-Maciel,Angelina Leigh,Rodney Snyder,Jill L Silverman,F Ivy Carroll,Timothy R Fennell,Brian C Trainor,Tiffany Copeland,Evelyn Ordoñes Sanchez

doi:10.3389/fphar.2018.00093

Abigail Laman-Maharg, Rebecca Hao + Show 12 more

Open Access

https://doi.org/10.3389/fphar.2018.00093

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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.

Highlights

Psychosocial stress exposure is an important risk factor for the development of depression and anxiety disorders (Bruce, 2002)
We investigated the effects of norBNI and the kappa opioid receptor (KOR) agonist U50,488 on immobility in female California mice
On day 2, repeated measures ANOVA showed a trend for the effects of KOR ligands to have different effects in control and stressed mice (Figure 1C; drug × stress × trial interaction; F6,141 = 1.77, p = 0.09)

Summary

INTRODUCTION

Psychosocial stress exposure is an important risk factor for the development of depression and anxiety disorders (Bruce, 2002). The overwhelming majority of preclinical studies on KOR antagonists have been conducted in male rodents (but see, Russell et al, 2014), so it is unclear whether these antagonists have similar properties in females This is an essential question because women are almost twice as likely to develop depression as men (Kessler, 2003), and sex differences in physiological responses to stress may affect risk for depression (Bale and Epperson, 2015; Laman-Maharg et al, 2017). One modified form uses repeated 5 min bouts of forced swim on day 2, and in this protocol, the selective KOR antagonist norBNI decreases immobility (McLaughlin et al, 2003) This 2-day protocol has been found to induce other KOR-dependent behavioral (Land et al, 2008) and neurobiological (Bruchas et al, 2007a) responses. We examined the effects of norBNI on the phosphorylation of c-Jun N-terminal kinase (pJNK) in the nucleus accumbens (NAc). pJNK is thought to be an important mechanism of norBNI action in the forced swim test (Bruchas et al, 2007b)

Experiments

RESULTS

DISCUSSION