Investigating the effects of sex on depression-related behaviour evoked by kappa opioid receptor activation in the forced swim test

Introduction: Emerging evidence across a number of disciplines highlight that there are significant sex differences in psychopharmacology (Bolea et al. J Psychopharmacol. 2018; 32; p125-133). Kappa opioid (KOP) receptors play a role in the response to stress and have been investigated as potential targets for the treatment of psychiatric disorders including depression and drug dependence (Carlezon & Krystal. Depress Anxiety. 2016; 33; p895-906). Studies have shown the sexual dimorphic nature of the response to KOP receptor activation in preclinical behavioural tasks, for example; California mice develop a conditioned place aversion at different doses of U50,488. In addition, the females show a biphasic response to U50488 but not the males (AR Laman-Maharg et al. Behav Brain Res. 2017; 332; p299-307). Here we have investigated the effects of the KOP receptor agonist, U50,488, on behaviours in the forced swim test in C57BL/6J and CD1 mice of both sexes. Methods: Adult female and male C57BL/6J and CD1 mice (7-10 weeks) were housed in groups of 4. Female and male mice received either saline (0.9%) or U50,488 (0.1mg/kg, 1mg/kg or 5mg/kg) subcutaneously at a volume of 10ml/kg and n=5-8 per treatment group. Pilot studies evaluated the locomotor effects of U50,488 in an open field test. Drugs were administered 45 min prior to testing in a 6 min forced swim test. A video camera, Sony-DCR-SR52, was used to record the mice’s behaviour and behaviour in the final 4 minutes was analysed, blind to treatment. Two way ANOVA was used to assess the effects of sex and treatment (InVivoStat). Results: There was a significant effect of treatment with U50,488 on time spent immobile in the forced swim test in CD1 mice (F (3, 48) = 13.10, P<0.0001) but not C57BL/6J mice (F (3, 46) = 0.38, P=0.77). There was no significant effect of sex on immobility behaviour in the forced swim test in either mouse strain (F (1, 48) =0.21, P=0.65; F (1, 46) =0.36, P=0.55). Pairwise analysis of U50,488’s effects showed a significant increase in the time spent immobile in both male and female CD1 mice at 5mg/kg (P<0.001) but the 0.1 mg/kg dose only produced a significant effect in male mice (P<0.05). Conclusions: Taken together, the results show that KOP receptor activation by U50,488 causes a pro-depressant effect in both female and male CD1 mice, at doses that are without significant locomotor effects. There were no significant effects of sex in these studies although male CD1 mice may be more susceptible to the prodepressant effects of KOP activation than their female counterparts as lower doses of U50,488 produced a significant increase in the time spent immobile. There is clear evidence of a difference in responding to KOP receptor activation between strains, highlighting again the importance of strain specific differences in preclinical behavioural studies (Lucki et al. Psychopharmacology (Berl). 2001; 155; p315-322).