Sex differences in the effects of kappa opioid receptors agonists and acute stress on the mouse brain

Abstract

Stress is a risk factor for the development of psychiatric disorders (e.g. depression, anxiety) and drug addiction. Stress induces the release of endogenous neuropeptide, dynorphin, which primarily activates kappa opioid receptor (KOPr) and produces aversive and depressive-like behaviours in rodents. Stress-induced depressive-like behaviours and stressed-induced potentiation of drug self-administration are inhibited, at least in part, by blocking KOPrs, showing that KOPr plays an important role in mediating stress responses and motivational behaviours, and acts as a potential therapeutic target for the treatment of affective disorders. However, accumulating studies have reported that stress-induced behavioural effects or stress-induced KOPrs activation are sex dependent. In this study, the effects of acute forced swim stress (FSS) and activation of KOPr by the selective agonist, U50,488 (20mg/kg, i.p.) on neuronal activation in different brain regions (prefrontal cortex (PFCx), nucleus accumbens (NAc), hippocampus and amygdala) were investigated in both male and female mice.
Adult (9-13 weeks old) male and female C57BL/6 cFos-GFP transgenic mice were used, where the cFos acts as a neuronal activity marker and drives the production of green fluorescent protein (GFP) upon neuron activation. FSS and U50,488-induced neuronal activity (cFos or cFos-driven GFP expression) was detected by immunohistochemistry. Our data showed that there is an overlap in brain regions that are activated by U50,488 and FSS in male mice, with significant increases in cFos and cFos-driven GFP expression seen in the PFCx, NAc and basolateral amygdala following both types of stimuli. Only U50,488, not FSS, induced significant cFos expression in the hippocampal CA1 region and central amygdala in male mice. Different patterns were observed in female mice; in the PFCx, neither U50,488 nor FSS induced significant cFos expression. In the NAc, only FSS, not U50,488, increased cFos expression. Other regions in females, including hippocampal CA1, central amygdala and basolateral amygdala, showed similar cFos expression patterns that were seen in male mice. Generally, KOPr activation-induced cFos or GFP expression was significantly blocked by pretreatment KOPr antagonist, norBNI (10mg/kg, i.p.), whereas FSS-induced effects were not affected by norBNI. Overall, this study provided a better understanding of stress mechanisms, especially in PFCx and NAc, highlighting that PFCx and NAc are the regions that showed different effects following KOPr activation and in vivo stressor between male and female mice, which may underlie sex differences in stress-induced behaviours.

Date of Award	15 Jan 2020
Original language	English
Awarding Institution	University of Bath
Supervisor	Chris Bailey (Supervisor), Sue Wonnacott (Supervisor) & Sarah Bailey (Supervisor)