Sex differences in brain region-specific activation of c-Fos following kappa opioid receptor stimulation or acute stress in mice

Kappa opioid receptors (KOPr) are involved in the response to stress. KOPr are also targets for the treatment of stress-related psychiatric disorders including depression, anxiety, and addiction although effects of KOPr are often sex-dependent. Here we investigated c-Fos expression in a range of brain regions in male and female mice following an acute stressor, and a single injection of KOPr agonist. Using adult C57BL/6 c-Fos-GFP transgenic mice and quantitative fluorescence microscopy, we identified brain regions activated in response to a challenge with the KOPr agonist U50,488 (20 mg/kg) or an acute stress (15 min forced swim stress, FSS). In male mice, U50,488 increased expression of c-Fos in the prelimbic area of the prefrontal cortex (PFCx), nucleus accumbens (NAcc), and basolateral nuclei of the amygdala (BLA). In contrast, in female mice U50,488 only activated the BLA but not the PFCx or the NAcc. FSS increased activation of PFCx, NAcc, and BLA in males while there was no activation of the PFCx in female mice. In both sexes, the KOPr antagonist norBNI significantly blocked U50,488-induced, but not stress-induced activation of brain regions. In separate experiments, activated cells were confirmed as non-GABAergic neurons in the PFCx and NAcc. Together these data demonstrate sex differences in activation of brain regions that are key components of the ‘reward’ circuitry. These differential responses may contribute to sex differences in stress-related psychiatric disorders and in the treatment of depression, anxiety, and addiction.