Effects of defeat stress on behavioral flexibility in males and females: modulation by the mu‐opioid receptor

Abstract

Behavioral flexibility is a component of executive functioning that allows individuals to adapt to changing environmental conditions. Independent lines of research indicate that the mu opioid receptor (MOR) is an important mediator of behavioral flexibility and responses to psychosocial stress. The current study bridges these two lines of research and tests the extent to which social defeat and MOR affect behavioral flexibility and whether sex moderates these effects in California mice (Peromyscus californicus). Males and females assigned to social defeat or control conditions were tested in a Barnes maze. In males, defeat impaired behavioral flexibility but not acquisition. Female performance was unaffected by defeat. MOR binding in defeated and control mice in the orbitofrontal cortex (OFC), striatum, and hippocampus was examined via autoradiography. Stressed males had reduced MOR binding in the OFC whereas females were unaffected. The MOR antagonist beta-funaltrexamine (1 mg/kg) impaired performance in males naïve to defeat during the reversal phase but had no effect on females. Finally, we examined the effects of the MOR agonist morphine (2.5, 5 mg/kg) on stressed mice. As expected, morphine improved behavioral flexibility in stressed males. The stress-induced deficits in behavioral flexibility in males are consistent with a proactive coping strategy, including previous observations that stressed male California mice exhibit strong social approach and aggression. Our pharmacological data suggest that a down-regulation of MOR signaling in males may contribute to sex differences in behavioral flexibility following stress. This is discussed in the framework of coping strategies for individuals with mood disorders.

The effects of acute stress on core executive functions: A meta-analysis and comparison with cortisol

“…We also expected that sex would moderate stress effects on cognitive flexibility, given some evidence suggesting stress impairs cognitive flexibility more in males than females (Laredo et al, 2015). Although the effect was in the expected direction, with a greater proportion of males descriptively associated with a greater impairment, percentage male participants did not emerge as a significant moderator of stress effects on cognitive flexibility, B = −.009, t (1.0)= −1.96, p =.299.…”

“…Nonetheless, the few studies of stress effects on cognitive flexibility are relatively consistent in showing an impairment in cognitive flexibility following stress (e.g., Alexander et al, 2007; Laredo et al, 2015; Plessow et al, 2011). …”

“…Even so, one study in humans (Shields et al, 2016b) and another in rodents (Laredo et al, 2015) found that stress-induced impairments of cognitive flexibility are greater for males than females. Although the reason for this sex difference is not completely clear, this sex difference appears to be mediated by sex differences in μ-opioid receptor binding in the orbitofrontal cortex following stress (Laredo et al, 2015). Thus, sex may play an important role in stress effects on cognitive flexibility.…”

Inhibition of vasopressin V1a receptors in the medioventral bed nucleus of the stria terminalis has sex- and context-specific anxiogenic effects

“…The damaged sections were distributed across all four groups. On each section we also measured a nearby white matter tract that did not show receptor binding and subtracted this from the measurements for the area of interest to account for background (Inoue et al, 2013; Laredo et al, 2015). There was no difference in signal in these regions and sections used to control for non-specific binding.…”

Acute stress impairs cognitive flexibility in men, not women

“…Prior research with both humans (Alexander et al, 2007; Plessow et al, 2011) and rodents (Laredo et al, 2015) has suggested that stress may impair cognitive flexibility—that is, the ability to flexibly switch between thoughts or rules in a goal-directed manner. However, when studying effects of stress, it is important to examine potential sex differences, given the dramatically different effects stress can have on males and females (Trainor et al, 2013); stress should not be presumed to influence males and females similarly (Cahill, 2012; Felmingham et al, 2012; Schoofs et al, 2013; Zoladz et al, 2013).…”