Background Oxytocin (OT) is considered to be a stress buffering hormone, dampening the physiological effects of stress. However, OT can also be anxiogenic. We examined acute and long lasting effects of social defeat on OT neurons in male and female California mice. Methods We used immunohistochemistry for OT and c-fos to examine OT neuron activity immediately after defeat (n = 6-9) as well as two (n = 6-9) and ten weeks (n = 4-5) later. We quantified Oxt mRNA with qPCR (n = 5-9). Intranasal OT was administered to naïve and stressed mice tested in social interaction and resident-intruder tests (n = 8-14). Results Acute exposure to a third episode of defeat increased OT/c-fos colocalizations in the paraventricular nucleus (PVN) of both sexes. In the medioventral bed nucleus of the stria terminalis (BNSTmv), defeat increased Oxt mRNA, total OT neurons, and OT/c-fos colocalizations in females but not males. Intranasal OT failed to reverse stress-induced social withdrawal in females, and reduced social interaction behavior in females naïve to defeat. In contrast, intranasal OT increased social interaction in stressed males and reduced freezing in the resident-intruder test. Conclusions Social defeat induces long lasting increases in OT production and OT/c-fos cells in the BNSTmv of females but not males. Intranasal OT largely reversed effects of stress on behavior in males but effects were mixed in females. These results suggest changes in OT sensitive networks contribute to sex differences in behavioral responses to stress.

There is compelling evidence for important sex differences in behavioral and hormonal responses to psychosocial stress. Here we examined the effects of gonadal hormones on behavioral responses to social defeat stress in monogamous California mice (Peromyscus californicus). Three episodes of social defeat induced social withdrawal in intact females but not males. Gonadectomy blocked corticosterone responses to defeat in females and sensitized male corticosterone responses. However, gonadectomy had no effects on social interaction behavior, suggesting that social withdrawal is not dependent on gonadal hormones in the adult California mouse. In contrast, defeat reduced exploratory behavior in the open field test for intact but not castrated males. We also examined the effects of social defeat on social interaction behavior when California mice were raised on corncob bedding, which has estrogenic properties. In this dataset of over 300 mice, we observed that social defeat did not induce social withdrawal when females were raised on corncob bedding. This finding suggests that the use of corncob in rodent studies could mask important sex differences in the effects of stress on brain and behavior. Although gonadal hormones do not affect social withdrawal behavior in adults, our data suggest that hormones may act earlier in development to induce a more resilient social phenotype.

Depression and anxiety disorders are more common in women than men, and little is known about the neurobiological mechanisms that contribute to this disparity. Recent data suggest that stress-induced changes in neurotrophins have opposing effects on behavior by acting in different brain networks. Social defeat has been an important approach for understanding neurotrophin action, but low female aggression levels in rats and mice have limited the application of these methods primarily to males. We examined the effects of social defeat in monogamous California mice (Peromyscus californicus), a species in which both males and females defend territories. We demonstrate that defeat stress increases mature brain-derived neurotrophic factor (BDNF) protein but not mRNA in the bed nucleus of the stria terminalis (BNST) in females but not males. Changes in BDNF protein were limited to anterior subregions of the BNST, and there were no changes in the adjacent nucleus accumbens (NAc). The effects of defeat on social withdrawal behavior and BDNF were reversed by chronic, low doses of the antidepressant sertraline. However, higher doses of sertraline restored social withdrawal and elevated BDNF levels. Acute treatment with a low dose of sertraline failed to reverse the effects of defeat. Infusions of the selective tyrosine-related kinase B receptor (TrkB) antagonist ANA-12 into the anterior BNST specifically increased social interaction in stressed females but had no effect on behavior in females naïve to defeat. These results suggest that stress-induced increases in BDNF in the anterior BNST contribute to the exaggerated social withdrawal phenotype observed in females.

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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.

Psychosocial stress leads to the activation of kappa opioid receptors (KORs), which induce dysphoria and facilitate depression-like behaviors. However, less is known about the long-term effects of stress and KORs in females. We examined the long-term effects of social defeat stress on the aversive properties of KOR activation in male and female California mice (Peromyscus californicus) using a conditioned place aversion paradigm. Female California mice naïve to social defeat, formed a place aversion following treatment with 2.5 mg/kg of the KOR agonist U50,488, but females exposed to defeat did not form a place aversion to this dose. This supports the finding by others that social defeat weakens the aversive properties of KOR agonists. In contrast, both control and stressed males formed an aversion to 10 mg/kg of U50,488. We also examined EGR1 immunoreactivity, an indirect marker of neuronal activity, in the nucleus accumbens (NAc) and found that stress and treatment with 10 mg/kg of U50,488 increased EGR1 immunoreactivity in the NAc core in females but reduced activation in males. The effects of stress and U50,488 on EGR1 were specific to the NAc, as we found no differences in the bed nucleus of the stria terminalis. In summary, our data indicate important sex differences in the long-term effects of stress and indicate the need for further study of the molecular mechanisms mediating the behavioral effects of KOR in both males and females.

Kappa opioid receptors (KOR) are considered to be a promising therapeutic target for stress-induced psychiatric disorders such as anxiety and depression. Preclinical data show that KOR antagonists have greater efficacy if administered before stressful experiences as opposed to afterwards. However, almost all of these studies use long-acting antagonists, leaving it unclear whether inhibition of KOR after stress is required for efficacy. Here we show that administration of the short-acting KOR antagonist AZ-MTAB before episodes of social defeat stress block the induction of anhedonia (both males and females) and social avoidance responses (females) that persist two weeks after stress. In both males and females pre-stress AZ-MTAB treatment also blunted anticipatory autogrooming behavior immediately prior to the third episode of defeat. In contrast when AZ-MTAB was administered two weeks after defeat (immediately before behavior testing) in female California mice, it was ineffective at reversing anhedonia and social avoidance. These results suggest that short-acting KOR antagonists may have greater therapeutic potential if administered before exposure to psychosocial stressors.

Stress is a major risk factor for the development of psychiatric disorders, such as depression, and the development of substance use disorder. Although there are important sex differences in the prevalence of these disorders, the majority of preclinical models used to study stress induced disorders use males only. Social defeat stress is a commonly used method to induce stress in an ethologically relevant way, but has only recently begun to be used in female rodents. Using these new female models, recent studies have examined how social defeat stress affects males and females differently at the behavioral, circuit, and molecular levels. This review discusses sex differences in the effects of social defeat stress on social behavior and drug seeking behavior, as well as its impact on the mesolimbic dopamine system and the highly connected region of the bed nucleus of the stria terminalis.