There are profound sex differences in the incidence of many psychiatric disorders. Although these disorders are frequently linked to social stress and to deficits in social engagement, little is known about sex differences in the neural mechanisms that underlie these phenomena. Phenotypes characterized by dominance, competitive aggression, and active coping strategies appear to be more resilient to psychiatric disorders such as posttraumatic stress disorder (PTSD) compared with those characterized by subordinate status and the lack of aggressiveness. Here, we report that serotonin (5-HT) and arginine-vasopressin (AVP) act in opposite ways in the hypothalamus to regulate dominance and aggression in females and males. Hypothalamic injection of a 5-HT1a agonist stimulated aggression in female hamsters and inhibited aggression in males, whereas injection of AVP inhibited aggression in females and stimulated aggression in males. Striking sex differences were also identified in the neural mechanisms regulating dominance. Acquisition of dominance was associated with activation of 5-HT neurons within the dorsal raphe in females and activation of hypothalamic AVP neurons in males. These data strongly indicate that there are fundamental sex differences in the neural regulation of dominance and aggression. Further, because systemically administered fluoxetine increased aggression in females and substantially reduced aggression in males, there may be substantial gender differences in the clinical efficacy of commonly prescribed 5-HT-active drugs such as selective 5-HT reuptake inhibitors. These data suggest that the treatment of psychiatric disorders such as PTSD may be more effective with the use of 5-HT-targeted drugs in females and AVP-targeted drugs in males.hamster | gender differences | agonistic | social behavior | fluoxetine P rominent sex differences occur in the incidence, development, and clinical course of many psychiatric disorders. Women, for example, have higher rates of depression and anxiety disorders such as posttraumatic stress disorder (PTSD), whereas men more frequently suffer from autism and attention deficit disorders (1-4). Because little is known about sex differences in the efficacy of treatments for these disorders, current treatment strategies are largely the same for both sexes. The development of effective treatments for both women and men can proceed with a clear understanding of sex differences in the mechanisms and etiology of psychiatric disorders. Many of these disorders are linked to deficits in adaptive social skills (5, 6); therefore, understanding the neural mechanisms underlying social engagement in both sexes is essential. In most mammalian species, social interactions among both sexes are governed by dominance relationships. As such, behaviors associated with these relationships (e.g., social recognition, stress, competitive aggression) are the foundation for social interactions and are highly relevant for understanding psychiatric disorders (7-9). Emerging genetic and environmental...

Social reward is critical for social relationships, and yet we know little about the characteristics of social interactions that are rewarding or the neural mechanisms underlying that reward. Here, we investigate the sex-dependent role of oxytocin receptors within the ventral tegmental area (VTA) in mediating the magnitude and valence of social reward. Operant and classical conditioning tests were used to measure social reward associated with same-sex social interactions. The effects of oxytocin, selective oxytocin receptor agonists, antagonists, and vehicle injected into the VTA on social reward was determined in male and female Syrian hamsters. The colocalization of FOS and oxytocin in sites that project to the VTA following social interaction was also determined. Females find same-sex social interactions more rewarding than males and activation of oxytocin receptors in the VTA is critical for social reward in females, as well as males. These studies provide support for the hypothesis that there is an inverted U relationship between the duration of social interaction and social reward, mediated by oxytocin; and that in females the dose-response relationship is initiated at lower doses compared with males. Same-sex social interaction is more rewarding in females than in males, and an inverted U relationship mediated by oxytocin may have a critical role in assigning positive and negative valence to social stimuli. Understanding these sex differences in social reward processing may be essential for understanding the sex differences in the prevalence of many psychiatric disorders and the development of gender-specific treatments of neuropsychiatric disorders.Neuropsychopharmacology (2019) 44:785-792; https://doi.

When Syrian hamsters (Mesocricetus auratus) are defeated by a larger, more aggressive opponent, they subsequently produce more defensive and submissive behaviors and less chemosensory investigation and aggression, even when they are paired with a smaller, non-aggressive intruder. This persistent change in the behavior of defeated animals has been termed conditioned defeat. In the present study, we tested the hypothesis that the bed nucleus of the stria terminalis (BNST) is important for the acquisition and expression of conditioned defeat. We found that the GABA A receptor agonist muscimol infused into the BNST immediately prior to initial defeat training failed to disrupt the acquisition of conditioned defeat, while muscimol infused prior to testing caused a significant reduction in submissive/defensive behaviors and an increase in investigatory behaviors of the nonaggressive intruder. These results indicate that 1) the BNST, unlike the amygdala, does not appear to be critically involved in the consolidation process related to the memory of social defeat and 2) the BNST may be an important site for the execution of fear behaviors associated with social defeat. Considering the high degree of connectivity between the BNST and the amygdala, these findings provide further insight into the neural circuitry governing conditioned defeat and support the view of a functional dissociation between the amygdala and the BNST in the modulation of conditioned fear in an ethologically relevant model.

Exposure to social stressors can cause profound changes in an individual’s physiology and behavior. In Syrian hamsters, even a single social defeat results in conditioned defeat, which includes an abolishment of territorial aggression and the emergence of high levels of submissive behavior. The purpose of the current study was to determine whether the lateral septum (LS) is a component of the putative neural circuit underlying conditioned defeat. Experiment 1 explored the possibility that plasticity in the LS is necessary for the induction of conditioned defeat. Infusions of the protein synthesis inhibitor, anisomycin, prior to defeat training, however, failed to alter conditioned defeat during testing on the following day, suggesting that synaptic plasticity in the LS is not critical for defeat-induced suppression of aggression. Experiment 2 tested whether the LS is necessary for the expression of conditioned defeat. Infusions of the GABAA agonist muscimol into the LS prior to testing significantly increased aggression and decreased submission in previously defeated animals suggesting that the LS is an important component of the neural circuit mediating the expression of both aggression and submission in conditioned defeat. Experiment 3 examined whether the effects of muscimol on aggression were dependent on prior social defeat. Non-defeated animals receiving muscmol infusions prior to testing with a non-aggressive intruder displayed significantly more aggression than did hamsters receiving control injections. Thus, these data suggest that the activation of GABAA receptors in the LS increases aggression regardless of whether or not a hamster has previously experienced social defeat.

Conditioned defeat (CD) is a behavioral response that occurs in Syrian hamsters after they experience social defeat. Subsequently, defeated hamsters no longer produce territorial aggression but instead exhibit heightened levels of avoidance and submission, even when confronted with a smaller, non-aggressive intruder. Dopamine in the nucleus accumbens is hypothesized to act as a signal of salience for both rewarding and aversive stimuli to promote memory formation and appropriate behavioral responses to significant events. The purpose of the present study was to test the hypothesis that dopamine in the nucleus accumbens modulates the acquisition and expression of behavioral responses to social defeat. In Exp. 1, bilateral infusion of the non-specific D1/D2 receptor antagonist cis(z)flupenthixol (3.75 μg/150 nl saline) into the nucleus accumbens 5 min prior to defeat training significantly reduced submissive and defensive behavior expressed 24 hr later in response to a non-aggressive intruder. In Exp. 2, infusion of 3.75 μg cis(z)flupenthixol 5 min before conditioned defeat testing with a non-aggressive intruder significantly increased aggressive behavior in drug-infused subjects. In Exp. 3, we found that the effect of cis(z)flupenthixol on aggression was specific to defeated animals as infusion of drug into the nucleus accumbens of non-defeated animals did not significantly alter their behavior in response to a non-aggressive intruder. These data demonstrate that dopamine in the nucleus accumbens modulates both acquisition and expression of social stress-induced behavioral changes and suggest that the nucleus accumbens plays an important role in the suppression of aggression that is observed after social defeat.