The Effects of a Dual Hypocretin Receptor Antagonist on Maternal Behavior and Depressive-Like Symptoms in Lactating Mice

Postpartum depression (PPD) is a debilitating mental disorder that affects approximately 15% of all women after childbirth. PPD is disruptive to maternal care and has negative health consequences for both mothers and infants. Stress and hormonal changes have been associated with PPD, however the underlying neuromechanisms that influence the presentation of this disorder remain unclear. Hypocretin (an excitatory neuropeptide) has been shown to have a direct influence on stress regulation, maternal care, and depressive-like behavior in rodents, yet no research has examined the potential role of hypocretin in the pathology of PPD. Therefore, this study explored the role of hypocretin regulation in lactating mice on depressive-like behavior using a chronic variable stress model of postpartum depression. Specifically, it was hypothesized that exposure to a dual hypocretin receptor antagonist would rescue pup-directed maternal care and reduce depressive-like symptoms from the adverse effects of chronic variable stress exposure. On postpartum days 1-4, lactating dams were administered a dual hypocretin receptor antagonist (suvorexant) at either a 10 mg/kg or 30 mg/kg dose before exposure to a chronic variables stress schedule. On postpartum day 5, stressors and injections ceased and dams were measured on a tail-suspension test, sucrose-preference test, and a T-maze measure of pup-retrieval and maternal behaviors. Results show that there were no differences between groups on depressive-like behavior in the tail-suspension test. Further, there were no differences in overall sucrose consumption between groups, indicating no changes to anhedonia-like behavior. In the T-maze pup-retrieval measure, dams exhibited no differences in pup-directed or maternal behaviors. The results do not support the hypothesis that dual hypocretin receptor antagonism will rescue depressive-like behavior or maternal behaviors following a chronic variable stress schedule in lactating dams. These findings may be influenced by the upregulation of corticotrophin-releasing hormones (CRH) in response to stress. CRH and hypocretin function in a bidirectional manner where CRH release may drive the release of hypocretin; and while hypocretin activity was inhibited via antagonist action, CRH was unopposed. Further, both hypocretin-1 and hypocretin-2 receptors have been shown to produce both prodepressent and antidepressant effects, respectively. However, a definitive role for each hypocretin receptor in the presentation of depressive-like behavior has yet to be defined. Ultimately, the results of the present study demonstrate that a dual hypocretin receptor antagonist has no rescuing effects on depressive-like behavior, anhedonia-like behavior, or maternal behaviors in a model of postpartum depression.