Sex-specific And Estrous Cycle-dependent Antidepressant-like Effects And Hippocampal Akt Signaling Of Leptin

Objective: Sex differences in the incidence of depression and antidepressant treatment response are well documented. Depression is twice as common in women as in men. Recent studies indicate that low levels of leptin, are associated with increased symptoms of depression in women,independent of body fat and weight. Previous work has demonstrated that leptin produces antidepressant-like effects in male animals. The aim of this study was to investigate whether antidepressant-like responses to leptin in female mice are similar to, or distinct from, those observed in male mice and further identify the possible interactions between gonadal hormones and leptin actions in regulating depressive behavior and activating intracellular signaling pathways.Methods: Female mice in diestrus/ proestrus received an ip injection with either vehicle (saline)or leptin (1.0 mg/kg), and 30 minutes later animals were subjected to the FST/TST. Another some naive female mice were used to examine leptin-stimulated Akt phosphorylation in the hippocampus during diestrus or proestrus. The estrus cycle phases were identified based on vaginal lavage.The OVX female mice were injected with saline or leptin (1.0 mg/kg) and 30 minutes later were subjected to the tail suspension test and forced swim test spaced 7 days apart. And OVX female mice were used to examine the influence of pretreatment with 17-β-estradiol on leptin-induced antidepressant-like effects. Also the influence of 17-β-estradiol pretreatment on leptin-stimulated Akt phosphorylation in the hippocampus.Intact male mice and castrated male mice were injected with either saline or leptin (1.0 mg/kg, ip)2 weeks /4 weeks after castration and subjected to the TST or FST, spaced 7 days apart.Results: In intact cycling female mice, leptin reduced behavioral despair in the forced swim test in proestrus but not in diestrus. Consistent with the behavioral effects, leptin stimulated Akt signaling in the hippocampus in proestrus but not in diestrus. Ovariectomy (OVX) abolished the effects of leptin on behavior and Akt signaling. Furthermore, estrodiol pretreatment in OVX female mice restored the antidepressant-like effects and hippocampal Akt signaling induced by leptin. In contrast, intact male and castrated male mice displayed similar antidepressant-like effects of leptin.Conclusions: These results suggest leptin regulates depressive behavior in a sex- and estrous cycle-dependent manner.