Abstract
Major depressive disorder (MDD) is a debilitating disease with a high worldwide prevalence. Despite its greater prevalence in women, male animals are used in most preclinical studies of depression even though there are many sex differences in key components of depression, such as stress responses and immune system functions. In the present study, we found that chronic restraint stress-induced depressive-like behaviors are quite similar in male and female mice, with both sexes displaying increased immobility time in the tail suspension test and reduced social interactions, and both sexes exhibited deficits in working and spatial memories. However, in contrast to the similar depressive-like behaviors developed by male and female mice in response to stress, they displayed different patterns of pro-inflammatory cytokine increases in the periphery and the brain, different changes in microglia, and different changes in the expression of Toll-like receptor 4 in response to stress. Treatment with (+)-naloxone, a Toll-like receptor 4 antagonist that previously demonstrated anti-depressant-like effects in male mice, was more efficacious in male than female mice in reducing the deleterious effects of stress, and its effects were not microbiome-mediated. Altogether, these results suggest differential mechanisms to consider in potential sex-specific treatments of depression.