Abstract
Abstract The immune system has been shown to affect the brain, and consequently behaviors. In particular, increasing evidence indicates that inflammation contributes to susceptibility to depression, which is a leading cause of disability, and for which current treatments are often inadequate. We hypothesized that targeting Toll-like receptor 4 (TLR4), one of the main signaling pathways for triggering an inflammatory response, would lessen stress-induced depression-like behaviors in mice. TLR4 inhibition with the CNS-penetrating drug (+)-naloxone that is a TLR4 antagonist but is inactive at opiate receptors, reversed chronic restraint stress-induced impairments of various depression-like behaviors, as well as cognitive tests in male mice but had no effect in female mice. These effects might be mediated by interferon-β (IFNβ) pathway in microglial cells. Altogether, our results confirmed the critical role of TLR4 in mediating depressive-like behaviors and cognitive impairments and demonstrated that (+)-naloxone might be a promising therapeutic strategy for depression.