(+)-Naloxone blocks Toll-like receptor 4 to ameliorate deleterious effects of stress on male mouse behaviors

Depression is a leading cause of disability worldwide and current treatments are often inadequate for many patients. Increasing evidence indicates that inflammation contributes to susceptibility to depression. 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 male mice. TLR4 inhibition with the CNS-penetrating drug (+)-naloxone that is a TLR4 antagonist but is inactive at opiate receptors increased resistance to the learned helplessness model of depression and provided an antidepressant-like effect in the tail suspension test. (+)-Naloxone administration also reversed chronic restraint stress-induced impairments in social behavior and novel object recognition. These effects involved blockade of stress-induced activation of glycogen synthase kinase 3β (GSK3β), NF-κB, IFN regulatory factor 3 (IRF3) and nitric oxide production, and reduced levels of the cytokines tumor necrosis factor-α (TNFα) and interferon-β (IFNβ). These findings demonstrate that blocking TLR4 with (+)-naloxone effectively diminishes several detrimental responses to stress and raise the possibility that (+)-naloxone may be a feasible intervention for depression.