Effects of Minocycline on Changes in Brain Tryptophan Metabolism and the Behavior of Juvenile Mice Elicited By Inescapable-Predator Stress

Study background: Traumatic stress in early life can have long-term effects on neurobiological systems and result in morepronounced responses to stress exposure in adulthood, which may underlie an increased risk of psychiatric disorders such as depression and anxiety disorder (including post-traumatic stress disorder). Acute stress in early life activates the brain kynurenine (KYN) pathway, the main tryptophan (TRP) metabolic pathway, which shares TRP with the serotonin (5-HT) pathway. Although the activated KYN pathway is known to play an important role in the pathophysiology of depression, it may also be related to neurobiological changes elicited by stress. In addition, earlylife acute stress induces prolonged behavioral changes such as disinhibition and/or reduced anxiety. Thus, a drug that inhibits the activation of the KYN pathway elicited by early-life stress may prevent the onset of these psychiatric disorders related to traumatic events in early life. We investigated the effects of minocycline, which has powerful anti-inflammatory and neuroprotective effects, on changes in mouse behavior and brain TRP metabolism elicited by stress exposure in early life. Methods: Four-week-old male mice were exposed to inescapablepredator stress. Minocycline (100 mg/kg) was injected intraperitoneally 1 h prior to the stress. The behavior in an elevated plus maze (EPM) and the levels of TRP, KYN, and 5-HT in the prefrontal cortex, hippocampus, amygdala, and dorsal raphe nuclei were measured 1 wk later. Results: In the EPM, stress decreased the ratio of protected head dips (PHD) to all head dips, whereas minocycline increased the PHD. In the amygdala, stress increased the levels of KYN and 5-HT, whereas minocycline prevented the stress-induced KYN elevation and increased the level of 5-HT. Minocycline inhibited the stress-elicited increase in the KYN/TRP ratio. Conclusion: Minocycline counteracted the stress-induced KYN pathway and behavioral changes and attenuated the influence of early-life trauma.