Research in the field of neuroimmunology, including work from our group, has shown that peripheral and systemic inflammation is transduced into the central nervous system (CNS) by several mechanisms resulting in neuroinflammatory processes characterized by increased expression of cytokines and other inflammatory mediators. These mechanisms have been shown to affect neuroendocrine function, monoaminergic neurotransmission and neuronal plasticity negatively impacting brain function and behavior. These processes have been associated with the high incidence of emotional and cognitive impairments in people suffering from chronic inflammatory diseases such as autoimmune, allergic and systemic inflammatory diseases. Despite the broad use of current anti-inflammatory drugs to treat these conditions, they are ineffective in ameliorating the neurobehavioral component, which has been related to the persistence of neuroinflammation once it is triggered from the periphery. Therefore, there is the need to find new treatment options targeting these neuroinflammatory processes. It has been long known that the anesthetic drug ketamine has anti-inflammatory properties in surgical settings. Using rodent models, it has been shown that KET reduces inflammatory molecules in the brain triggered by immune and psychogenic stressors, offering hope for the use of KET as an anti-neuroinflammatory drug in humans. However, the dissociative, addictive, and sedative effects are limitations for the development of KET based therapies. Our preliminary studies reveal that a metabolite of KET, (2R, 6R)-hydroxynorketamine (HNK), which lacks the sedative and addictive effects of KET, possesses powerful anti-neuroinflammatory properties in the mouse model of peripheral administration of bacterial lipopolysaccharides (LPS). Notably, our preliminary studies also revealed that HNK administered alone induces sustained transcription in the brain of the cytokine IFN-g, raising the possibility that HNK mediates these effects through the production of this cytokine. The present application will comprehensively assess the anti-neuroinflammatory properties of HNK and test the role of IFN-g in mediating HNK effects in two models of peripherally-induced neuroinflammation using LPS or bacterial superantingens (SEA). In specific aim #1 we will characterize the dose, timing and effects of HNK on CNS inflammatory processes, as well as identify the cellular source of IFN-g production in the CNS induced by HNK. We will also evaluate whether metabolism of KET to HNK is required for sustained anti-neuroinflammatory effects of KET. In specific aim #2 we will utilize mice lacking IFN-g, as well as pharmacological blockade of IFN-g using neutralizing antibodies, to test the role of this cytokine in the anti-neuroinflammatory effects of HNK. We will also test if this cytokine is required for HNK antidepressant actions in the LPS model. This aim will also employ telemetry to monitor activity, temperature and E...