Drug abuse and misuse is a major health hazard in the military as well as in the population more generally.There have been major recent advances in our understanding of the alterations in the brain produced by drugs of abuse, and in how the addicted brain differs from the normal brain. However, many individuals who experience, or are exposed to a drug of abuse do not develop addiction, or abuse the drug. For example, the overwhelming majority of patients that receive opiates for pain relief while hospitalized do not develop opiate addiction. That is, use does not always develop into abuse, and the factors that mediate this transition are largely unknown. The development of an understanding of the factors and brain mechanisms that throw the balance towards the development of abuse from use would be a major step in the development of therapies that can ameliorate addiction. The core hypothesis is that stressors, via their production of increased glucocorticoids GCs, sensitize microglia so that these cells produce excessively high levels of inflammatory mediators such as IL-1 whenacted upon by drugs of abuse, and that this process is responsible, in whole or in part, for the increased vulnerability to drug abuse produced by stressful experiences. This is a novel, and previously unexplored hypothesis. The work, if successful, could lead to a re-conceptualization of GCs as a sensitization factor that induces a vulnerability to neuroinflammatory processes and thereby open a new field of investigation into the role of stress and GCs in the etiology of substance abuse disorders.