Psychostimulant Abuse and Neuroinflammation: Emerging Evidence of Their Interconnection

Kenneth H. Clark, Clayton A. Wiley, Charles W. Bradberry

During the past two decades, there has been a tremendous expansion of knowledge regarding the neurobiological effects of substance abuse and how these effects impact behavior. At the same time, there has been a profound change in our understanding of the way in which the central nervous system responds to noxious stimuli. Most often referred to as the innate immune response (IIR), this defense mechanism is activated by a number of agents (toxic, microbial, ischemic) and has been implicated in the progression of a number of neurodegenerative diseases. We review evidence that psychostimulants of abuse (cocaine, methamphetamine, ecstasy) are associated with activation of the IIR. We first present background on what is currently known about the IIR including some of the cellular elements involved (microglia, astrocytes, vascular endothelial cells), key receptor pathways, and primary inflammatory cytokines (IL-1β, IL-6, TNF-α). We then present a variety of protein and gene expression data taken from animal studies that show increased expression of various components of the IIR following acute or repeated psychostimulant administration. Collectively the data indicate an association of psychostimulant use with IIR activation in the brain even at exposures not traditionally associated with neurotoxicity. Thus, the gradually escalating deleterious effects of psychostimulant use could in part involve neuroinflammatory mechanisms. Finally, we offer one hypothesis of a possible mechanism by which psychostimulants result in IIR activation and discuss the potential therapeutic implications of these findings for treatment of the recovering addict.