Neurotoxicity Research

, Volume 23, Issue 2, pp 174–188 | Cite as

Psychostimulant Abuse and Neuroinflammation: Emerging Evidence of Their Interconnection

  • Kenneth H. Clark
  • Clayton A. Wiley
  • Charles W. BradberryEmail author
Review Article


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.


Cocaine Psychostimulant Innate immunity Microglia Neuroinflammation 



(Inducible) nitric oxide synthase


A disintegrin and metalloproteinase


A disintegrin and metalloproteinase and thrombospondin


Activator protein-2




Blood–brain barrier


B cell lymphoma 2


Brain-derived neurotrophic factor


Basic fibroblast growth factor


Bone morphogenetic protein




FBJ murine osteosarcoma viral oncogene homolog




Chemokine ligand


Chemokine receptor


Damage-associated molecular pattern




Epidermal growth factor


Early growth response protein


Glial-derived neurotrophic factor




Insulin-like growth factor


Innate immune response




Inducible nerve growth factor


Junction adhesion molecule


Leukemia inhibitory factor


Monocyte chemotactic protein-1


Macrophage colony stimulating factor


Major histocompatibility complex II


Matrix metalloproteinase


Nuclear factor-kappaB


Nerve growth factor


Nitric oxide synthase trafficker protein






Pathogen-associated molecular pattern


Platelet-derived growth factor


Polyinosinic:polycytidylic acid


Superoxide dismutase


Transforming growth factor-beta


Toll-like receptor


Tumor necrosis factor


Vascular endothelial growth factor


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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Kenneth H. Clark
    • 1
  • Clayton A. Wiley
    • 1
  • Charles W. Bradberry
    • 2
    • 3
    Email author
  1. 1.Department of NeuropathologyUniversity of Pittsburgh School of MedicinePittsburghUSA
  2. 2.VA Pittsburgh Health ServicesUniversity of PittsburghPittsburghUSA
  3. 3.Department of PsychiatryUniversity of PittsburghPittsburghUSA

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