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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

Abstract

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.

Keywords

Cocaine Psychostimulant Innate immunity Microglia Neuroinflammation 

Abbreviations

(i)NOS

(Inducible) nitric oxide synthase

ADAM

A disintegrin and metalloproteinase

ADAMts

A disintegrin and metalloproteinase and thrombospondin

AP-2

Activator protein-2

Areg

Amphiregulin

BBB

Blood–brain barrier

Bcl-2

B cell lymphoma 2

BDNF

Brain-derived neurotrophic factor

bFGF

Basic fibroblast growth factor

BMP

Bone morphogenetic protein

CDH

Cadherin

cFOS

FBJ murine osteosarcoma viral oncogene homolog

CLDN

Claudin

CXCL

Chemokine ligand

CXCR

Chemokine receptor

DAMP

Damage-associated molecular pattern

EDN

Endothelin

EGF

Epidermal growth factor

EGR

Early growth response protein

GDNF

Glial-derived neurotrophic factor

IFN

Interferon

IGF

Insulin-like growth factor

IIR

Innate immune response

IL

Interleukin

iVGF

Inducible nerve growth factor

JAM

Junction adhesion molecule

LIF

Leukemia inhibitory factor

MCP-1

Monocyte chemotactic protein-1

MCSF

Macrophage colony stimulating factor

MHC-II

Major histocompatibility complex II

MMP

Matrix metalloproteinase

NF-κB

Nuclear factor-kappaB

NGF

Nerve growth factor

NOSTRIN

Nitric oxide synthase trafficker protein

NT

Neurotrophin

OCLN

Occludin

PAMP

Pathogen-associated molecular pattern

PDGF

Platelet-derived growth factor

Poly(I:C)

Polyinosinic:polycytidylic acid

SOD

Superoxide dismutase

TGF-β

Transforming growth factor-beta

TLR

Toll-like receptor

TNF

Tumor necrosis factor

VEGF

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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