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NEUROPHARMACOLOGY

Methamphetamine Neurotoxicity in Dopamine Nerve Endings of the Striatum Is Associated with Microglial Activation

Departments of Psychiatry and Behavioral Neurosciences (D.M.T., T.J.G., D.M.K.), Anatomy and Cell Biology (P.D.W.), and Neurology (J.A.B.), and Center for Molecular Medicine and Genetics (D.M.K.), Wayne State University School of Medicine and John D. Dingell VA Medical Center (D.M.T., T.J.G., D.M.K.), Detroit, Michigan

Methamphetamine intoxication causes long-lasting damage to dopamine nerve endings in the striatum. The mechanisms underlying this neurotoxicity are not known but oxidative stress has been implicated. Microglia are the major antigen-presenting cells in brain and when activated, they secrete an array of factors that cause neuronal damage. Surprisingly, very little work has been directed at the study of microglial activation as part of the methamphetamine neurotoxic cascade. We report here that methamphetamine activates microglia in a dose-related manner and along a time course that is coincident with dopamine nerve ending damage. Prevention of methamphetamine toxicity by maintaining treated mice at low ambient temperature prevents drug-induced microglial activation. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), which damages dopamine nerve endings and cell bodies, causes extensive microglial activation in striatum as well as in the substantia nigra. In contrast, methamphetamine causes neither microglial activation in the substantia nigra nor dopamine cell body damage. Dopamine transporter antagonists (cocaine, WIN 35,428 [(–)-2--carbomethoxy-3--(4-fluorophenyl)tropane 1,5-naphthalenedisulfonate], and nomifensine), selective D1 (SKF 82958 [(±)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide]), D2 (quinpirole), or mixed D1/D2 receptor agonists (apomorphine) do not mimic the effect of methamphetamine on microglia. Hyperthermia, a prominent and dangerous clinical response to methamphetamine intoxication, was also ruled out as the cause of microglial activation. Together, these data suggest that microglial activation represents an early step in methamphetamine-induced neurotoxicity. Other neurochemical effects resulting from methamphetamine-induced overflow of DA into the synapse, but which are not neurotoxic, do not play a role in this response.

Address correspondence to: Dr. Donald M. Kuhn, Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, 2125 Scott Hall, 540 E. Canfield, Detroit, MI 48201. E-mail: donald.kuhn{at}wayne.edu

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