Abstract
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-β-carbomethoxy-3-β-(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.
Footnotes
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This research was supported by National Institutes of Health Grants DA10756 and DA014392 and a VA Merit Award. Preliminary aspects of this work were presented at the National Institute on Drug Abuse-sponsored USA/Spain Binational Workshop on Drug Abuse and Addiction Research (October 2003) and the annual meeting of the Society for Neuroscience (November 2003).
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doi:10.1124/jpet.104.070961.
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ABBREVIATIONS: DA, dopamine; WIN 35,428, (–)-2-β-carbomethoxy-3-β-(4-fluorophenyl)tropane 1,5-naphthalenedisulfonate; SKF 82958, (±)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; DOI, (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane; HRP, horseradish peroxidase; DAB, 3,3′-diaminobenzidine; HPLC, high-performance liquid chromatography; GFAP, glial fibrillary acidic protein; DAT, dopamine transporter; ILB4, isolectin B4 from Griffonia simplicifolia; PBS, phosphate-buffered saline; ANOVA, analysis of variance; 5-HT, 5-hydroxytryptamine (serotonin); HIV, human immunodeficiency virus.
- Received May 4, 2004.
- Accepted May 25, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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