A single dose model of methamphetamine-induced neurotoxicity in rats: effects on neostriatal monoamines and glial fibrillary acidic protein.
The neurotoxic effects of a single administration of methamphetamine (MA) were studied under conditions conducive to MA-induced hyperthermia. After a single dose of MA (10, 20, 30, or 40 mg/kg, s. c.) or saline (3 ml/kg) to Sprague-Dawley CD rats, rectal temperatures were monitored for 9 h in a room with an ambient temperature of 22.0+/-0.5 degrees C. MA induced significant dose-dependent hyperthermia, however, no significant increase in mortality occurred. Neostriatal DA, 5-HT, TH, and GFAP were assayed 3 days following treatment. MA induced dose-dependent reductions of DA, 5-HT and TH, and increased GFAP. For DA, at doses of 20, 30, or 40 mg/kg the reductions were to 71%, 49%, and 29%, and for 5-HT were to 73%, 44%, and 19% of control values. No reductions were seen after the 10 mg/kg dose. Semiquantitative analysis Western blots of TH and GFAP demonstrated that TH was reduced to 52%, 75%, and 28%, and GFAP was increased to 125%, 134%, and 149% of control values at MA doses of 20, 30, or 40 mg/kg, respectively. No significant changes in TH or GFAP were seen at the 10 mg/kg MA dose. These results demonstrate that a single-dose of MA can be as effective as the widely used four-dose every 2 h regimen. Moreover, mortality can be minimized by monitoring core body temperature and preventing MA-induced hyperthermia from exceeding 41.5 degrees C.
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Division of Developmental Biology, Children's Hospital Research Foundation, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
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Broening
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D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism; D005334:Fever / Q000139:chemically induced; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism*; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage* / Q000506:poisoning; D009498:Neurotoxins / Q000008:administration & dosage* / Q000506:poisoning; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D015306:Biogenic Monoamines; D005904:Glial Fibrillary Acidic Protein; D009498:Neurotoxins; D012701:Serotonin; D008694:Methamphetamine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine