Ontogeny of methamphetamine-induced neurotoxicity and associated hyperthermic response.
Methamphetamine (MA) administration to adult rats results in neurotoxicity characterized by depletion of caudate-putamen (CP) dopamine (DA) and serotonin (5-HT) and an accompanying increase in glial fibrillary acidic protein (GFAP) content. The severity of MA-induced neurotoxicity correlates with the accompanying thermoregulatory response, i.e., a hyperthermic response facilitates neurotoxicity while a hypothermic response is neuroprotective. In the following study, the thermoregulatory and neurotoxic effects of MA administration (4 x 10 mg/kg) were investigated in developing rats at postnatal days (PND) 20, 40 and 60. Rats at PND 20 and PND 40 were administered MA at ambient temperatures of 22 degrees C and 30 degrees C; and PND 60 rats were administered MA at 22 degrees C only. Temperatures were measured and thermal responses were compared by calculating the total thermal response (TTR) induced by MA treatment. MA administration to PND 60 rats at 22 degrees C induced a hyperthermic response, resulted in a 47% reduction of neostriatal DA and a 49% increase of GFAP content. Administration of MA to PND 40 rats at 22 degrees C failed to induce a hyperthermic response and did not result in reduced DA or increased GFAP. However, administration of MA to PND 40 rats at 30 degrees C induced hyperthermia, reduced neostriatal DA by 54% and increased GFAP by 70%. MA administration to PND 20 rats at either 22 degrees C or 30 degrees C did not result in DA depletion or increased GFAP, even though MA administration to PND 20 rats at 30 degrees C induced hyperthermia. These results demonstrate that the induction of hyperthermia is necessary to exhibit MA-induced neurotoxicity at PND 40; however, PND 20 rats are resistant to the DA depleting effects of MA despite the induction of hyperthermia.
Cappon
G D
GD
Children's Hospital Research Foundation, Neuroscience Program and Department of Pediatrics, University of Cincinnati, OH 45229, USA.
Morford
L L
LL
Vorhees
C V
CV
D000375:Aging / Q000502:physiology*; D000704:Analysis of Variance; D000818:Animals; D001833:Body Temperature Regulation / Q000187:drug effects* / Q000502:physiology; D002421:Caudate Nucleus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004298:Dopamine / Q000378:metabolism*; D005334:Fever / Q000139:chemically induced / Q000503:physiopathology*; D005904:Glial Fibrillary Acidic Protein / Q000096:biosynthesis; D008694:Methamphetamine / Q000633:toxicity*; D009498:Neurotoxins; D011699:Putamen / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D013696:Temperature
D005904:Glial Fibrillary Acidic Protein; D009498:Neurotoxins; D012701:Serotonin; D008694:Methamphetamine; D004298:Dopamine