Environment-, drug- and stress-induced alterations in body temperature affect the neurotoxicity of substituted amphetamines in the C57BL/6J mouse.
In the companion paper we demonstrated that d-methamphetamine (d-METH), d-methylenedioxyamphetamine (d-MDA) and d-methylenedioxymethamephetamine (d-MDMA), but not d-fenfluramine (d-FEN), appear to damage dopaminergic projections to the striatum of the mouse. An elevation in core temperature also was associated with exposure to d-METH, d-MDA and d-MDMA, whereas exposure to d-FEN lowered core temperature. Given these findings, we examined the effects of temperature on substituted amphetamine (AMP)-induced neurotoxicity in the C57BL/6J mouse. Levels of striatal dopamine (DA) and glial fibrillary acidic protein (GFAP) were taken as indicators of neurotoxicity. Alterations in ambient temperature, pretreatment with drugs reported to cause hypothermia in the mouse and hypothermia induced by restraint stress were used to affect AMP-induced neurotoxicity. Mice received d-METH (10 mg/kg), d-MDA (20 mg/kg) or d-MDMA (20 mg/kg) every 2 hr for a total of four s.c. injections. All three AMPs increased core temperature and caused large (> 75%) decreases in striatal dopamine and large (> 300%) increases in striatal glial fibrillary acidic protein 72 hr after the last injection. Lowering ambient temperature from 22 degrees C to 15 degrees C blocked (d-MDA and d-MDMA) or severely attenuated (d-METH) these effects. Pretreatment with MK-801 lowered core temperature and blocked AMP-induced neurotoxicity; elevation of ambient temperature during this regimen elevated core temperature and markedly attenuated the neuroprotective effects of MK-801. Pretreatment with MK-801 also lowered core temperature in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice but did not block 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)
Miller
D B
DB
Neurotoxicology Division, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina.
O'Callaghan
J P
JP
D000662:Amphetamines / Q000633:toxicity*; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects*; D003342:Corpus Striatum / Q000187:drug effects*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D013312:Stress, Physiological
D000662:Amphetamines; D005904:Glial Fibrillary Acidic Protein; D016291:Dizocilpine Maleate; D004298:Dopamine