ENVIRONMENT-INDUCED, DRUG-INDUCED 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-methylenedioxymethamphetam ine (d-MDMA), but not d-fenfluramine (d-FEN), appear to damage dopamin ergic projections to the striatum of the mouse. An elevation in core t emperature also was associated with exposure to d-METH, d-MDA and d-MD MA, whereas exposure to d-FEN lowered core temperature. Given these fi ndings, we examined the effects of temperature on substituted amphetam ine (AMP)-induced neurotoxicity in the C57BL/6J mouse. Levels of stria tal dopamine (DA) and glial fibrillary acidic protein (GFAP) were take n 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-induc ed 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%) decreas es in striatal dopamine and large (>300%) increases in striatal glial fibrillary acidic protein 72 hr after the last injection. Lowering amb ient temperature from 22 degrees C to 15 degrees C blocked (d-MDA and d-MDMA) or severely attenuated (d-METH) these effects. Pretreatment wi th MK-801 lowered core temperature and blocked AMP-induced neurotoxici ty; 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-meth yl-Cphenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice but did not block methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity . Elevation of ambient temperature during treatment with d-FEN did not result in evidence of neurotoxicity. Pretreatment with drugs that cau sed hypothermia (ethanol, pentobarbital, diethyldithiocarbamate and d- FEN) blocked or attenuated d-MDMA-induced neurotoxicity. MK-801 and et hanol caused the greatest hypothermia and provided complete protection against d-MDMA-induced neurotoxicity. Likewise, restraining mice duri ng dosing with d-MDMA resulted in severe hypothermia and completely bl ocked d-MDMA-induced neurotoxicity. These data suggest that the neurot oxic effects of AMPs in the mouse are sensitive to changes in body tem perature.