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ROLE OF TEMPERATURE STRESS AND OTHER FACTORS IN THE NEUROTOXICITY OF THE SUBSTITUTED AMPHETAMINES: 3,4-METHYLENEDIOXYMETHAMPHETAMINE AND FENFLURAMINE
Citation:
Miller, D. AND J. O'Callaghan. ROLE OF TEMPERATURE STRESS AND OTHER FACTORS IN THE NEUROTOXICITY OF THE SUBSTITUTED AMPHETAMINES: 3,4-METHYLENEDIOXYMETHAMPHETAMINE AND FENFLURAMINE. U.S. Environmental Protection Agency, Washington, D.C., EPA/600/J-95/544.
Description:
Amphetamines (AMPS) can cause long-term depletions in striatal dopamine (DA) and serotonin (5-HT) and these decrements are often accepted as prima facie evidence of AMP-induced damage to the dopaminergic and serotonergic projections to striatum. arely are indices linked to neural damage used to evaluate the neurotoxicity of the AMPs. ere, we determined the potential neurotoxic effects of 2 substituted AmPs, d-methylenedioxymethamphetamine (d-MDMA) and d-fenfluramine (d-FEN) in group-housed female C57BL6/J mice. strogliosis, assessed by quantification of flial fibrillary acidic protein (GFAP) was the main indicator of d-NDMA-induced neural damage. ssays of tyrosine hydroxylase (TH), DA and 5-HT were used to determine effects on DA and 5HT systems. s AMPs are noted for both their stimulatory and hyperthermia-inducing properties, activity as well as core temperature was monitored in several experiments. o extend the generality of our findings these same endpoints were examined in singly-housed female C57BL6/J mice and in group-housed male C57BL6/J or female B6C3F1 mice after treatment with D-MDMA. ice received either D-MDMA (20 mg/kg)(singly-housed mice received dosages of 20, 30 or 40 mg/kg) or D-FEN (25 mg/kg) every 2 hours for a total of 4 s.c. inj. -MDMA caused hyperthermia while D-FEN induced hypothermia. -MDMA cause a large (300%) increase in striatal GFAP that resolved by 3 weeks and a 50-75% decrease in TH and DA that was still apparent at 3 weeks. -FEN did not affect any parameters in striatum. -MDMA is a striatal dopaminergic neurotoxicant in both male and female C57BL6/mice as evidenced y astrogliosis and depletions DA in this area in both sexes. The greater lethality to males suggest they may be more sensitive, at least to the general toxicity of D-MDMA, than females. 20 mg/kg of D-MDMA induced the same degree of damage whether mice were housed singly or in groups. igher dosages in singly-housed mice induced greater lethality but not greater neurotoxicity. -MDMA was also effective in inducing striatal damage in mice of the B6C3F1 strain. Significant increases in activity were induced by D-MDMA and these ncreases were not blocked pretreatment with MK-801 despite the rofound lowering of body temperature induced by this combination. A lowering of body temperature, whether by a 15 degree C ambient temperature, pretreatment with Mk-801 (1.0 mg/kg prior to the 1st and 3rd D-MDMA inj) or restraint, was effective in blocking the neurotoxicity of D-MDMA in both C57BL6/i or. The stimulatory effects of D-MDMA appeared to have little impact on the neurotoxicity induced by D-MDMA or the protection conferred by MK801. hese data suggest that in the mouse the neurotoxic effects of D-MDMA, and most likely other AMPS, are linked to an effect on body temperature.