The role of temperature,stress, and other factors in the neurotoxicity of the substituted amphetamines 3,4-methylenedioxymethamphetamine and fenfluramine |
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Authors: | Diane B Miller James P O’Callaghan |
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Institution: | (1) Neurotoxicology Division, US Environmental Protection Agency, 17711 Research Triangle Park, NC |
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Abstract: | Amphetamines (AMPs) can cause long-term depletions in striatal dopamine (DA) and serotonin (5-HT), and these decrements are
often accepted asprima facie evidence of AMP-induced damage to the dopaminergic and serotonergic projections to striatum. Rarely are indices linked to
neural damage used to evaluate the neurotoxicity, of the AMPs. Here, were determined the potential neurotoxic effects of two
substituted AMPs,d-methylenedioxymethamphetamine (d-MDMA), andd-fenfluramine (d-FEN) in group-housed female C57BL6/J mice. Astrogliosis, assessed by quantification of glial fibrillary acidic
protein (GFAP), was the main indicator of d-MDMA-induced neural damage. Assays of tyrosine hydroxylase (TH), DA, and 5-HT
were used to determine effects on DA and 5-HT systems. Since AMPs are noted for both their stimulatory and hyperthermia-inducing
properties, activity, as well as core temperature, was monitored in several experiments. To extend the generality of our findings,
these same end points were examined in singly housed female C57BL6/J mice in and group-housed male C57BL6/J or female B6C3F1
mice after treatment with d-MDMA. Mice, 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 h for a total of four sc injections. d-MDMA caused hyperthermia, whereas d-FEN induced
hypothermia. d-MDMA cause a large (300%) increase in striatal GFAP that resolved by 3 wk and a 50–75% decrease in TH and DA
that was still apparent at 3 wk, d-FEN did not affect any parameters in striatum. d-MDMA is a striatal dopaminergic neurotoxicant
in both male and female C57BL6/mice, as evidence by astrogliosis and depletions of DA in this area in both sexes. The greater
lethality to males suggests they may be more sensitive, at least to the general toxicity of d-MDMA, than females. d-MDMA (20
mg/kg) induced the same degree of damage whether mice were housed singly or in groups. Higher dosages in singly housed mice
induced greater lethality, but not greater neurotoxicity. d-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 increases were not blocked by pretreatment
with MK-801, despite the profound lowering of body temperature induced by this combination. A lowering of body temperature,
whether by a 15°C ambient temperature (approx 2°C drop), pretreatment with MK-801 (1.0 mg/kg prior to the first and third
d-MDMA injections; approx 5–6°C drop) or restraint (approx 5–6°C drop), was effective in blocking the neurotoxicity of d-MDMA
in both C57BL6/J and B6C3F1. The stimulatory effects of d-MDMA appeared to have little impact on the neurotoxicity induced
by d-MDMA or the protection conferred by MK-801. These 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. |
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Keywords: | AMPs d-MDMA d-FEN GFAP stress MK-801 dopamine neurotoxicity striatum temperature |
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