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The role of temperature, stress, and other factors in the neurotoxicity of the substituted amphetamines 3,4-methylenedioxymethamphetamine and fenfluramine.

D B Miller, J P O'Callaghan

Molecular Neurobiology August 1, 1995 DOI: 10.1007/bf02740694 (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Experimental animal study Peer reviewed
Population Group-housed and singly housed female C57BL6/J mice, group-housed male C57BL6/J mice, and female B6C3F1 mice
Interventions d-methylenedioxymethamphetamine (d-MDMA) d-fenfluramine (d-FEN) MK-801 restraint
Dose d-MDMA 20 mg/kg (singly housed mice also received 20, 30, or 40 mg/kg); d-FEN 25 mg/kg; MK-801 1.0 mg/kg prior to the first and third d-MDMA injections
Duration Four subcutaneous injections every 2 h; follow-up to 3 weeks
Measures glial fibrillary acidic protein (GFAP), tyrosine hydroxylase (TH), dopamine (DA), serotonin (5-HT), core temperature, activity
Topics Serotonin MDMA
Keywords Corpus striatum Animals Mice, inbred c57bl Fever Hypothermia Dopamine N-methyl-3,4-methylenedioxyamphetamine Fenfluramine Dizocilpine maleate Tyrosine 3-monooxygenase Neurotoxins Restraint, physical Stress, psychological Motor activity Social isolation Body temperature regulation Sex characteristics Kinetics Time factors Female
Key findings Repeated d-MDMA produced hyperthermia and striatal dopaminergic damage (300% GFAP increase; 50-75% dopamine and tyrosine hydroxylase depletion persisting at 3 weeks), whereas d-FEN produced hypothermia and no striatal effects. Lowering body temperature by cold ambient temperature, MK-801, or restraint blocked d-MDMA neurotoxicity, suggesting the neurotoxic effects of d-MDMA, and most likely other amphetamines, are linked to body temperature.

Abstract

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. Rarely are indices linked to neural damage used to evaluate the neurotoxicity of the AMPs. Here, we determined the potential neurotoxic effects of two substituted AMPs, d-methylenedioxymethamphetamine (d-MDMA) and d-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 and in 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 evidenced 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, that 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 degree C ambient temperature (approx 2 degree drop), pretreatment with MK-801 (1.0 mg/kg prior to the first and third d-MDMA injections; approx 5-6 degrees C drop) or restraint (approx 5-6 degrees 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 likly other AMPs, are linked to an effect on body temperature.

Comparable studies

Other preclinical and animal studies on MDMA, most cited first.

Study Year Design Participants
Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) 1987 Experimental study
3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain 1987 Animal experiment
Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells 2006 In vitro laboratory study
Small Changes in Ambient Temperature Cause Large Changes in 3,4-Methylenedioxymethamphetamine (MDMA)-Induced Serotonin Neurotoxicity and Core Body Temperature in the Rat Rats 1998 Experimental study
Altered Serotonin Innervation Patterns in the Forebrain of Monkeys Treated with (±)3,4-Methylenedioxymethamphetamine Seven Years Previously: Factors Influencing Abnormal Recovery Squirrel monkeys treated with MDMA 1999 Observational cohort

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