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Temperature and neurotoxicity - lessons from the amphetamines.
Toxicologist 2006 Mar; 90(1):311-312
Toxicity is impacted by many factors - the nature of the agent, the exposure situation and the organism. How the agent or various aspects of testing impact body temperature are rarely considered when assessing toxicity or its mechanism(s); our work examining the neurotoxicity of the substituted amphetamines (SAs) (e.g., amphetamine, methamphetamine, MDMA, fenfluramine) illustrate how temperature factors may affect toxicity. Some SAs induce a profound hyperthermia and early work examined how body and ambient temperature contributed to the aggregate toxicity frequently found in rodents but rarely emphasized how altered temperature might affect other SA toxicities. Recently the neurotoxic potential of the SAs is a focus because of the popularity of MDMA within the Rave dance culture and interest in its use as a psychotherapy adjunct as well as treatment of ADHD with amphetamine. The SAs are dopaminergic neurotoxicants in the mouse and we showed how temperature factors contribute because manipulations that alter body or ambient temperature also alter their neurotoxicity. Test factors (strain/species, housing, handling) profoundly impact SA neurotoxicity and confound its assessment. Restraint stress because of its ability to lower body temperature provided neuroprotection rather than the expected increased toxicity. NMDA receptor antagonists protect against SA neurotoxicity but the cause is lowered body temperature rather than reduced glutamatergic signaling. The SAs and extreme hyperthermia induce distinctly different brain insults suggesting an as yet unknown necessary link between the hyperthermia induced by the SAs and their other actions in their ability to cause dopaminergic neurotoxicity. Links between temperature and SA neurotoxicity are clearly established but no agreement exists as to how SA temperature modulating aspects figure in the mechanism(s) of toxicity. The relevance of these observations for assessing brain and liver toxicity of the SAs in man is subject to current debate because of the extreme differences in thermal mass and thermoregulatory characteristics between man and laboratory species.
Temperature-effects; Neurotoxicity; Neurotoxins; Neurotoxicology; Neurotoxic-effects; Laboratory-animals; Animals; Animal-studies; Amines
Issue of Publication
Research Tools and Approaches: Exposure Assessment Methods
The Toxicologist. Society of Toxicology 45th Annual Meeting and ToxExpo, March 5-9, 2006, San Diego, California