METHAMPHETAMINE-INDUCED HYPERTHERMIA AND DOPAMINERGIC NEUROTOXICITY IN MICE - PHARMACOLOGICAL PROFILE OF PROTECTIVE AND NONPROTECTIVE AGENTS

Neurotoxic doses of methamphetamine (METH) can cause hyperthermia in e xperimental animals. Damage sustained to dopaminergic nerve terminals by this stimulant can be reduced by environmental cooling or by pharma cological manipulation which attenuates the hyperthermia. Many pharmac ological agents with very diverse actions protect against METH-induced neuropathology. Several of these compounds, as well as drugs which do not protect, were investigated to determine if there was a relationsh ip between protection and METH-induced hyperthermia. Mice received MET H with or without concurrent administration of other drugs and core (i .e., colonic) temperature was monitored during treatment. The animals were sacrificed greater than or equal to 5 days later and neostriatal tyrosine hydroxylase activity and dopamine were measured. Core tempera ture was significantly elevated (greater than or equal to 2 degrees C) in mice treated with doses of METH which produced greater than or equ al to 90% losses in striatal dopamine but not in mice less severally a ffected (only 50% loss of dopamine). Concurrent treatment of mice with METH and pharmacological agents which protected partially or complete ly from METH-induced toxicity also prevented the hyperthermic response (i.e., dopamine receptor antagonists, fenfluramine, dizocilpine, alph a-methyl-p-tyrosine, phenytoin, aminooxyacetic acid and propranolol). These findings are consistent with the hypothesis that the hyperthermi a produced by METH contributes to its neuropathology. However, studies with reserpine, a compound which dramatically lowers core temperature , demonstrated that hyperthermia per se is not a requirement for METH- induced neurotoxicity. Although core temperature was elevated in reser pinized mice treated with METH as compared with reserpinized control m ice, their temperatures remained significantly lower than in nonreserp inized control mice. However, the hypothermic state produced in the re serpinized mice did not provide protection from METH-induced toxicity. These data demonstrate that hyperthermia per se contributes to but is not solely responsible for the METH-induced neuropathology.