1. Multiple injections of METH (4 x 10 mg/kg, i.p.) at room temperature (23 degrees C) produced a significant depletion of dopamine (DA) and its metabolites DOPAC and HVA in striatum at 24 and 72 hr, and 1 and 2 wk. 2. Three days post 4 x 10 mg/kg METH at 23 degrees C, an 80% decrease in striatal dopamine (DA) occurred, while the same dose at 4 degrees C produced only a 20% DA decrease, and 4 x 20 mg/kg METH at 4 degrees C produced a 54% DA decrease. A similar pattern in the decreases of the DA metabolites DOPAC and HVA was observed after METH administration. 3. At 23 degrees C (+)MK-801 completely blocked while phenobarbital (40% decrease) and diazepam (65% decrease) partially blocked decreases in striatal DA produced by 4 x 10 mg/kg METH. Decreases in DOPAC and HVA were similar to the decreases in DA after METH and antagonists. 4. Multiple injections of METH (4 x 10 mg/kg, i.p.) at room temperature also produced a significant depletion of serotonin (5-HT) in striatum at 24 and 72 hr, and 1 and 2 wk. The depletion of 5-HT metabolite 5-HIAA was found only at 72 hr post-dosing. 5. This depletion of 5-HT and its metabolite 5-HIAA at room temperature was blocked either by changing the environmental temperature to 4 degrees C, or by pretreatment with MK-801, diazepam and phenobarbital after METH treatment. 6. Therefore, these data suggest that drugs that block METH toxicity, such as haloperidol (D2 receptors), pentobarbital and phenobarbital (chloride channels) and MK-801 (NMDA/glutamate receptors), do not necessarily have the same mechanism of action but may either induce hypothermia or block induction of hyperthermia. 7. In summary, these studies show that in the mouse, environmental temperature greatly influences METH neurotoxicity, and that the protective effects of compounds such as diazepam, phenobarbital and MK-801 may be mediated by blockade of METH-induced hyperthermia.