Data from human and animal studies suggest that hyperpyrexia contributes to both the neurotoxic and the lethal effects of stimulant drugs such as methamphetamine (METH). Because many of the effects of METH involve the release of dopamine from CNS neurons, we examined the effects of D1 and D2 dopamine receptor antagonists on METH-induced lethality and determined whether these effects correlated with changes in body temperature. In the first set of experiments, we found that the D2 antagonist sulpiride (SUL; 20, 40 or 80 mg/kg) potentiated the lethality caused by a single injection of METH (10 mg/kg). Pretreatment with the D1 antagonist SCH 23390 (SCH; 0.5 mg/kg) reduced the lethality induced by METH alone or by SUL/METH. Other D2 or 5-hydroxytryptamine antagonists prevented, rather than potentiated, METH-induced lethality. In a second set of experiments, rectal temperatures were recorded in METH-injected animals pretreated with SCH or SUL. METH caused a significant increase (i.e., above vehicle-injected levels) in body temperature at 2.5 hr after injection. The effects of SCH or SUL pretreatment on METH-induced changes in body temperature suggest that the lethality-potentiating and -protective effects of SUL and SCH, respectively, were not due to altered thermoregulatory responses. These data support the idea that D1 receptor activation is an important event in the lethality caused by METH and that SUL may potentiate D1 receptor activation by augmenting METH-induced DA release.