EFFECTS OF SULPIRIDE AND SCH-23390 ON METHAMPHETAMINE-INDUCED CHANGESIN BODY-TEMPERATURE AND LETHALITY

Data from human and animal studies suggest that hyperpyrexia contribut es to both the neurotoxic and the lethal effects of stimulant drugs su ch as methamphetamine (METH). Because many of the effects of METH invo lve the release of dopamine from CNS neurons, we examined the effects of D-1 and D-2 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 D-2 an tagonist sulpiride (SUL; 20, 40 or 80 mg/kg) potentiated the lethality caused by a single injection of METH (10 mg/kg). Pretreatment with th e D-1 antagonist SCH 23390 (SCH; 0.5 mg/kg) reduced the lethality indu ced by METH alone or by SUL/METH. Other D-2 or 5-hydroxytryptamine ant agonists prevented, rather than potentiated, METH-induced lethality. I n a second set of experiments, rectal temperatures were recorded in ME TH-injected animals pretreated with SCH or SUL. METH caused a signific ant 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-po tentiating and -protective effects of SUL and SCH, respectively, were not due to altered thermoregulatory responses. These data support the idea that D-1 receptor activation is an important event in the lethali ty caused by METH and that SUL may potentiate D-1 receptor activation by augmenting METH-induced DA release.