The effect of
SCH 23390, a
dopamine-one (D1) antagonist, in preventing acute toxicity induced by lethal doses of
cocaine,
d-amphetamine, and
methamphetamine was studied in the rat. Animals were first pretreated with
SCH 23390 (0.0, 0.5, 1.0, and 2.5 mg/kg, i.p.) and then were challenged with
cocaine (70 mg/kg, i.p., an LD85),
d-amphetamine (75 mg/kg, i.p., an LD95), and
methamphetamine (100 mg/kg, i.p., an LD90).
SCH 23390 did not alter the incidence of stimulant-induced
seizures compared to the vehicle controls. Significant protection against
cocaine-induced death was afforded only by the lowest dose of
SCH 23390 tested. Significant protection against
d-amphetamine-induced death was provided by all doses, with a dose dependent effect noted so that the incidence decreased from 95% for vehicle to 30% (p less than or equal to 0.01) with 2.5 mg/kg
SCH 23390 pretreatment. No statistically significant reduction in the incidence of
methamphetamine-induced death was seen with
SCH 23390 pretreatment. The ability of
SCH 23390 to protect against
d-amphetamine, but apparently not against
methamphetamine-induced death, suggests that different mechanisms of toxicity may exist between these drugs at high doses.