Antagonism of cocaine, amphetamine, and methamphetamine toxicity.
The effect of diazepam, haloperidol, MK-801, and propranolol in antagonizing behavioral symptoms induced by lethal doses of cocaine, amphetamine, and methamphetamine were studied in a rat model. Animals were first pretreated IP with potential antagonists, diazepam (2, 5, and 10 mg/kg), haloperidol (5, 10, and 20 mg/kg), propranolol (5, 10, and 20 mg/kg), MK-801 (0.5, 1.0, and 2.5 mg/kg), and then were challenged IP with cocaine (70 mg/kg) (LD85), d-amphetamine (75 mg/kg) (LD100), and methamphetamine (100 mg/kg) (LD90). Diazepam, at all doses, provided significant protection against cocaine- (p less than or equal to 0.01) and methamphetamine- (p less than or equal to 0.05) induced seizures and produced a dose-dependent effect against amphetamine-induced seizures. MK-801, at all doses, reduced seizures in all groups (p less than or equal to 0.01). Propranolol altered the incidence of methamphetamine-induced seizures. Significant protection against cocaine-induced death was afforded by diazepam (p less than or equal to 0.01) and propranolol (p less than or equal to 0.05). Significant protection against amphetamine-induced death was provided by haloperidol (all doses, p less than or equal to 0.1), MK-801 (all doses, p less than or equal to 0.1), and propranolol (10 and 20 mg/kg, p less than or equal to 0.1). No agent reduced the incidence of methamphetamine- (50 or 100 mg/kg) induced death. The failure of d-amphetamine antagonists to protect against methamphetamine-induced toxicity and death suggest that different mechanisms of toxicity may exist between these drugs.
Derlet
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Department of Pharmacology, University of California, Davis.
Albertson
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Rice
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D000661:Amphetamine / Q000037:antagonists & inhibitors* / Q000633:toxicity; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D003042:Cocaine / Q000037:antagonists & inhibitors* / Q000633:toxicity; D003975:Diazepam / Q000494:pharmacology; D004121:Dimethyl Sulfoxide; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004567:Electrodes, Implanted; D006220:Haloperidol / Q000494:pharmacology; D007928:Lethal Dose 50; D008297:Male; D008694:Methamphetamine / Q000037:antagonists & inhibitors* / Q000633:toxicity; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control
D008694:Methamphetamine; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D011433:Propranolol; D000661:Amphetamine; D003042:Cocaine; D006220:Haloperidol; D003975:Diazepam; D004121:Dimethyl Sulfoxide