Modulation of the lethal effects of cocaine by cholinomimetics

In view of the toxicity of cocaine and recent reports on the antimuscarinic properties of cocaine, the present study evaluated the effects of manipulations in cholinergic neurotransmission on the lethal effects of cocaine. Physostigmine pretreatment significantly altered the lethality of cocaine, increasing the LD 50 from 82.5 mg/kg to 96.9 mg/kg in male F344 rats. Atropine alone did not alter the lethal effects of cocaine at doses that are effective in preventing parasympathetic effects and lethality of oxotremorine. The prophylactic effect of physostigmine was not prevented by atropine. Neostigmine did not significantly affect the cocaine lethality dose-effect function. Both oxotremorine and (-)-nicotine were also devoid of protective actions. At higher doses, all of the cholinomimetics potentiated the lethal effects of cocaine. These results suggest that whereas cocaine lethality may be enhanced by stimulation of muscarinic receptors, low doses of physostigmine protect against lethality through actions at noncholinergic sites.