ACUTE COCAINE TOXICITY - THE EFFECT OF AGENTS IN NON-SEIZURE-INDUCED DEATH

Death from cocaine intoxication results from one or more of the multip le mechanisms including seizures, cardiovascular collapse, or apnea. I n the free-moving rat model, continuous seizures are a major cause of death. To study other mechanisms of death unrelated to seizures in thi s model, we suppressed lethal seizures with diazepam (DZP) and investi gated the effect of several pharmacological agents. Rats were pretreat ed with vehicle alone, diazepam 5 mg/kg alone, or a combination of DZP plus either nifedipine (NIFD) 2 mg/kg, propranolol (PROP) 10 mg/kg, o r prazosin (PRAZ) 5 mg/kg. Five minutes after pretreatment, all animal s received cocaine 100 mg/kg. Each test group consisted of 15 animals and all agents were given IP. Two animals in each group had cortical e lectrodes implanted. Animals that received vehicle followed by cocaine had 100% incidence of seizures and death. Those rats that received DZ P alone followed by cocaine had no seizures and 53% death. Rats that r eceived DZP plus NIFD or DZP plus PROP had suppression of seizures but no significant change in the incidence of death. The group that recei ved DZP and PRAZ followed by cocaine had no seizures and 13% incidence of death (p < 0.001). Electroencephalogram recordings showed cortical electrical spike activity or spike-and-wave afterdischarges in all an imals clinically observed to have seizures. In the absence of clinical seizure activity, no significant cortical spike activity was noted. I t is concluded that animals protected from seizures with diazepam can still have nonseizure deaths after high-dose cocaine. The incidence of death in these animals is not reduced with nifedipine or propranolol pretreatment but is reduced with prazosin pretreatment.