Cocaine-induced respiratory depression and seizures are synergistic mechanisms of cocaine-induced death in rats.
OBJECTIVE
To determine if respiratory depression is an important mechanism of cocaine-induced death in conscious rats.


METHODS
Male Sprague-Dawley rats weighing between 200 and 300 g and fitted with cortical electrodes were pretreated intraperitoneally with either saline (vehicle), MK-801, or valproic acid for 30 minutes before challenge with 70 mg/kg IP cocaine followed by spontaneous breathing or mechanical ventilation after acute tracheostomy. Behavior, seizures, death, EEGs, and ECGs were observed and measured.


RESULTS
In group 1, animals received saline followed by cocaine. The incidence rates of seizures and death were 92% and 83%, respectively. Group 2 received saline followed by cocaine and then were ventilated mechanically through an acute tracheostomy after respiratory arrest (late mechanical ventilation). This group experienced seizures in 100% and death in 67% of animals. Group 3 also received saline followed by cocaine but were ventilated mechanically immediately after the first seizures (early mechanical ventilation). They had experienced seizures in 100% and death in 30%, the latter being significantly (P less than .025) reduced compared with group 1. In group 4, an anticonvulsant (1 mg/kg MK-801) was given before cocaine challenge, resulting in seizures in 10% (P less than .002 compared with group 1) and death in 90%. Group 5 received MK-801 followed by cocaine and then were ventilated mechanically after respiratory arrest (late mechanical ventilation). They experienced seizures in 20% (P less than .002 compared with group 1), and no animals in this group died (P less than .002 compared with group 1 or 4). Group 6 received an anticonvulsant (400 mg/kg valproic acid), followed by cocaine. This resulted in seizures in 20% (P less than .002 compared with group 1) and death in 90%. Group 7 received valproic acid followed by cocaine and then were ventilated mechanically (late mechanical ventilation). They experienced seizures in 30% (P less than .002 compared with group 1), and all animals survived (P less than .002 compared with group 1 or 6).


CONCLUSIONS
Early mechanical ventilation reduces cocaine toxicity. Control of seizure activity with specific anticonvulsants allows delayed mechanical ventilation to protect against cocaine toxicity. This suggests that respiratory depression in conjunction with seizure activity plays a major role in the mechanisms of cocaine-induced death in this model.
Tseng
C C
CC
Department of Medical Pharmacology and Toxicology, School of Medicine, University of California, Davis.
Derlet
R W
RW
Albertson
T E
TE
D000818:Animals; D003042:Cocaine / Q000494:pharmacology / Q000633:toxicity*; D003643:Death; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004357:Drug Synergism; D004562:Electrocardiography; D004569:Electroencephalography; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D012121:Respiration, Artificial; D012131:Respiratory Insufficiency / Q000139:chemically induced*; D012640:Seizures / Q000139:chemically induced*; D012965:Sodium Chloride / Q000494:pharmacology; D014139:Tracheostomy; D014635:Valproic Acid / Q000494:pharmacology
D012965:Sodium Chloride; D014635:Valproic Acid; D016291:Dizocilpine Maleate; D003042:Cocaine