Protection against cocaine and combined cocaine-ethanol toxicities in mice by imidazobenzodiazepine Ro 15-4513.
The effects of Ro 15-4513 in preventing cocaine and combined cocaine-ethanol toxicities were examined in mice. Ro 15-4513 is a partial inverse agonist of benzodiazepine receptors, which has been implicated in ethanol lethality and cocaine-induced seizures. Ro 15-4513 (5 mg/kg, 10 mg/kg, or 15 mg/kg) was administered intraperitoneally 10 min before the administration of saline and cocaine (75 mg/kg) in the cocaine groups, or before ethanol (3 g/kg) and cocaine (75 mg/kg) in the cocaine-ethanol groups. In both cocaine and cocaine-ethanol groups, two distinct groups of dead animals meeting the same criteria, the IL (immediate lethal) and DL (delayed lethal) groups, could be differentiated, depending on their survival times, observed disorders, and drug levels at the time of death. Differences in the seizure scores further subdivided the two groups. Ro 15-4513 protected mainly against the immediate lethality in the cocaine groups and mainly against the delayed lethality in the cocaine-ethanol groups. The dose of Ro 15-4513 providing the maximal protection against the lethal effects of these drugs was 10 mg/kg in the cocaine groups, and 5 mg/kg in the cocaine-ethanol groups. The sum of the lethalities was still higher with the maximal effective dose of Ro 15-4513 in the cocaine-ethanol groups than in the cocaine groups. In the cocaine-ethanol groups, 5 mg/kg of Ro 15-4513 attenuated both brain and liver cocaethylene levels. Cocaine-induced seizures were also attenuated by any dose of Ro 15-4513 used in the cocaine groups. Although some discrepancies were observed in the protective properties, some validity for the use of Ro 15-4513, a drug with more than one mode of protective action, was demonstrated in this study.
Hayase
T
T
Department of Legal Medicine, Kyoto University Faculty of Medicine, Japan.
Yamamoto
Y
Y
Yamamoto
K
K
D000818:Animals; D001386:Azides / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology*; D001923:Brain Chemistry; D002492:Central Nervous System Depressants / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000097:blood / Q000633:toxicity*; D003042:Cocaine / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000097:blood / Q000633:toxicity*; D004338:Drug Combinations; D004357:Drug Synergism; D000431:Ethanol / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000097:blood / Q000633:toxicity*; D007274:Injections, Intraperitoneal; D008099:Liver / Q000737:chemistry; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009026:Mortality; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D011963:Receptors, GABA-A / Q000187:drug effects*; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control; D016019:Survival Analysis; D015996:Survival Rate
D001386:Azides; D002492:Central Nervous System Depressants; D004338:Drug Combinations; D009292:Narcotic Antagonists; D009294:Narcotics; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D000431:Ethanol; C042957:Ro 15-4513; D003042:Cocaine