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.