Protective effects of buprenorphine against amplified cocaine and ethanol lethality in mice: role of cocaethylene.

The lethal effects of combining cocaine and ethanol administration in mice and the protective effects of buprenorphine, a mixed opioid agonist-antagonist, were examined with consideration to the involvement of cocaethylene. In Experiment 1, buprenorphine (0.25 or 0.5 mg/kg, i.p.) protected against a dose of cocaine exceeding the LD50 value (75 mg/kg, i.p.) combined with ethanol (3 g/kg, i.p.), although this attenuated lethality was not lower than the non-ethanol group (acute administration experiment). In Experiment 2, daily administrations of non-lethal doses of cocaine (40 mg/kg, i.p.) were combined with ethanol (1.5 g/kg, i.p.) for up to 5 days (repeated administration experiment). In Experiment 3, one dose of cocaine (75 mg/kg, i.p.) was administered after the ad libitum ingestion of an ethanol liquid diet, created by replacing 35% of the total calories with ethanol, for five days (ethanol liquid diet experiment). In all three experiments, 2 lethal groups could be discerned: an immediate lethal group (IL group) and a delayed lethal group (DL group). These groups were differentiated based on their survival times after the cocaine administrations, observed respiratory and locomotive disorders, and drug concentrations. The number of the DL group animals were elevated only in the combined cocaine-ethanol groups of Experiment 1. Buprenorphine (0.25 mg/kg, i.p.) administered before each cocaine injection attenuated the total percent lethality to levels not higher than the total percent lethality of the non-ethanol groups in the latter two experiments. This supports the validity of the protective effects of buprenorphine on cocaine toxicity amplified by non-lethal doses of ethanol. Quantitative postmortem drug analyses of mice from the IL groups, in which the drug levels were high enough to be determined, suggested that buprenorphine had a protective effect against combined cocaine-ethanol lethality without significantly decreasing the drug distributions, except for the concentration of cocaethylene in the brain.