Intravenous self-administration of an enkephalin analog, EK-399, by rats

The novel enkephalin analog Tyr-D-Met (O)-Gly-EtPhe-NHNHCOCH3 . AcOH (EK-399) was examined for psychic dependence potential by a self-administration test in rats. Five groups of experimentally naive rats were given an intravenous dose of EK-399 (0.032, 0.064 or 0.125 mg/kg), morphine HCl (0.5 mg/kg) or cocaine HCl (0.5 mg/kg) via a cannula implanted in the jugular vein when they pressed a lever. No animals initiated self-administration of EK-399 in the first 3 or 4 weeks of the experimental period. In contrast, almost all of the animals receiving morphine or cocaine initiated a high rate of self-administration within 1 or 2 weeks. However, when the doses of EK-399 were subsequently decreased, 4 of the 10 animals increased their rate of self-administration slightly. Furthermore, an increase in the rate of EK-399 self-administration was observed in 1 of 4 rats made physically dependent on EK-399. These results suggest that EK-399 has a very weak reinforcing effect on drug-taking behavior, which is slightly enhanced by the development of physical dependence on the compound, and it may possess a low psychic dependence potential.