Modification of pharmacological and toxicological effects of acetophenazine, chlorpromazine and thloridazine in morphine-dependent mice.

The pharmacological and toxicological responses of three phenothiazine neuroleptics, acetophenazine, chlorpromazine and thioridazine were determined in morphine-dependent mice. The mice were rendered dependent on morphine by implantation of a morphine pellet for 3 days. The control animals received placebo pellets. The pellets were removed and at 6, 24, 48 and 72 hr after the pellet removal, naloxone ED50's for the stereotyped jumping response were determined. The effect of phenothiazine derivatives administered intraperitoneally, at 6, 24 and 72 hr after pellet removal were determined on the 24 hr LD50, locomotor activity and body temperature. The LD50 of all phenothiazines was decreased significantly in mice from which morphine pellets were removed for 6 hr in comparison to placebo pelleted mice. This was the time when maximum degree of dependence on morphine was observed. At 24 and 72 hr after pellet removal, the LD50's in morphine and placebo treated mice were not different. The relative decrease in locomotor activity by all the phenothiazines was less in morphine withdrawn mice as compared to placebo withdrawn mice. The hypothermic response of phenothiazines was enhanced in morphine withdrawn mice. It is concluded that the effects of phenothiazine neuroleptic drugs can be modified in narcotic-dependent subjects. Possible mechanisms of such altered effects are discussed.