PSYCHOPHARMACOLOGICAL EFFECTS OF REVERSIBLE CHOLINESTERASE INHIBITION INDUCED BY N-METHYL 3-ISOPROPYL PHENYL CARBAMATE (COMPOUND 10854)

¹ Mellon Institute, Pittsburgh, Pennsylvania

N-methyl 3-isopropyl phenyl carbamate (Compound 10854) has been studied for its psychopharmacological and acetylcholinesterase inhibitory effects. Male rats were 3 to 4 times as sensitive as females to the lethal and effective dose on avoidance behavior; in both cases a comparison of the LD5O with the ED5O revealed about a 25-fold factor. Atropine sulfate inhibited the effects of Compound 10854 on both avoidance and escape behavior, while methyl atropine blocked only the inhibitory effects on escape behavior.

Dose-response studies, utilizing dust inhalation techniques, for behavioral and anticholinesterase effects, indicated that threshold effects on discrete avoidance studies are associated with about a 50% inhibition of total brain cholinesterase. A linear decrease on avoidance efficiency was obtained when brain enzyme activity was decreased from 50 to 25% of normal. Peak effect on behavior and brain cholinesterase occurred at 30 minutes following intraperitoneal administration of Compound 10854. Inhibitory effects were of short duration, avoidance performance was normal after 75 minutes and enzyme activity was within control limits by 180 minutes following injection.

Studies on forced and spontaneous motor activity indicated that the carbamate elicited activity patterns similar to chlorpromazine. Barbiturate potentiation induced by Compound 10854 was blocked only by pretreatment with a dose of atropine sulfate which alone significantly reduced barbiturate sleeping time. Potentiation also occurred when the carbamate was given 24 hours prior to the barbiturate.

It is concluded that the behavioral changes induced by Compound 10854, but not barbiturate potentiation, are mediated by central anticholinesterase effects.