BEHAVIORAL DETERMINATION OF TIME AND DOSE PARAMETERS OF MONOAMINE OXIDASE INHIBITORS

¹ Department of Pharmacology, Hoffmann-La Roche Inc., Nutley, New Jersey

The time course and other characteristics of the action of short- and long-duration monoamine oxidase (MAO) inhibitors were determined by measuring the duration of avoidance responding following administration of a standard test dose of tetrabenazine to rats pretreated with the MAO inhibitor. The duration of avoidance responding after tetrabenazine depended upon the dose and potency as an MAO inhibitor of the pretreatment compound, and upon its time of pretreatment in relation to its time course of action.

The activity of iproniazid reached a maximum in about 4 hours, remained at a high level for several days, and then slowly fell, but was still detectable for as long as 30 days. Similar results were obtained with isocarboxazid, another long-duration MAO inhibitor.

Determinations of the time courses of action for short duration MAO inhibitors showed that the curve for harmaline returned to base line in less than 8 hours, while SKF 385A lasted from 4 to 7 days. In keeping with its short duration of action, repeated administrations of harmaline at 24-hour intervals did not produce cumulative effects. When iproniazid was given at 72-hour intervals, cumulative effects were clearly demonstrated.

The magnitude and duration of activity of the various MAO inhibitors in this tetrabenazine blocking test corresponded closely to their activity as MAO inhibitors in vivo.