The time-dependent effects of the selective monoamine oxidase (MAO) type A-inhibiting antidepressant clorgyline were studied in rodents. Functional adaptive changes in both the noradrenergic and serotonergic neurotransmitter systems in the central nervous system were observed to develop following long-term administration of clorgyline. The importance of these adaptive changes in understanding the molecular mechanisms responsible for the efficacy of antidepressants is supported by our recent finding that self-stimulation behavior in rodents was enhanced only after long-term administration of clorgyline. The slow return of adaptational changes following discontinuation of clorgyline observed recently has implications for understanding some delayed drug interactions associated with MAO-inhibiting antidepressants in man.