Although repeated but not single administration of antidepressants exerts therapeutic effect on clinical depression, the mechanism of the clinical efficacy of antidepressants remains unknown. This report shows a novel action of antidepressants which can explain the delayed onset of clinical action of the drugs. Continuous infusion of the antidepressants maprotiline or desipramine into the rat cerebral cortex pretreated with the catecholamine neurotoxin 6-hydroxydopamine induced regeneration of noradrenergic axon terminals. This finding provides evidence that antidepressants possess the ability to cause axonal sprouting of central noradrenergic (and possibly dopaminergic) neurons in the mature brain.