Plastic changes in axon terminals of NA LC neurons following repeated stress and antidepressant treatments were examined using electrophysiological or morphological methods. For stress treatment, rats restrained in a small cage were immersed up to the neck in warm water for 10 min daily. Electrophysiological experiments were performed under urethane anesthesia on the day following the termination of stress treatment. To quantify the density of cortical axon terminals arising in the LC, the percentage of LC neurons activated antidromically from the cerebral cortex was assessed. The percentage of LC neurons showing antidromic response to cortical stimulation was increased in the animals stressed for two weeks but not for one week. Since threshold currents for antidromic activation were not changed by the stress treatment, the observed changes were interpreted as morphological (axonal sprouting) rather than physiological consequences in NA axon terminals of LC neurons. To test the ability of antidepressants to induce the regeneration of central NA axons, local injections of 6-OHDA were made bilaterally into the symmetrical sites of the FC. Two weeks after the 6-OHDA injections, the same cortical site of one hemisphere was infused with the antidepressant MPL, DMI, or MIA, and the corresponding site of the other hemisphere with SAL. The density of glyoxylic acid-induced catecholamine fibers was greater in the cortical hemisphere infused with the antidepressants than that infused with SAL. These findings indicate that repeated mild stress and antidepressant treatments induce sprouting of NA LC axons in the cerebral cortex. Axonal sprouting of LC neurons can explain both the delayed onset of the clinical response to antidepressants and subsensitivity of beta-adrenoceptors following repeated stress and antidepressant treatments, and may be a common mechanism for the clinical efficacy of antidepressant drugs and electroconvulsive shock. Furthermore, the findings suggest the possibility that axonal retraction or degeneration of central NA neurons may be involved, at least in part, in the pathology of clinical depression.