The imipramine-sensitive serotonin transporter appears to be the receptor for clinically important antidepressants. Some studies suggest that this protein may fall under the influence of abnormal and as yet uncharacterized regulatory effects during depressive illness. Despite these putative disease-related effects, regulation has never been demonstrated in either the platelet or synaptosome model systems. Here we demonstrate for the first time that the imipramine-sensitive serotonin transport activity in either JAr choriocarcinoma or PC12 pheochromocytoma cell lines is subject to regulation by cAMP. Unexpectedly, the regulatory effect is opposite in the two cases, causing stimulation in JAr (increased Vmax) and inhibition in PC12 (kinetically complex). Appearance of these kinetic effects lagged 15 to 20 hours behind peak cAMP levels. The results are consistent with the interesting possibility that different tissues may express isoforms of the recently cloned serotonin transporter cDNAs. We suggest, therefore, that JAr and PC12 are attractive models in which to pursue detailed analysis of serotonin transport and its manner of regulation by cAMP.