The placenta is a unique nonneuronal tissue which expresses biogenic amine transporters that are otherwise only expressed in neuronal tissue. There has been limited investigation of the regulation of biogenic amine transporters. It has been shown that uptake inhibitors like cocaine or antidepressants cause an increase in serotonin (SERT) and norepinephrine (NET) transporter expression in the central nervous system in vivo. In cell culture, increased intracellular cyclic AMP or protein kinase A activity have been shown to increase serotonin transport. The mechanism for this increase is both transcriptional and posttranslational. The purpose of our studies was to examine the mechanisms for regulation of the NET in neuronal and placental cells. We used SK-N-SH cells, a human neuroblastoma cell line, and primary placental cells isolated after collagenase digestion and density gradient centrifugation. Uptake of tritiated norepinephrine was determined after treatment with a variety of pharmacologic agents. Norephrine (NE) alone had a time and dose dependent effect. Short term exposure to 1μM NE caused a modest increase in uptake. Longer exposure or higher doses decreased uptake by 15-30%. SK-N-SH cells treated with 10-100 μM Forskolin, 1-10mM dBcAMP or 10-100 nM phorbol ester (TPA) showed a significant decrease in uptake. Primary placental cells showed a similar biphasic response NE and similar, though less pronounced, regulation by the same pharmacologic agents. We conclude: 1) Neuroblastoma cells and primary placental cells take up norepinephrine by a transporter-dependent uptake mechanism. 2) Norepinephrine has a time-and dose-dependent effect on uptake. 3) Inhibition of norepinephrine uptake is mediated in part by cyclic AMP and protein kinase C. Speculation: Our previous results demonstrate that placental norepinephrine clearance is vital to fetal homeostasis and that chronic intrauterine stress results in a significant decrease in norepinephrine transport. The mechanisms identified here help to explain this decrease in norepinephrine clearance and the pathogenesis of the exaggerated effects on the fetus of drugs, such as cocaine, which block catecholamine transport.