The human placenta represents a unique non-neuronal site of monoamine transporter expression, with pathophysiological relevance during the prenatal period. Monoamines (serotonin, dopamine, norepinephrine) are crucial neuromodulators for proper placenta functions and fetal development, including cell proliferation, differentiation, and neuronal migration. Accumulating evidence suggests that even a transient disruption of monoamine balance during gestation may lead to permanent changes in the fetal brain structures and functions, projecting into adulthood. Nonetheless, little is known about the transfer of dopamine and norepinephrine across the placental syncytiotrophoblast. Employing the method of isolated membranes from the human term placenta, here we delineate the transport mechanisms involved in dopamine and norepinephrine passage across the apical microvillous (MVM) and basal membranes. We show that the placental uptake of dopamine and norepinephrine across the mother-facing MVM is mediated via the high-affinity and low-capacity serotonin (SERT/SLC6A4) and norepinephrine (NET/SLC6A2) transporters. In the fetus-facing basal membrane, however, the placental uptake of both monoamines is controlled by the organic cation transporter 3 (OCT3/SLC22A3). Our findings thus provide insights into physiological aspects of dopamine and norepinephrine transport across both the maternal and fetal sides of the placenta. As monoamine transporters represent targets for several neuroactive drugs such as antidepressants, our findings are pharmacologically relevant to ensure the safety of drug use during pregnancy.

Department of Pharmacology and Toxicology Faculty of Pharmacy in Hradec Králové Charles University Akademika Heyrovskeho 1203 500 05 Hradec Králové Czech Republic

Zobrazit více v PubMed

Rosenfeld CS. The placenta-brain-axis. J. Neurosci. Res. 2021;99:271–283. doi: 10.1002/jnr.24603. PubMed DOI PMC

Levitt P, Harvey JA, Friedman E, Simansky K, Murphy EH. New evidence for neurotransmitter influences on brain development. Trends Neurosci. 1997;20:269–274. doi: 10.1016/s0166-2236(96)01028-4. PubMed DOI

McCarthy D, Lueras P, Bhide PG. Elevated dopamine levels during gestation produce region-specific decreases in neurogenesis and subtle deficits in neuronal numbers. Brain Res. 2007;1182:11–25. doi: 10.1016/j.brainres.2007.08.088. PubMed DOI PMC

Todd RD. Neural development is regulated by classical neurotransmitters: Dopamine D2 receptor stimulation enhances neurite outgrowth. Biol. Psychiatry. 1992;31:794–807. doi: 10.1016/0006-3223(92)90311-M. PubMed DOI

Ohtani N, Goto T, Waeber C, Bhide PG. Dopamine modulates cell cycle in the lateral ganglionic eminence. J. Neurosci. 2003;23:2840–2850. doi: 10.1523/jneurosci.23-07-02840.2003. PubMed DOI PMC

Popolo M, McCarthy DM, Bhide PG. Influence of dopamine on precursor cell proliferation and differentiation in the embryonic mouse telencephalon. Dev. Neurosci. 2004;26:229–244. doi: 10.1159/000082140. PubMed DOI PMC

Saboory E, Ghasemi M, Mehranfard N. Norepinephrine, neurodevelopment and behavior. Neurochem. Int. 2020;135:104706. doi: 10.1016/j.neuint.2020.104706. PubMed DOI

Padbury JF. 5—Functional maturation of the adrenal medulla and peripheral sympathetic nervous system. Baillieres Clin. Endocrinol. Metab. 1989;3:689–705. doi: 10.1016/S0950-351X(89)80049-7. PubMed DOI

Thomas SA, Matsumoto AM, Palmiter RD. Noradrenaline is essential for mouse fetal development. Nature. 1995;374:643–646. doi: 10.1038/374643a0. PubMed DOI

Macaron C, Famuyiwa O, Singh SP. In vitro effect of dopamine and pimozide on human chorionic somatomammotropin (hCS) secretion*. J. Clin. Endocrinol. Metab. 1978;47:168–170. doi: 10.1210/jcem-47-1-168. PubMed DOI

Petit A, et al. Presence of D2-dopamine receptors in human term placenta. J. Recept. Res. 1990;10:205–215. doi: 10.3109/10799899009064666. PubMed DOI

Previc FH. Prenatal influences on brain dopamine and their relevance to the rising incidence of autism. Med. Hypotheses. 2007;68:46–60. doi: 10.1016/j.mehy.2006.06.041. PubMed DOI

Robinson PD, Schutz CK, Macciardi F, White BN, Holden JJ. Genetically determined low maternal serum dopamine beta-hydroxylase levels and the etiology of autism spectrum disorders. Am. J. Med. Genet. 2001;100:30–36. doi: 10.1002/ajmg.1187. PubMed DOI

Holzman C, et al. Maternal catecholamine levels in midpregnancy and risk of preterm delivery. Am. J. Epidemiol. 2009;170:1014–1024. doi: 10.1093/aje/kwp218. PubMed DOI PMC

Jones CM, Greiss FC. The effect of labor on maternal and fetal circulating catecholamines. Am. J. Obstet. Gynecol. 1982;144:149–153. doi: 10.1016/0002-9378(82)90616-0. PubMed DOI

Möller IR, et al. Conformational dynamics of the human serotonin transporter during substrate and drug binding. Nat. Commun. 2019;10:1687. doi: 10.1038/s41467-019-09675-z. PubMed DOI PMC

Mandela P, Ordway GA. The norepinephrine transporter and its regulation. J. Neurochem. 2006;97:310–333. doi: 10.1111/j.1471-4159.2006.03717.x. PubMed DOI

Borre L, Andreassen TF, Shi L, Weinstein H, Gether U. The second sodium site in the dopamine transporter controls cation permeation and is regulated by chloride. J. Biol. Chem. 2014;289:25764–25773. doi: 10.1074/jbc.M114.574269. PubMed DOI PMC

Stamford JA, Kruk ZL, Millar J. Striatal dopamine terminals release serotonin after 5-HTP pretreatment: In vivo voltammetric data. Brain Res. 1990;515:173–180. doi: 10.1016/0006-8993(90)90593-z. PubMed DOI

Vizi ES, Zsilla G, Caron MG, Kiss JP. Uptake and release of norepinephrine by serotonergic terminals in norepinephrine transporter knock-out mice: Implications for the action of selective serotonin reuptake inhibitors. J. Neurosci. Off. J. Soc. Neurosci. 2004;24:7888–7894. doi: 10.1523/JNEUROSCI.1506-04.2004. PubMed DOI PMC

Gasser PJ. Roles for the uptake(2) transporter OCT3 in regulation of dopaminergic neurotransmission and behavior. Neurochem. Int. 2019;123:46–49. doi: 10.1016/j.neuint.2018.07.008. PubMed DOI PMC

Miura Y, et al. Characterization of murine polyspecific monoamine transporters. FEBS Open Bio. 2017;7:237–248. doi: 10.1002/2211-5463.12183. PubMed DOI PMC

Ingebretsen OC, Flatmark T. Active and passive transport of dopamine in chromaffin granule ghosts isolated from bovine adrenal medulla. J. Biol. Chem. 1979;254:3833–3839. doi: 10.1016/S0021-9258(18)50662-1. PubMed DOI

Scholze P, Sitte HH, Singer EA. Substantial loss of substrate by diffusion during uptake in HEK-293 cells expressing neurotransmitter transporters. Neurosci. Lett. 2001;309:173–176. doi: 10.1016/s0304-3940(01)02058-4. PubMed DOI

Staud F, Karahoda R. Trophoblast: The central unit of fetal growth, protection and programming. Int. J. Biochem. Cell Biol. 2018;105:35–40. doi: 10.1016/j.biocel.2018.09.016. PubMed DOI

Prasad PD, et al. Functional expression of the plasma membrane serotonin transporter but not the vesicular monoamine transporter in human placental trophoblasts and choriocarcinoma cells. Placenta. 1996;17:201–207. doi: 10.1016/S0143-4004(96)90039-9. PubMed DOI

Bottalico B, et al. Norepinephrine transporter (NET), serotonin transporter (SERT), vesicular monoamine transporter (VMAT2) and organic cation transporters (OCT1, 2 and EMT) in human placenta from pre-eclamptic and normotensive pregnancies. Placenta. 2004;25:518–529. doi: 10.1016/j.placenta.2003.10.017. PubMed DOI

Shearman LP, Meyer JS. Norepinephrine transporters in rat placenta labeled with [3H]nisoxetine. J. Pharmacol. Exp. Ther. 1998;284:736–743. PubMed

Ramamoorthy S, et al. Expression of a cocaine-sensitive norepinephrine transporter in the human placental syncytiotrophoblast. Biochemistry. 1993;32:1346–1353. doi: 10.1021/bi00056a021. PubMed DOI

Ramamoorthy S, Leibach FH, Mahesh VB, Ganapathy V. Active transport of dopamine in human placental brush-border membrane vesicles. Am. J. Physiol. 1992;262:C1189–C1196. doi: 10.1152/ajpcell.1992.262.5.C1189. PubMed DOI

Karahoda R, et al. Serotonin homeostasis in the materno-foetal interface at term: Role of transporters (SERT/SLC6A4 and OCT3/SLC22A3) and monoamine oxidase A (MAO-A) in uptake and degradation of serotonin by human and rat term placenta. Acta Physiol. 2020;229:e13478. doi: 10.1111/apha.13478. PubMed DOI PMC

Sodha RJ, Proegler M, Schneider H. Transfer and metabolism of norepinephrine studied from maternal-to-fetal and fetal-to-maternal sides in the in vitro perfused human placental lobe. Am. J. Obstet. Gynecol. 1984;148:474–481. doi: 10.1016/0002-9378(84)90729-4. PubMed DOI

Koepsell H. Organic cation transporters in health and disease. Pharmacol. Rev. 2020;72:253–319. doi: 10.1124/pr.118.015578. PubMed DOI

Glazier JD, Jones CJ, Sibley CP. Purification and Na+ uptake by human placental microvillus membrane vesicles prepared by three different methods. Biochem. Biophys. Acta. 1988;945:127–134. doi: 10.1016/0005-2736(88)90475-0. PubMed DOI

Farrugia W, de Gooyer T, Rice GE, Moseley JM, Wlodek ME. Parathyroid hormone(1–34) and parathyroid hormone-related protein(1–34) stimulate calcium release from human syncytiotrophoblast basal membranes via a common receptor. J. Endocrinol. 2000;166:689–695. doi: 10.1677/joe.0.1660689. PubMed DOI

Horackova H, et al. Effect of selected antidepressants on placental homeostasis of serotonin: Maternal and fetal perspectives. Pharmaceutics. 2021 doi: 10.3390/pharmaceutics13081306. PubMed DOI PMC

Zhou J. Norepinephrine transporter inhibitors and their therapeutic potential. Drugs Future. 2004;29:1235–1244. doi: 10.1358/dof.2004.029.12.855246. PubMed DOI PMC

Berger P, Elsworth JD, Arroyo J, Roth RH. Interaction of [3H]GBR 12935 and GBR 12909 with the dopamine uptake complex in nucleus accumbens. Eur. J. Pharmacol. 1990;177:91–94. doi: 10.1016/0014-2999(90)90554-J. PubMed DOI

Horton RE, et al. Decynium-22 enhances SSRI-induced antidepressant-like effects in mice: Uncovering novel targets to treat depression. J. Neurosci. Off. J. Soc. Neurosci. 2013;33:10534–10543. doi: 10.1523/JNEUROSCI.5687-11.2013. PubMed DOI PMC

Haka MS, Kilbourn MR. Synthesis and regional mouse brain distribution of [11C]nisoxetine, a norepinephrine uptake inhibitor. Int. J. Rad. Appl. Instrum. B. 1989;16:771–774. doi: 10.1016/0883-2897(89)90160-8. PubMed DOI

Rothman RB, et al. Identification of a GBR12935 homolog, LR1111, which is over 4,000-fold selective for the dopamine transporter, relative to serotonin and norepinephrine transporters. Synapse. 1993;14:34–39. doi: 10.1002/syn.890140106. PubMed DOI

Bhat, S. et al. Handling of intracellular K+ determines voltage dependence of plasmalemmal monoamine transporter function. bioRxiv 2021.2003.2011.434931. 10.1101/2021.03.11.434931 (2021). PubMed PMC

Bzoskie L, Blount L, Kashiwai K, Humme J, Padbury JF. The contribution of transporter-dependent uptake to fetal catecholamine clearance. Biol. Neonate. 1997;71:102–110. doi: 10.1159/000244403. PubMed DOI

Ganapathy V, Ramamoorthy S, Leibach FH. Transport and metabolism of monoamines in the human placenta: A review. Placenta. 1993;14:35–51. doi: 10.1016/S0143-4004(05)80281-4. DOI

Watanabe T, Matsuhashi K, Takayama S. Placental and blood–brain barrier transfer following prenatal and postnatal exposures to neuroactive drugs: Relationship with partition coefficient and behavioral teratogenesis. Toxicol. Appl. Pharmacol. 1990;105:66–77. doi: 10.1016/0041-008x(90)90359-3. PubMed DOI

Morgan CD, Sandler M, Panigel M. Placental transfer of catecholamines in vitro and in vivo. Am. J. Obstet. Gynecol. 1972;112:1068–1075. doi: 10.1016/0002-9378(72)90182-2. PubMed DOI

Coleman JA, Green EM, Gouaux E. X-ray structures and mechanism of the human serotonin transporter. Nature. 2016;532:334–339. doi: 10.1038/nature17629. PubMed DOI PMC

Pidathala S, Mallela AK, Joseph D, Penmatsa A. Structural basis of norepinephrine recognition and transport inhibition in neurotransmitter transporters. Nat. Commun. 2021;12:2199. doi: 10.1038/s41467-021-22385-9. PubMed DOI PMC

Morón JA, Brockington A, Wise RA, Rocha BA, Hope BT. Dopamine uptake through the norepinephrine transporter in brain regions with low levels of the dopamine transporter: Evidence from knock-out mouse lines. J. Neurosci. 2002;22:389–395. doi: 10.1523/jneurosci.22-02-00389.2002. PubMed DOI PMC

Larsen MB, et al. Dopamine transport by the serotonin transporter: A mechanistically distinct mode of substrate translocation. J. Neurosci. 2011;31:6605–6615. doi: 10.1523/jneurosci.0576-11.2011. PubMed DOI PMC

Jansson T, Illsley NP. Osmotic water permeabilities of human placental microvillous and basal membranes. J. Membr. Biol. 1993;132:147–155. doi: 10.1007/bf00239004. PubMed DOI

Bzoskie L, et al. Placental norepinephrine clearance: In vivo measurement and physiological role. Am. J. Physiol. 1995;269:E145–E149. doi: 10.1152/ajpendo.1995.269.1.E145. PubMed DOI

Cengiz H, et al. Plasma serotonin levels are elevated in pregnant women with hyperemesis gravidarum. Arch. Gynecol. Obstet. 2015;291:1271–1276. doi: 10.1007/s00404-014-3572-2. PubMed DOI

Carrasco G, et al. Plasma and platelet concentration and platelet uptake of serotonin in normal and pre-eclamptic pregnancies. Life Sci. 1998;62:1323–1332. doi: 10.1016/S0024-3205(98)00066-6. PubMed DOI

Khatun S, et al. Increased concentrations of plasma epinephrine and norepinephrine in patients with eclampsia. Eur. J. Obstet. Gynecol. Reprod. Biol. 1996;69:61–67. doi: 10.1016/0301-2115(95)02511-1. PubMed DOI

Middelkoop CM, Dekker GA, Kraayenbrink AA, Popp-Snijders C. Platelet-poor plasma serotonin in normal and preeclamptic pregnancy. Clin. Chem. 1993;39:1675–1678. doi: 10.1093/clinchem/39.8.1675. PubMed DOI

Greenwood SL, Sibley CP. In vitro methods for studying human placental amino acid transport placental villous fragments. Methods Mol. Med. 2006;122:253–264. PubMed

Characterization of a human placental clearance system to regulate serotonin levels in the fetoplacental unit