Abuse of illicit drugs during pregnancy is currently a serious concern pertaining to women's health because of the deleterious effects these drugs have on the mother and on the fetus. The objective of the current project is to investigate the role of placenta in the pathogenesis of complications arising from abuse of cocaine and amphetamines during pregnancy and to establish that placenta is a direct target for these drugs. Human placenta expresses the serotonin transporter and the norepinephrine transporter, both of which are targets for cocaine and/or amphetamines. These transporters most likely function in the clearance of the vasoactive monoamines serotonin and norepinephrine from the intervillous space. Interference with their functions by cocaine and amphetamines would have had effects on the developing fetus. The current project will investigate the normal function, regulation, and ontogeny of these two transporters in the placenta. Studies will include detailed characterization of the interaction of cocaine and amphetamines with these two transporters. These studies will be done with isolated plasma membrane vesicles from the placenta and also with intact trophoblast cells and choriocarcinoma cells. The placental syncytiotrophoblast is a polarized cell and immunolocalization studies will be performed to determined whether or not the expression of the serotonin and norepinephrine transporters is polarized with regard to the maternal-facing brush border membrane and the fetal-facing basal membrane. Proposed studies will also delineate the differential role of hormones/cytokines in the modulation of these transporters using primary trophoblast cultures and choriocarcinoma cells. These studies will include analysis of hormone/cytokine-induced changes in the transport activity, transporter density and steady state levels of transporter-specific mRNAs. The specific signalling pathways mediating the hormone/cytokine effects will be identified and the involvement of transcriptional and translational processes and posttranslational modifications in the regulation will be delineated. Studies will also test the hypothesis that impaired function of one or both of these transporters is a pathogenic factor in preeclampsia, a condition which clinically resembles in many respects the complications arising from use of cocaine and amphetamines during pregnancy. The ontogenic development of the serotonin and norepinephrine transporters in placenta will be studied using the rat as the experimental model.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
Human Development Research Subcommittee (NIDA)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Medical College of Georgia (MCG)
Schools of Medicine
United States
Zip Code
Inoue, Katsuhisa; Fei, You-Jun; Huang, Wei et al. (2002) Functional identity of Drosophila melanogaster Indy as a cation-independent, electroneutral transporter for tricarboxylic acid-cycle intermediates. Biochem J 367:313-9
Hatanaka, T; Huang, W; Ling, R et al. (2001) Evidence for the transport of neutral as well as cationic amino acids by ATA3, a novel and liver-specific subtype of amino acid transport system A. Biochim Biophys Acta 1510:10-7
Seth, P; Ganapathy, M E; Conway, S J et al. (2001) Expression pattern of the type 1 sigma receptor in the brain and identity of critical anionic amino acid residues in the ligand-binding domain of the receptor. Biochim Biophys Acta 1540:59-67
Nakanishi, T; Kekuda, R; Fei, Y J et al. (2001) Cloning and functional characterization of a new subtype of the amino acid transport system N. Am J Physiol Cell Physiol 281:C1757-68
Fei, Y J; Sugawara, M; Nakanishi, T et al. (2000) Primary structure, genomic organization, and functional and electrogenic characteristics of human system N 1, a Na+- and H+-coupled glutamine transporter. J Biol Chem 275:23707-17
Wang, H; Fei, Y J; Kekuda, R et al. (2000) Structure, function, and genomic organization of human Na(+)-dependent high-affinity dicarboxylate transporter. Am J Physiol Cell Physiol 278:C1019-30
Hatanaka, T; Huang, W; Wang, H et al. (2000) Primary structure, functional characteristics and tissue expression pattern of human ATA2, a subtype of amino acid transport system A. Biochim Biophys Acta 1467:6-Jan
Wang, H; Huang, W; Sugawara, M et al. (2000) Cloning and functional expression of ATA1, a subtype of amino acid transporter A, from human placenta. Biochem Biophys Res Commun 273:1175-9
Ganapathy, V; Prasad, P D; Ganapathy, M E et al. (2000) Placental transporters relevant to drug distribution across the maternal-fetal interface. J Pharmacol Exp Ther 294:413-20
Huang, W; Wang, H; Kekuda, R et al. (2000) Transport of N-acetylaspartate by the Na(+)-dependent high-affinity dicarboxylate transporter NaDC3 and its relevance to the expression of the transporter in the brain. J Pharmacol Exp Ther 295:392-403

Showing the most recent 10 out of 32 publications