Human placental monoamine transporters as targets for amphetamines.
OBJECTIVE
The use of amphetamine and its derivatives during pregnancy is known to have adverse effects on the outcome of pregnancy. These effects are at least partly a result of impairment of placental function caused by these abusable drugs. We hypothesized that the two monoamine transporters, namely, the serotonin transporter and the norepinephrine transporter, that are expressed in the human placenta are direct targets for these drugs.


METHODS
The interaction of amphetamine and methamphetamine with human placental serotonin and norepinephrine transporters was examined. Activity of the serotonin transporter was assessed by serotonin uptake in both maternal-facing brush border membrane vesicles isolated from normal term human placentas and in JAR choriocarcinoma cells. Activity of the norepinephrine transporter was assessed by dopamine uptake and nisoxetine binding in placental brush border membrane vesicles.


RESULTS
Amphetamine and methamphetamine are potent inhibitors of the serotonin and norepinephrine transporters expressed in the human placenta. The inhibitory potency of amphetamine is greater than that of methamphetamine. In each case, the S(+)diastereoisomer is more potent than the corresponding R(-)diastereoisomer. The sensitivity of the norepinephrine transporter to inhibition by these drugs is at least two orders of magnitude greater than that of the serotonin transporter. At concentrations known to occur in the plasma of users, these drugs cause a marked inhibition of the norepinephrine transporter.


CONCLUSIONS
The results show that the norepinephrine transporter and, to a lesser extent, the serotonin transporter are cellular targets in the human placenta for the abusable drugs amphetamine and methamphetamine.
Ramamoorthy
J D
JD
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta 30912-2100, USA.
Ramamoorthy
S
S
Leibach
F H
FH
Ganapathy
V
V
D000662:Amphetamines / Q000494:pharmacology*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002822:Choriocarcinoma; D005260:Female; D006801:Humans; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D026901:Membrane Transport Proteins; D008694:Methamphetamine / Q000494:pharmacology; D009419:Nerve Tissue Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D010920:Placenta / Q000187:drug effects* / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins; D027981:Symporters; D014407:Tumor Cells, Cultured
D000662:Amphetamines; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; C493227:SLC6A2 protein, human; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D027981:Symporters; D008694:Methamphetamine