MK-801 blocks monoamine transporters expressed in HEK cells.
(+)-MK-801 is known to be a specific non-competitive antagonist of N-methyl-D-aspartate (NMDA) receptors. However, besides having an anticonvulsant effect, this compound possesses a central sympathomimetic effect and an anxiolytic-like action, raising the possibility that (+)-MK-801 might affect monoamine uptake systems. To elucidate this possibility, we investigated the effects of (+)-MK-801 on monoamine transporters expressed in HEK cells. (+)-MK-801 significantly inhibited the uptake of all three monoamine transporters in a dose-dependent manner and the inhibitions were competitive with respect to monoamines. The Ki values of (+)-MK-801 on the norepinephrine, dopamine and serotonin transporters were 3.2 microM, 40 microM and 43 microM, respectively. In addition, (-)-MK-801, a less potent antagonist of NMDA receptors, also inhibited monoamine transporters with a similar potency as that of (+)-MK-801. These results clearly indicate that MK-801, a non-competitive antagonist of NMDA receptors, competitively inhibits monoamine transporters without stereoselectivity.
Nishimura
M
M
Department of Anatomy and Neuroscience, Osaka University Medical School, Suita, Japan. mnishimu@anat2.med.osaka-u.ac.jp
Sato
K
K
Okada
T
T
Schloss
P
P
Shimada
S
S
Tohyama
M
M
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D027322:Amino Acid Transport System X-AG; D001667:Binding, Competitive / Q000502:physiology; D015306:Biogenic Monoamines / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D002460:Cell Line; D016291:Dizocilpine Maleate / Q000737:chemistry / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D018492:Dopamine Antagonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006801:Humans; D007668:Kidney / Q000196:embryology; D007700:Kinetics; D009638:Norepinephrine / Q000037:antagonists & inhibitors / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology; D013237:Stereoisomerism
D018528:ATP-Binding Cassette Transporters; D027322:Amino Acid Transport System X-AG; D015306:Biogenic Monoamines; D002352:Carrier Proteins; D018492:Dopamine Antagonists; D018691:Excitatory Amino Acid Antagonists; D010879:Piperazines; D016194:Receptors, N-Methyl-D-Aspartate; D012702:Serotonin Antagonists; C104291:3-(2-carboxypiperazine-4-yl)propyl-1-phosphate; D012701:Serotonin; D016291:Dizocilpine Maleate; D004298:Dopamine; D009638:Norepinephrine