The N-methyl-D-aspartate receptor channel blockers memantine, MRZ 2/579 and other amino-alkyl-cyclohexanes antagonise 5-HT(3) receptor currents in cultured HEK-293 and N1E-115 cell systems in a non-competitive manner.
The type 3 serotonin (5-HT(3)) receptor is a ligand-gated ion channel. In concentration-clamp experiments, we investigated the effects of the uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists memantine, amantadine and MRZ 2/579 on 5-HT receptors stabley expressed in HEK-293 cells and on native 5-HT(3) receptors in the N1E-115 cell line. All agents antagonized serotonin (10 microM)-induced inward currents with similar potency to that reported for NMDA receptors. This effect was characterized by inducing a pronounced receptor desensitization, and was probably non-competitive and voltage-independent. In contrast, (S)-ketamine was much weaker as an antagonist of 5-HT(3) receptors than NMDA receptors. Similar effects on 5-HT(3) receptors have been reported previously for a variety of anti-depressants and it is possible that the clinical anti-depressant effects reported for both memantine and amantadine are mediated, at least in part, by antagonistic effects at 5-HT(3) receptors.
Rammes
G
G
Max-Planck-Institute of Psychiatry, Kraepelinstrabetae 2-10, D-80804, München, Germany. rammes@mpipsykl.mpg.de
Rupprecht
R
R
Ferrari
U
U
Zieglgänsberger
W
W
Parsons
C G
CG
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D003510:Cyclohexanes / Q000737:chemistry / Q000494:pharmacology; D003517:Cyclopentanes / Q000737:chemistry / Q000494:pharmacology*; D003863:Depression / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D018691:Excitatory Amino Acid Antagonists / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008559:Memantine / Q000737:chemistry / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists / Q000737:chemistry / Q000494:pharmacology*
D000928:Antidepressive Agents; D003510:Cyclohexanes; D003517:Cyclopentanes; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists; C114144:neramexane; D008559:Memantine