Abstract
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.
MeSH terms
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Animals
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Antidepressive Agents / pharmacology
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Binding, Competitive / drug effects
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Binding, Competitive / physiology
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Cell Membrane / drug effects
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Cell Membrane / metabolism
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Cells, Cultured / drug effects
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Cells, Cultured / metabolism
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Cyclohexanes / chemistry
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Cyclohexanes / pharmacology
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Cyclopentanes / chemistry
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Cyclopentanes / pharmacology*
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Depression / drug therapy
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Depression / metabolism
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Depression / physiopathology
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Dose-Response Relationship, Drug
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Drug Interactions / physiology
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Excitatory Amino Acid Antagonists / chemistry
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Excitatory Amino Acid Antagonists / pharmacology*
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Humans
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Memantine / chemistry
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Memantine / pharmacology*
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Membrane Potentials / drug effects
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Membrane Potentials / physiology
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Mice
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Neuroprotective Agents / chemistry
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Neuroprotective Agents / pharmacology*
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Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
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Receptors, N-Methyl-D-Aspartate / metabolism
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Receptors, Serotonin / drug effects*
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Receptors, Serotonin / genetics
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Receptors, Serotonin / metabolism
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Receptors, Serotonin, 5-HT3
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Serotonin Antagonists / chemistry
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Serotonin Antagonists / pharmacology*
Substances
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Antidepressive Agents
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Cyclohexanes
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Cyclopentanes
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Excitatory Amino Acid Antagonists
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Neuroprotective Agents
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Receptors, N-Methyl-D-Aspartate
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Receptors, Serotonin
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Receptors, Serotonin, 5-HT3
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Serotonin Antagonists
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neramexane
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Memantine