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

Neurosci Lett. 2001 Jun 22;306(1-2):81-4. doi: 10.1016/s0304-3940(01)01872-9.

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

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

Substances

  • Antidepressive Agents
  • Cyclohexanes
  • Cyclopentanes
  • Excitatory Amino Acid Antagonists
  • Neuroprotective Agents
  • Receptors, N-Methyl-D-Aspartate
  • Receptors, Serotonin
  • Receptors, Serotonin, 5-HT3
  • Serotonin Antagonists
  • neramexane
  • Memantine