Open channel block of NMDA receptor responses evoked by tricyclic antidepressants.
The action of desipramine (DMI) and promazine on the response of mouse hippocampal neurons to the excitatory amino acid N-methyl-D-aspartic acid (NMDA) was investigated using whole-cell and single-channel recording. DMI at 20-50 microM was a potent, selective antagonist of responses to NMDA but not kainate or quisqualate. At -60 mV, the Kd for DMI block of responses to NMDA was 10 microM. The potency of DMI as an NMDA antagonist was highly voltage-dependent and behaved as though the Kd increased e-fold per 36 mV depolarization, reflecting an increase in the dissociation rate constant. Prior block of NMDA receptors with Mg2+ prevented binding of DMI, suggesting an action in the open channel. Single-channel analysis showed a decrease in the open time and burst length distributions, consistent with binding of DMI to open channels. We suggest that the action of DMI on NMDA receptor channels is similar to that of MK-801 and does not reflect binding to other domains, such as the regulatory sites for Zn2+ and glycine.
Sernagor
E
E
Unit of Neurophysiology and Biophysics, NICHD, National Institutes of Health, Bethesda, Maryland 20892.
Kuhn
D
D
Vyklicky
L
L
Mayer
M L
ML
D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D002478:Cells, Cultured; D003292:Convulsants / Q000494:pharmacology; D003891:Desipramine / Q000494:pharmacology*; D004622:Embryo, Mammalian; D006624:Hippocampus / Q000502:physiology*; D007473:Ion Channels / Q000187:drug effects / Q000502:physiology*; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D016202:N-Methylaspartate; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010069:Oxadiazoles / Q000494:pharmacology; D016318:Quisqualic Acid; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000502:physiology*
D000929:Antidepressive Agents, Tricyclic; D003292:Convulsants; D007473:Ion Channels; D010069:Oxadiazoles; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D001224:Aspartic Acid; D016202:N-Methylaspartate; D016318:Quisqualic Acid; D003891:Desipramine