Molecular mechanisms of inhibition of nicotinic acetylcholine receptors by tricyclic antidepressants

Fernanda Gumilar, Hugo R. Arias, Guillermo Spitzmaul, Cecilia Bouzat

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

In addition to their well known actions on monoamine reuptake, tricyclic antidepressants have been shown to modulate ligand-gated ion channels (LGICs). Since the muscle nicotinic acetylcholine receptor (AChR) has been the model for studying structure-function relationships of LGICs, we analyzed the action of tricyclic antidepressants on this type of AChR at both single-channel and macroscopic current levels. We also determined their effects on ACh equilibrium binding and their interactions with the different conformational states of the AChR. Antidepressants produce a significant concentration-dependent decrease in the duration of clusters of single-channels (eight fold at 20 μM). They also decrease the peak amplitude and increase the decay rate of currents elicited by rapid perfusion of ACh to outside-out patches. In equilibrium binding assays, antidepressants promote the typical high-affinity desensitized state and inhibit binding of [piperidyl-3,4-3H (N)]-(N-(1-(2-thienyl) cyclohexyl)-3,4-piperidine ([3H]TCP) to its locus in resting and desensitized AChRs. The results indicate that tricyclic antidepressants: (i) interact with resting (closed), open, and desensitized channels; (ii) do not affect significantly channel opening and closing rates; (iii) do not act as fast open-channel blockers; (iv) inhibit activation of resting channels; and (v) may increase the rate of long-lived desensitization from the open state.

Original languageEnglish
Pages (from-to)964-976
Number of pages13
JournalNeuropharmacology
Volume45
Issue number7
DOIs
StatePublished - 1 Jan 2003
Externally publishedYes

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Tricyclic Antidepressive Agents
Nicotinic Receptors
Ligand-Gated Ion Channels
Cholinergic Receptors
Antidepressive Agents
Perfusion
Muscles

Keywords

  • Acetylcholine
  • Nicotinic receptor
  • Noncompetitive inhibitor
  • Tricyclic antidepressant

Cite this

Gumilar, Fernanda ; Arias, Hugo R. ; Spitzmaul, Guillermo ; Bouzat, Cecilia. / Molecular mechanisms of inhibition of nicotinic acetylcholine receptors by tricyclic antidepressants. In: Neuropharmacology. 2003 ; Vol. 45, No. 7. pp. 964-976.
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Molecular mechanisms of inhibition of nicotinic acetylcholine receptors by tricyclic antidepressants. / Gumilar, Fernanda; Arias, Hugo R.; Spitzmaul, Guillermo; Bouzat, Cecilia.

In: Neuropharmacology, Vol. 45, No. 7, 01.01.2003, p. 964-976.

Research output: Contribution to journalArticle

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