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Tricyclic antidepressants inhibit hippocampal α7* and α9α10 nicotinic acetylcholine receptors by different mechanisms

Author:
Arias, Hugo R., Vázquez-Gómez, Elizabeth, Hernández-Abrego, Andy, Gallino, Sofía, Feuerbach, Dominik, Ortells, Marcelo O., Elgoyhen, Ana Belén, García-Colunga, Jesús
Source:
The international journal of biochemistry & cell biology 2018 v.100 pp. 1-10
ISSN:
1357-2725
Subject:
antidepressants, calcium, electrophysiology, inhibitory concentration 50, mechanism of action, molecular models, nicotinic receptors, tritium
Abstract:
The activity of tricyclic antidepressants (TCAs) at α7 and α9α10 nicotinic acetylcholine receptors (AChRs) as well as at hippocampal α7-containing (i.e., α7*) AChRs is determined by using Ca²⁺ influx and electrophysiological recordings. To determine the inhibitory mechanisms, additional functional tests and molecular docking experiments are performed. The results established that TCAs (a) inhibit Ca²⁺ influx in GH3-α7 cells with the following potency (IC50 in μM) rank: amitriptyline (2.7 ± 0.3) > doxepin (5.9 ± 1.1) ∼ imipramine (6.6 ± 1.0). Interestingly, imipramine inhibits hippocampal α7* AChRs (42.2 ± 8.5 μM) in a noncompetitive and voltage-dependent manner, whereas it inhibits α9α10 AChRs (0.53 ± 0.05 μM) in a competitive and voltage-independent manner, and (b) inhibit [³H]imipramine binding to resting α7 AChRs with the following affinity rank (IC50 in μM): imipramine (1.6 ± 0.2) > amitriptyline (2.4 ± 0.3) > doxepin (4.9 ± 0.6), whereas imipramine’s affinity was no significantly different to that for the desensitized state. The molecular docking and functional results support the notion that imipramine noncompetitively inhibits α7 AChRs by interacting with two overlapping luminal sites, whereas it competitively inhibits α9α10 AChRs by interacting with the orthosteric sites. Collectively our data indicate that TCAs inhibit α7, α9α10, and hippocampal α7* AChRs at clinically relevant concentrations and by different mechanisms of action.
Agid:
5981268