Selectivity of (±)-citalopram at nicotinic acetylcholine receptors and different inhibitory mechanisms between habenular α3β4* and α9α10 subtypes

  • Neurochem Int. 2019 Dec;131:104552. doi: 10.1016/j.neuint.2019.104552.
Hugo R Arias  1 ,  Xiao-Tao Jin  2 ,  Sofía Gallino  3 ,  Can Peng  2 ,  Dominik Feuerbach  4 ,  Jesús García-Colunga  5 ,  Ana Belén Elgoyhen  6 ,  Ryan M Drenan  2 ,  Marcelo O Ortells  7
Affiliations
  • 1. Department of Pharmacology and Physiology, College of Osteopathic Medicine, Oklahoma State University Center for Health Sciences, Tahlequah, OK, USA. Electronic address: [email protected].
  • 2. Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
  • 3. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Dr. Héctor N. Torres, CONICET, Universidad de Buenos Aires, Argentina.
  • 4. Novartis Institutes for Biomedical Research, Basel, Switzerland.
  • 5. Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, Mexico.
  • 6. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Dr. Héctor N. Torres, CONICET, Universidad de Buenos Aires, Argentina; Instituto de Farmacología, Facultad de Medicina, Universidad de Buenos Aires, Argentina.
  • 7. Facultad de Medicina, Universidad de Morón, Morón and CONICET, Argentina. Electronic address: [email protected].
PMID: 31545995 DOI: 10.1016/j.neuint.2019.104552
Abstract

The inhibitory activity of (±)-citalopram on human (h) α3β4, α4β2, and α7 nicotinic acetylcholine receptors (AChRs) was determined by CA2+ influx assays, whereas its effect on rat α9α10 and mouse habenular α3β4* AChRs by electrophysiological recordings. The CA2+ influx results clearly establish that (±)-citalopram inhibits (IC50's in μM) hα3β4 AChRs (5.1 ± 1.3) with higher potency than that for hα7 (18.8 ± 1.1) and hα4β2 (19.1 ± 4.2) AChRs. This is in agreement with the [3H]imipramine competition binding results indicating that (±)-citalopram binds to imipramine sites at desensitized hα3β4 with >2-fold higher affinity than that for hα4β2. The electrophysiological, molecular docking, and in silico mutation results indicate that (±)-citalopram competitively inhibits rα9α10 AChRs (7.5 ± 0.9) in a voltage-independent manner by interacting mainly with orthosteric sites, whereas it inhibits a homogeneous population of α3β4* AChRs at MHb (VI) neurons (7.6 ± 1.0) in a voltage-dependent manner by interacting mainly with a luminal site located in the middle of the ion channel, overlapping the imipramine site, which suggests an ion channel blocking mechanism. In conclusion, (±)-citalopram inhibits α3β4 and α9α10 AChRs with higher potency compared to Other AChRs but by different mechanisms. (±)-Citalopram also inhibits habenular α3β4*AChRs, supporting the notion that these receptors are important endogenous targets related to their anti-addictive activities.

Keywords
(±)-Citalopram; Brain slices; Medial habenula; Nicotinic acetylcholine receptor; Selective serotonin reuptake inhibitor.
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