Therapeutic concentrations of varenicline in the presence of nicotine increase action potential firing in human adrenal chromaffin cells
| Autor: | Almudena Albillos, Juan Passas, J. Michael McIntosh, Arik J. Hone, Cristina de Castro-Guerín, Lola Rueda-Ruzafa, Jesús Blázquez, Carmen González-Enguita |
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| Rok vydání: | 2016 |
| Předmět: |
Adult
Male 0301 basic medicine Agonist Nicotine medicine.medical_specialty medicine.drug_class Chromaffin Cells Action Potentials Stimulation Pharmacology Biochemistry Article Xenopus laevis 03 medical and health sciences Cellular and Molecular Neuroscience chemistry.chemical_compound 0302 clinical medicine Internal medicine medicine Animals Humans Nicotinic Agonists Neurotransmitter Varenicline Aged Dose-Response Relationship Drug Drug Synergism Middle Aged Nicotinic acetylcholine receptor 030104 developmental biology Nicotinic agonist Endocrinology chemistry Adrenal Cortex Female 030217 neurology & neurosurgery Acetylcholine medicine.drug |
| Zdroj: | Journal of Neurochemistry. 140:37-52 |
| ISSN: | 0022-3042 |
| DOI: | 10.1111/jnc.13883 |
| Popis: | Varenicline is a nicotinic acetylcholine receptor (nAChR) agonist used to treat nicotine addiction but a live debate persists concerning its mechanism of action in reducing nicotine consumption. Although initially reported as α4β2-selective, varenicline was subsequently shown to activate other nAChR subtypes implicated in nicotine addiction including α3β4. However, it remains unclear whether activation of α3β4 nAChRs by therapeutically relevant concentrations of varenicline is sufficient to affect the behavior of cells that express this subtype. We used patch-clamp electrophysiology to assess the effects of varenicline on native α3β4* nAChRs (asterisk denotes the possible presence of other subunits) expressed in human adrenal chromaffin cells and compared its effects to those of nicotine. Varenicline and nicotine activated α3β4* nAChRs with EC50 values of 1.8 (1.2-2.7) μM and 19.4 (11.1-33.9) μM, respectively. Stimulation of adrenal chromaffin cells with 10 ms pulses of 300 μM acetylcholine (ACh) in current-clamp mode evoked sodium channel-dependent action potentials (APs). Under these conditions, perfusion of 50 nM or 100 nM varenicline showed very little effect on AP firing compared to control conditions (ACh stimulation alone) but at higher concentrations (250 nM) varenicline increased the number of APs fired up to 436 ± 150%. These results demonstrate that therapeutic concentrations of varenicline are unlikely to alter AP firing in chromaffin cells. In contrast, nicotine showed no effect on AP firing at any of the concentrations tested (50, 100, 250, and 500 nM). However, perfusion of 50 nM nicotine simultaneously with 100 nM varenicline increased AP firing by 290 ± 104% indicating that exposure to varenicline and nicotine concurrently may alter cellular behavior including excitability and neurotransmitter release. This article is protected by copyright. All rights reserved. |
| Databáze: | OpenAIRE |
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