Therapeutic concentrations of varenicline in the presence of nicotine increase action potential firing in human adrenal chromaffin cells.
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 EC50values 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 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 such as excitability and neurotransmitter release.
Departamento de Farmacología y Terapéutica, Universidad Autónoma de Madrid, Madrid, Spain.|Departments of Biology, University of Utah, Salt Lake City, Utah, USA.
Arik J
AJ
Hone
Departments of Biology, University of Utah, Salt Lake City, Utah, USA.|Psychiatry, University of Utah, Salt Lake City, Utah, USA.|The George E. Whalen Veterans Affairs Medical Center, Salt Lake City, Utah, USA.
J
J
Michael McIntosh
Departamento de Farmacología y Terapéutica, Universidad Autónoma de Madrid, Madrid, Spain.
Lola
L
Rueda-Ruzafa
Hospital Doce de Octubre, Madrid, Spain.
Juan
J
Passas
Hospital La Paz, Madrid, Spain.
Cristina
C
de Castro-Guerín
Hospital Clínico San Carlos, Madrid, Spain.
Jesús
J
Blázquez
Fundación Jiménez Díaz, Madrid, Spain.
Carmen
C
González-Enguita
Departamento de Farmacología y Terapéutica, Universidad Autónoma de Madrid, Madrid, Spain.
Almudena
A
Albillos
D000200:Action Potentials / Q000187:drug effects* / Q000502:physiology; D000302:Adrenal Cortex / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D000328:Adult; D000368:Aged; D000818:Animals; D019439:Chromaffin Cells / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009538:Nicotine / Q000008:administration & dosage*; D018722:Nicotinic Agonists / Q000008:administration & dosage*; D000068580:Varenicline / Q000008:administration & dosage*; D014982:Xenopus laevis
D018722:Nicotinic Agonists; D009538:Nicotine; D000068580:Varenicline
nicotine addiction; nicotinic receptor; varenicline; α-conotoxin