Therapeutic concentrations of varenicline in the presence of nicotine increase action potential firing in human adrenal chromaffin cells

Abstract

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.

The firing frequency of spontaneous action potentials and their corresponding evoked exocytosis are increased in chromaffin cells of CCl4‐induced cirrhotic rats with respect to control rats

“…,b; Hone et al . , ), and also in rat chromaffin cells (Hone et al ., unpublished data). We tested a very short duration of ACh pulses (10 ms) applied at the resting membrane potential of the cell and at the basal firing frequency of the splanchnic nerve, to mimick conditions closer to the physiological situation.…”

Nicotinic acetylcholine receptors in neuropathic and inflammatory pain

“…Additionally, α3β4* nAChRs are the predominant nAChR subtype expressed by human adrenal chromaffin cells , the primary source of circulating catecholamines. Exposure of adrenal chromaffin cells to nicotinic agonists increases cell excitability and may result in increased release of catecholamines, potentially producing cardiovascular effects . Lastly, stimulation of α3β4* receptors may, in fact, be pronociceptive.…”

Full activation of an α7-α3β4 nicotinic receptor complex avoids receptor desensitization in human chromaffin cells

“…It is the major adrenaline-secreting cell in our organism. This cell mainly expresses α7 and α3β4 receptor subtypes (Hone et al , 2015; Hone et al , 2017; Perez-Alvarez et al , 2012a; Perez-Alvarez et al , 2012b). Here we show that these receptor subtypes physically interact with each other in human chromaffin cells.…”

“…Chromaffin cells allow the study of these receptor subtypes and their involvement in neurotransmitter secretion process in an incomparable manner (Albillos et al , 1997; Perez-Alvarez & Albillos 2007). In humans, these cells mainly express α7 and α3β4 receptor subtypes (Hone et al , 2015; Hone et al , 2017; Perez-Alvarez et al , 2012a; Perez-Alvarez et al , 2012b). In this study we have discovered key aspects for the understanding the functioning of nicotinic receptors.…”