Abstract
Nicotine is acknowledged as the key addictive compound of tobacco. Varenicline (Champix® or Chantix®), mainly acting as a partial agonist at the α4β2 nicotinic receptor, is an approved smoking cessation pharmacotherapy, although with efficacy limited to a portion of smokers. Smokers differ in the motives that drive their drug seeking and Varenicline might be more efficient in some groups more than others. Studies in rodents revealed that nicotine-seeking is strongly supported by complex interactions between nicotine and environmental cues, and notably the ability of nicotine to enhance the reinforcing properties of salient environmental stimuli. It is not yet understood whether the decrease of nicotine-seeking by acute Varenicline in rats results from antagonism of the primary reinforcing effects of nicotine, of the reinforcement-enhancing effect of nicotine on cues, or of a combination of both. Thanks to a protocol that allows assessment of the reinforcement-enhancing effect of nicotine on cues during self-administration in rats, we showed that Varenicline targets both nicotine reinforcing effects and reinforcement-enhancing effect of nicotine on cues. Importantly, individual variations in the latter determined the amplitude of acute Varenicline-induced decrease in seeking. These results suggest that Varenicline might be more beneficial in smokers who are more sensitive to nicotine effects on surrounding stimuli.
Highlights
Tobacco dependence continues to be a worldwide health burden, being responsible for as many as 7 million deaths per year (WHO, 2017)
From all Varenicline Targets Nicotine-Cue Interactions patients treated with Varenicline (Champix or Chantix ), one of the most effective approved pharmacotherapies in supporting smoking cessation (Cahill et al, 2013; HartmannBoyce et al, 2014), only 40% remain abstinent at the end of a 12-week-long treatment, while post-treatment abstinence rates drop to 20% in the following months after treatment cessation (Oncken et al, 2006; Niaura et al, 2008; Jordan and Xi, 2018)
Up to session 6, the saline + cue group produced a higher number of self-infusions than the nicotine one (Group, F(1,36) = 8.5, p < 0.01) and the two profile of self-infusions differ with decrease, and progressive increase, up to stabilization, respectively (Group × Session, F(5,180) = 5.7, p < 0.0005)
Summary
Tobacco dependence continues to be a worldwide health burden, being responsible for as many as 7 million deaths per year (WHO, 2017). The interplay between nicotine and environmental cues is complex and difficult to disentangle, but plenty of evidence suggests it is a determinant factor in tobacco seeking (Caggiula et al, 2001, 2002; Garcia-Rivas and Deroche-Gamonet, 2019). Newer evidence suggests that smokers differ in the psychobiological mechanisms that drive their nicotineseeking (for review, see Garcia-Rivas and Deroche-Gamonet, 2019). In this regard, understanding the psychopharmacological dimensions of nicotine-seeking that are being affected by Varenicline could clarify its limited efficacy. The numerous studies that have shown that Varenicline can acutely decrease nicotine self-administration in rodents (Rollema et al, 2007b; O’Connor et al, 2010; Le Foll et al, 2012; Funk et al, 2016), have done so in experimental conditions that do not clearly allow the disentangling of the psychopharmacology of Varenicline against nicotine and nicotine-cue interactions
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