Varenicline Targets the Reinforcing-Enhancing Effect of Nicotine on Its Associated Salient Cue During Nicotine Self-administration in the Rat

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.

Evidence of individual differences in motives for nicotine seeking in classical nicotine self-administration and associated outcomes of varenicline administration

“…Our data support this: at a population level, varenicline can moderately enhance cue reinforcing effects in rats self-administering i.v. saline+cue (Fig5b), and antagonize nicotine-induced enhancement of cue reinforcing effects (FigS4k-l), in accordance with a previous study done in our laboratory (30). Critically, our self-administration data also reveal that the behavioral effects of varenicline in the absence of nicotine can be different, or even opposed, depending on the individual psychopharmacological profile of nicotine-cue interactions: varenicline decreases cue self-administration in cluster B, but slightly increased it in cluster A (Fig 5a-b), consistent with the observed effect in reinforcement enhancement (Fig5b).…”

“…The classical, and most widely used, preclinical model of nicotine intravenous self-administration in the rat involves the contingent delivery of nicotine with a visual stimulus ('cue') (28). We and others have shown that this type of visual stimuli is not neutral, but drives self-administration behavior by itself, working as a mild primary reinforcer (22,(29)(30)(31)(32). Hence, the two types of psychopharmacological interactions between the nicotine and the visual cue can contribute to nicotine+cue selfadministration.…”

Nicotine but not saline self-administering or yoked control conditions produces sustained neuroadaptations in the accumbens shell

“…However their active lever pressing was maintained significantly higher than the inactive lever responding and reinstated to baseline during cue-reinforced responding under extinction conditions. Other previous studies have confirmed the contribution of environmental cues in driving self-administration behavior, that when paired with contingent saline-SA produced even stronger responding than nicotine-SA in the absence of these stimuli ( Donny et al, 2003 ; Garcia-Rivas et al, 2019 ). However, this mild reinforcing effect of visual cues in driving operant behavior did not produce any sustained neuroadaptations in the saline-SA group when compared to yoked-treated control within the accumbens shell.…”

“…Conversely, a saline self-administering group can be used to control for neurophysiological transformations that may be shielded by neuroadaptations produced when conditioned visual cues are associated with operant responding. As a matter of fact, saline self-administering rats that respond for nicotine associated visual cues, present a stimulus-driven operant learning and are able to discriminate between active (rewarded) and inactive (non-rewarded) responses ( Donny et al, 2003 ; Garcia-Rivas et al, 2019 ).…”

Significant association of nicotine reinforcement and cue reactivity: a translational study in humans and rats

“…For instance, those individuals who are particularly vulnerable to tobacco cue-induced craving and relapse may benefit most from interventions that are likely to reduce nicotine reinforcement strength such as the nicotinic partial agonist, varenicline. Indeed, varenicline pre-treatment in rats reduces responding for nicotine under a PR schedule (Le Foll et al, 2012), has been shown to antagonise both the primary reinforcing effects of nicotine and the reinforcement-enhancing effect of nicotine on cues (Garcia-Rivas et al, 2019) and reduces cue reactivity (Franklin et al, 2011). Future research could ascertain if varenicline has greatest efficacy among smokers with the largest cue-reactivity.…”