Individual Variations in the Mechanisms of Nicotine Seeking: A Key for Research on Nicotine Dependence

Garcia-Rivas, Vernon; Cannella, Nazzareno; Deroche-Gamonet, Véronique

doi:10.1038/npp.2016.176

Cited by 11 publications

(8 citation statements)

References 14 publications

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“…Notably, intravenous self-administration of nicotine is lower in b4 -/mice despite a higher sensitivity of the VTA to nicotine in these mice 31 , and selfadministration is higher in TABAC mice despite reduced nicotine-induced activation of the VTA 43 . The increased consumption at high nicotine doses reported here for b4 -/mice resembles what was observed in mutant mice either lacking the a5 subunit 11 or with low levels of the a3 subunit 45 , likely because the a3, a5, and b4 nAChR subunits, which are encoded by the same gene cluster, co-assemble in brain structures, notably the MHb-IPN pathway, to produce functional heteromeric nAChRs that contribute to the control of nicotine intake.…”

Section: Discussionsupporting

confidence: 61%

Prolonged nicotine exposure reduces aversion to the drug in mice by altering nicotinic transmission in the interpeduncular nucleus

Mondoloni

Nguyen

Vicq

et al. 2021

Preprint

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Nicotine intake is likely to result from a balance between the rewarding and aversive properties of the drug, yet the individual differences in neural activity that control aversion to nicotine and their adaptation during the addiction process remain largely unknown. Using a two-bottle choice experiment, we observed a high heterogeneity in nicotine-drinking profiles in isogenic adult male mice, with about half of the mice persisting in consuming nicotine even at high concentrations, whereas the other half durably stopped consumption. We found that nicotine intake was negatively correlated with nicotine-evoked currents in the interpeduncular nucleus (IPN), and that prolonged exposure to nicotine, by weakening this response, decreased aversion to the drug, and hence boosted consumption. Lastly, using knock-out mice and local gene re-expression, we causally identified β4-containing nicotinic acetylcholine receptors of IPN neurons as the molecular and cellular correlates of nicotine aversion. Collectively, our results identify the IPN as a substrate of individual variabilities and adaptations in nicotine consumption.

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Section: Discussionsupporting

confidence: 61%

Prolonged nicotine exposure reduces aversion to the drug in mice by altering nicotinic transmission in the interpeduncular nucleus

Mondoloni

Nguyen

Vicq

et al. 2021

Preprint

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“…Altogether, Varenicline might be more beneficial for smoking cessation in those who are especially sensitive to nicotine effects on surrounding cues, and not for those who are more sensitive to the primary reinforcing effects of nicotine. Further studies need to clarify more precisely the action of Varenicline, using a preclinical model that would allow for the fine exploration of individual differences in the mechanisms that drive nicotine-seeking (Garcia-Rivas et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

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

Garcia-Rivas

Fiancette

Cannella

et al. 2019

Front. Behav. Neurosci.

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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.

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“…Whether all individuals are equal in how these different mechanisms contribute to nicotine seeking is unknown and largely ignored, while smokers may differ in their motives for tobacco seeking [for review (41)]. Based on this, we have recently proposed that the predictive validity of animal models may increase if individual variations are taken into account (33).…”

Section: Discussionmentioning

confidence: 99%

“…Whether they contribute equally in all rats is unknown. Therefore we explored qualitative differences in the interactions between nicotine and the associated discrete cue as a source of individual variations in the motives for nicotine seeking, as we have proposed before (33). We tested the hypothesis that nicotine and conditioned stimuli may exert a higher control on seeking behavior in some individuals, while others may seek nicotine for its ability to play as a reinforcer-enhancer.…”

Section: Introductionmentioning

confidence: 99%

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

Deroche-Gamonet

Garcia-Rivas

Fiancette

et al. 2021

Preprint

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Background Smokers vary in their motives for tobacco seeking, suggesting that they could benefit from personalized treatments. However, these variations have received little attention in animal models for the study of tobacco dependence. In the most classically used model, ie. intravenous self-administration of nicotine in the rat, seeking behaviour is reinforced by the combination of intravenous nicotine with a discrete stimulus (eg. discrete cue light). In both human and animals, two types of psychopharmacological interactions between nicotine and environmental stimuli have been evidenced. Whether these two types of interactions contribute equally to nicotine seeking in all individuals is unknown. Methods We combined behavioural pharmacology and clustering analysis. In an outbred male rat population, we tested whether nicotine and the discrete nicotine-associated cue light contributed equally to self-administration in all individuals. Two clusters of rats were identified, in which we further studied the nature of the psychopharmacological interaction between nicotine and the cue, as well as the response to the cessation aid varenicline when nicotine was withdrawn. Results Notably, withdrawing nicotine produced drastic opposed effects on seeking behavior in the two identified clusters of rats; a 50% increase vs a 18% decrease, respectively. The first cluster of rats sought for the primary reinforcing effects of nicotine and the discrete cue light that has gained nicotine-like secondary reinforcing properties. The second cluster sought nicotine for its ability to enhance the primary reinforcing effects of the discrete cue light. Critically, the approved cessation aid Varenicline counteracted the absence of nicotine in both, but eventually decreasing seeking in the former but increasing it in the latter. Conclusions Classical rodent models for the study of the reinforcing and addictive effects of nicotine hide individual variations in the psychopharmacological motives supporting seeking behavior. These variations may be a decisive asset for improving their predictive validity in the perspective of precision medicine for smoking cessation.

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Individual Variations in the Mechanisms of Nicotine Seeking: A Key for Research on Nicotine Dependence

Cited by 11 publications

References 14 publications

Prolonged nicotine exposure reduces aversion to the drug in mice by altering nicotinic transmission in the interpeduncular nucleus

Prolonged nicotine exposure reduces aversion to the drug in mice by altering nicotinic transmission in the interpeduncular nucleus

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

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

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