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

Abstract

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interaction between nicotine and the cue, as well as the response to the cessation aid varenicline when nicotine was withdrawn.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.