Psychobiological Correlates of Individual Variations in the Control of Nicotine Seeking by Nicotine and Nicotine-Associated Cues
PhD Supervisor: Véronique Deroche-Gamonet,team leader: Psychobiology of Drug Addiction, INSERM U1215, Neurocentre Magendie, Bordeaux
Abstract
Tobacco use leads to 6 million deaths every year due to severe long lasting diseases. The main component of tobacco, nicotine, is recognized as one of the most addictive drugs, making smoking cessation difficult, even when 70% of smokers wish to do so. Critically, even the most effective pharmacotherapies for smoking cessation, such as varenicline, have only limited efficacy. Clinical and preclinical studies have demonstrated consistently that nicotine seeking is a complex behavior involving various psychopharmacological mechanisms. Critically, converging psychological, genetic and neurobiological data from clinical studies support that the mechanisms controlling nicotine seeking may vary from individual to individual. This heterogeneity could explain the unequal efficiency of treatments, notably of varenicline, whose psychopharmacological targets are still poorly understood, and the poor predictive validity of preclinical models, which do not consider possible individual variations in the mechanisms of nicotine seeking. In this PhD work, using intravenous nicotine self-administration in the rat, we have explored individual variations in the control of nicotine seeking, by the primary reinforcing effects of nicotine, nicotine’s impact on environmental cues, or both. We have evidenced three sub-populations of individuals whose nicotine seeking is controlled by distinct contributions of nicotine primary reinforcing effects and nicotine-cue interactions. Their phenotypes of nicotine seeking have been supported and validated by pre-existing behavioral markers of Pavlovian conditioned approach, as well as by markers of nicotine metabolism, and neurobiological markers of cholinergic and dopamine transmissions in key brain structures. In parallel, we have explored psychopharmacological targets of varenicline. Using a novel approach that allows manipulating the reinforcing-enhancing effects of nicotine on cues, during nicotine self-administration, we evidenced that varenicline antagonizes both these cue reinforcing-enhancing effects and the primary reinforcing effect of nicotine, but as a function of the individual response amplitude for the former, and not for the latter. This PhD work evidences and validates preclinical individual variations in the mechanisms of nicotine seeking. It opens the perspective of exploring the neurobiological causal mechanisms for these individual variations, their long term impact on the development of nicotine dependence and whether varenicline efficacy benefits more to the subpopulation mostly driven by nicotine-induced enhancement of cue reinforcing effects.
Selected Publications:
García-Rivas, V. & Deroche-Gamonet, V. (2018), ‘Not all smokers appear to seek nicotine for the same reasons: implications for preclinical research in nicotine dependence’, Addiction Biology, ePub ahead of print doi: 10.1111/adb.12607
García-Rivas, V., Cannella, N & Deroche-Gamonet, V. (2017) ‘Individual Variations in the Mechanisms of Nicotine Seeking: A Key for Research on Nicotine Dependence’, Neuropsychopharmacology, 42(3), pp584-586
Jury
M. Philippe FAURE
Directeur de recherche,
Université Pierre et Marie Curie
(Président)
M. Marcello SOLINAS,
Directeur de recherche,
Université de Poitiers
(Rapporteur)
M. Mickael NAASSILA,
Directeur de recherche,
Université de Picardie Jules Verne
(Rapporteur)
Mme Stéphanie CAILLE-GARNIER ,
Chargée de recherche,
Université de Bordeaux
(Examinatrice)