A Cohen

AC Janes

AK Stoker

AM Falco

C Morel

CD Fowler

LE Hong

LM Yager

M Falcone

M Mamoun

N Hiroi

Nazzareno Cannella

PE Grebenstein

S Potvin

T Wang

Vernon Garcia-Rivas

Véronique Deroche-Gamonet

Garcia-Rivas, V.

Cannella, N.

Deroche-Gamonet, V.

Unicam Scientific Publications

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

Crossref

Neuropsychopharmacology

Garcia-Rivas V.

Cannella N.

Deroche-Gamonet V.

Archivio istituzionale della ricerca - Università di Camerino

PerspectiveIndividual Variations in the Mechanisms of Nicotine Seeking: AKey for Research on Nicotine DependenceVernon Garcia-Rivas1,2, Nazzareno Cannella1,2 and Véronique Deroche-Gamonet*,1,21INSERM U1215, Pathophysiology of Addiction, NeuroCentre Magendie, Bordeaux, France; 2University of Bordeaux, Bordeaux, FranceNeuropsychopharmacology (2017) 42, 584–586; doi:10.1038/npp.2016.176; published online 12 October 2016Tobacco users are estimated to be at least 1.1 billionworldwide. Although tobacco dependence is not associatedwith obvious behavioral disruptions, alleviating it is a majorpublic health concern and a main societal challenge, as itproduces severe long-lasting health-related problems, leadingto 6 million deaths every year. Available therapies forsmoking cessation have limited efficacy, warranting the needfor developing better therapeutic strategies, which depend onunderstanding the mechanisms that underlie tobacco depen-dence, in which nicotine is considered to have a central role.The relevance of preclinical animal models to nicotinedependence is questioned because their predictive validity isconsidered poor (Hong et al, 2010). In spite of this,preclinical animal models of nicotine seeking have beenproved useful, as they have helped in understanding themechanisms underlying nicotine seeking. These models, inline with clinical studies, have consistently demonstrated thatboth pharmacological factors (PF) and non-pharmacologicalfactors (NPF) promote nicotine seeking and have helpedidentify underlying neurobiological mechanisms (Stoker andMarkou, 2015).Increasing psychological, genetic, and neurobiological datasupport the notion that the contribution of PF and NPF tonicotine seeking differ from smoker to smoker, thus possiblycontributing to the observed heterogeneity in the populationof smokers (Hiroi and Scott, 2009). It could also contribute tothe incongruence between the multiple diagnosis tools, theinconsistent relationship between craving and smokingcessation outcome, and the limited predictive validity ofanimal models. This might also eventually reduce our abilityto identify relevant therapeutic targets for smoking cessation(Potvin et al, 2015).For instance, a single-nucleotide polymorphism of theCHRNA5 gene has been associated with heavy smoking,which appears to be caused by a lowered sensitivity to theaversive effects of nicotine (Fowler and Kenny, 2014). Insmokers who carry this CHRNA5 risk allele, compared withnoncarriers, nicotine seeking through PF is increased,namely through withdrawal avoidance, whereas susceptibil-ity to NPF, in particular cue-induced craving (Janes et al,2012), is decreased. This supports the notion that the twotypes of factors (PF/NPF) can vary independently. Fastnicotine metabolism is another risk factor for heavy smokingand low cessation rates (Mamoun et al, 2015). Fast nicotinemetabolizers are more sensitive to withdrawal than theirslow metabolizer counterparts, but differently from theCHRNA5 case, they are also more responsive to drug cues(Falcone et al, 2016); a difference possibly due to theirspecific nicotine pharmacodynamics that might favor cueconditioning. Altogether, specific combinations ofrisk and protective factors, like these and many others, willdetermine the individual mechanisms underlying nicotineseeking.We propose that the predictive validity of animal modelsmight increase by taking into account these individualvariations. This implies determining, within the sameindividuals, the influence of both PF and NPF in the controlof nicotine seeking, and evaluating how individual psycho-biological factors and length of nicotine exposure (early vslate nicotine use) affect this balance (Figure 1).The exploration of individual differences in nicotine self-administration is at a very early stage. A recent exhaustivereview by Falco and Bevins (2015) on individual differencesin the behavioral effects of nicotine refers to only four self-administration studies that investigated the relationshipsbetween impulsivity-related psychobehavioral traits andnicotine self-administration. However, even this very limitedbody of research has produced inconsistent results and hasyet to identify underlying mechanisms of nicotine seeking.Now important conditions are met for investigatingindividual variations in nicotine seeking. Over the last 15years, tremendous progress has been made in modelingnicotine taking in rodents using intravenous self-administration. Newer developments include the explorationof alternative routes of administration (Cohen and George,2013) or even self-administration (www.simply-lab.com) (ie,vapor inhalation), as well as the influence of social factors onnicotine taking (Wang et al, 2014). Thanks to these models,*Correspondence: Dr V Deroche-Gamonet, INSERM U1215,Pathophysiology of Addiction, Neuro Centre Magendie, 146 rue LéoSaignat, Bordeaux 33077, France, Tel: +33 5 57 57 36 80, Fax: +33 5 5757 36 69, E-mail: veronique.deroche@inserm.frReceived 12 July 2016; revised 24 August 2016; accepted 25 August2016; accepted article preview online 31 August 2016Neuropsychopharmacology (2017) 42, 584–586© 2017 American College of Neuropsychopharmacology. All rights reserved 0893-133X/17www.neuropsychopharmacology.orgkey information has been collected on the control of nicotineseeking by PF and notably NPF, thanks to the seminal workof Anthony Caggiula and Eric Donny (Pittsburgh University,USA) on the complex control of nicotine seeking byconditioned factors. Also significant, investigating themechanisms by which nicotine alters contextual learning,Thomas J Gould and colleagues (Temple University,Philadelphia, USA) have contributed to the current viewon how nicotine withdrawal might promote seeking throughcognitive impairments and negative affective state.Over the same time period, new mouse genetic modelshave been developed to reproduce human allelic variations innAChR subtypes associated with increased risk for nicotinedependence (Morel et al, 2014). Furthermore, newerexperimental tools, such as opto- and chemogenetics, viraltracing techniques, and brain calcium imaging in freelybehaving rodents allow for precise investigations of neuralcircuit function, including those relevant to nicotine seeking.Personality traits, like reactivity to novelty, anxiety, andimpulsivity, associated with increased risk for nicotinedependence in humans, are now also well characterized inrodents, providing the opportunity to study their role innicotine seeking.More recently, two promising studies support the notionthat consistent individual differences in the reinforcing andincentive effects of nicotine can be observed. In an outbredstrain of rats, Grebenstein et al (2015) reported individualvariations in nicotine self-administration. Superficially, thenicotine reinforcement threshold and degree of compensa-tion when decreasing nicotine dose were predicted bynicotine clearance, suggesting that nicotine seeking mightbe controlled by PF in some individuals, and less so in others,through biochemical differences affecting pharmacokinetics.Echoing the fast/slow metabolizer phenotypes in humans,the observations of Grebenstein et al (2015) offer interestingperspectives for studying the PF vs NPF balance incontrolling nicotine seeking by identifying individual differ-ences in nicotine metabolism.In search for the mechanisms of individual vulnerability tococaine or opioid addiction, sophisticated procedures havebeen developed to investigate psychobehavioral factors suchas attribution of incentive salience to drug cues that mightinfluence drug seeking. In the so-called sign trackers rats(STs), food- or drug- (cocaine, opioid) associated discretecues are both more attractive (elicit approach) and morewanted (are conditioned reinforcers) than in goal trackersrats (GTs), in which presentation of reward-associated cueselicits approach to the location of reward delivery. Fornicotine, Yager and Robinson (2015) showed that if STs ratswant more a nicotine-associated cue, they approach anicotine cue similarly to GTs, demonstrating nicotine-specific mechanisms of salience attribution. This model notonly opens perspectives for the study of the mechanisms ofsalience attribution in general, but offers the opportunity toFigure 1 Individual-based approach for the mechanisms of nicotine seeking. We propose a three-level strategy for an individual-based animal model ofnicotine seeking: (1) modeling, in the same individuals, and as a function of duration of nicotine self-administration, the impact of pharmacological factors (PF)and non-pharmacological factors (NPF) on nicotine seeking; (2) exploring individual variations in the balance between PF and NPF in the control of nicotineseeking, based on such a model, and (3) exploring the underlying psychobiological mechanisms of these individual differences, from a circuitry down to amolecular level, using complementary tools and approaches, such as outbred rodents characterized for personality traits associated with risk for nicotinedependence (impulsivity, novelty seeking and so on), genetically-manipulated rodents with altered expression of specific nAChR subtypes, or reproducinghuman allelic variations in nAChR subtypes associated with increased risk for nicotine dependence, and tools such as opto- and chemogenetics, viral tracingtechniques, and brain calcium imaging in freely behaving rodents that allow for precise investigations of neural circuit function, including those relevant tonicotine seeking.Individual variations in the mechanisms of nicotine seekingV Garcia-Rivas et al585Neuropsychopharmacologystudy the control of nicotine seeking by NPF and PF as afunction of individual differences in salience attribution tonicotine cues.CONCLUSIONTobacco use is the net balance between factors promotingsmoking maintenance (‘seeking mechanisms’) and factorspromoting smoking cessation (‘motivation to stop’). Even ifcapturing motivation to stop is a challenge in animal models,they allow exploring mechanisms promoting nicotine seek-ing and taking.Data support that individual variations in the mechanismsof nicotine seeking contribute to the heterogeneity of thepopulation of tobacco smokers and may explain in part thelimited efficacy of current therapeutic strategies for smokingcessation. Conditions are met to study these individualvariations and identify their underlying neurobiologicalmechanisms using preclinical models in rodents. Thisstrategy could increase our ability to develop individual-based therapeutic strategies for tobacco dependence.FUNDING AND DISCLOSUREThe authors declare no conflict of interest.ACKNOWLEDGMENTSResearch program of VD-G is supported by the FRM grantDPA20140629795, the EquipEx grant OptoPath (ANR-10-EQX-008-1), by INSERM, the University of Bordeaux, andthe Aquitaine Region Council. VG-R is supported by anInserm-Aquitaine Region Council fellowship (2015-1R30105). NC is supported by the FRM grantDPA20140629795.REFERENCESCohen A, George O (2013). Animal models of nicotine exposure:relevance to second-hand smoking, electronic cigarette use, andcompulsive smoking. Front Psychiatry 4: 41.Falco AM, Bevins RA (2015). Individual differences in thebehavioral effects of nicotine: a review of the preclinical animalliterature. Pharmacol Biochem Behav 138: 80–90.Falcone M, Cao W, Bernardo L, Tyndale RF, Loughead J, Lerman C(2016). Brain responses to smoking cues differ based on nicotinemetabolism rate. Biol Psychiatry 80: 190–197.Fowler CD, Kenny PJ (2014). Nicotine aversion: neurobiologicalmechanisms and relevance to tobacco dependence vulnerability.Neuropharmacology 76 Pt B: 533–544.Grebenstein PE, Burroughs D, Roiko SA, Pentel PR,LeSage MG (2015). Predictors of the nicotine reinforcementthreshold, compensation, and elasticity of demand in a rodentmodel of nicotine reduction policy. Drug Alcohol Depend 151:181–193.Hiroi N, Scott D (2009). Constitutional mechanisms of vulnerabilityand resilience to nicotine dependence. Mol Psychiatry 14:653–667.Hong LE, Hodgkinson CA, Yang Y, Sampath H, Ross TJ,Buchholz B et al (2010). A genetically modulated, intrinsiccingulate circuit supports human nicotine addiction. Proc NatlAcad Sci USA 107: 13509–13514.Janes AC, Smoller JW, David SP, Frederick BD, Haddad S,Basu A et al (2012). Association between CHRNA5genetic variation at rs16969968 and brain reactivity to smokingimages in nicotine dependent women. Drug Alcohol Depend120: 7–13.Mamoun M, Bergen AW, Shieh J, Wiggins A, Brody AL (2015).Biomarkers of response to smoking cessation pharmacotherapies:progress to date. CNS Drugs 29: 359–369.Morel C, Fattore L, Pons S, Hay YA, Marti F, Lambolez B et al(2014). Nicotine consumption is regulated by a humanpolymorphism in dopamine neurons. Mol Psychiatry 19:930–936.Potvin S, Tikàsz A, LL Dinh-Williams, Bourque J, Mendrek A(2015). Cigarette cravings, impulsivity, and the brain. 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Individual Variations in the Mechanisms of Nicotine Seeking: A Key for Research on Nicotine Dependence

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