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The tendency to sign-track predicts cue-induced reinstatement during nicotine self-administration, and is enhanced by nicotine but not ethanol

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Abstract

Rationale

Some individuals are particularly responsive to reward-associated stimuli (“cues”), including the effects of these cues on craving and relapse to drug-seeking behavior. In the cases of nicotine and alcohol, cues may acquire these abilities via the incentive-enhancing properties of the drug.

Objectives

To determine the interaction between cue-responsivity and nicotine reinforcement, we studied the patterns of nicotine self-administration in rats categorized based on their tendency to approach a food-predictive cue (“sign-trackers”) or a reward-delivery location (“goal-trackers”). In a second experiment, we determined whether nicotine and ethanol altered the incentive value of a food cue.

Methods

Rats were classified as sign- or goal-trackers during a Pavlovian conditioned approach paradigm. Rats then self-administered intravenous nicotine (0.03 mg/kg infusions) followed by extinction and cue-induced reinstatement tests. We also tested the effects of nicotine (0.4 mg/kg base s.c.) or ethanol (0.7 g/kg i.p.) on the approach to, and reinforcing efficacy of, a food cue.

Results

Sign-trackers showed greater reinstatement in response to a nicotine cue. Further, nicotine enhanced sign-tracking but not goal-tracking to a food cue and also enhanced responding for the food cue during the conditioned reinforcement test. Conversely, ethanol reduced sign-tracking and increased goal-tracking, but had no effect on conditioned reinforcement.

Conclusions

Our studies demonstrate that the tendency to attribute incentive value to a food cue predicts enhanced cue-induced reinstatement. Additionally, the incentive value of food cues is differentially modulated by nicotine and ethanol, which may be related to the reinforcing effects of these drugs.

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References

  • Asin KE, Wirtshafter D, Tabakoff B (1985) Failure to establish a conditioned place preference with ethanol in rats. Pharmacol Biochem Behav 22:169–173

    Article  CAS  PubMed  Google Scholar 

  • Bailey SR, Goedeker KC, Tiffany ST (2010) The impact of cigarette deprivation and cigarette availability on cue-reactivity in smokers. Addiction 105:364–372

    Article  PubMed  Google Scholar 

  • Belin D, Belin-Rauscent A, Murray JE, Everitt BJ (2013) Addiction: failure of control over maladaptive incentive habits. Curr Opin Neurobiol 23:564–572

    Article  CAS  PubMed  Google Scholar 

  • Bevins RA, Palmatier MI (2004) Extending the role of associative learning processes in nicotine addiction. Behav Cogn Neurosci Rev 3:143–158

    Article  PubMed  Google Scholar 

  • Boakes R (1977) Performance on learning to associate a stimulus with positive reinforcement. In: Davis H, Hurwitz H (eds) Operant-Pavlovian interactions. Lawrence Erlbaum Associates, Hillsdale, pp. 67–97

    Google Scholar 

  • Bormann NM, Cunningham CL (1998) Ethanol-induced conditioned place aversion in rats: effect of interstimulus interval. Pharmacol Biochem Behav 59:427–432

    Article  CAS  PubMed  Google Scholar 

  • Caggiula AR, Donny EC, Palmatier MI, Liu X, Chaudhri N, Sved AF (2009) The role of nicotine in smoking: a dual-reinforcement model. Neb Symp Motiv 55:91–109

    Article  Google Scholar 

  • Caggiula AR, Donny EC, White AR, Chaudhri N, Booth S, Gharib MA, Hoffman A, Perkins KA, Sved AF (2002) Environmental stimuli promote the acquisition of nicotine self-administration in rats. Psychopharmacology 163:230–237

    Article  CAS  PubMed  Google Scholar 

  • Cardinal RN, Parkinson JA, Marbini HD, Toner AJ, Bussey TJ, Robbins TW, Everitt BJ (2003) Role of the anterior cingulate cortex in the control over behavior by Pavlovian conditioned stimuli in rats. Behav Neurosci 117:566–587

    Article  PubMed  Google Scholar 

  • Carnicella S, Ron D, Barak S (2014) Intermittent ethanol access schedule in rats as a preclinical model of alcohol abuse. Alcohol 48:243–252

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chaudhri N, Caggiula AR, Donny EC, Booth S, Gharib M, Craven L, Palmatier MI, Liu X, Sved AF (2006a) Operant responding for conditioned and unconditioned reinforcers in rats is differentially enhanced by the primary reinforcing and reinforcement-enhancing effects of nicotine. Psychopharmacology 189:27–36

    Article  CAS  PubMed  Google Scholar 

  • Chaudhri N, Caggiula AR, Donny EC, Palmatier MI, Liu X, Sved AF (2006b) Complex interactions between nicotine and nonpharmacological stimuli reveal multiple roles for nicotine in reinforcement. Psychopharmacology 184:353–366

    Article  CAS  PubMed  Google Scholar 

  • Ciccocioppo R, Panocka I, Froldi R, Quitadamo E, Massi M (1999) Ethanol induces conditioned place preference in genetically selected alcohol-preferring rats. Psychopharmacology 141:235–241

    Article  CAS  PubMed  Google Scholar 

  • Crombag HS, Gorny G, Li Y, Kolb B, Robinson TE (2005) Opposite effects of amphetamine self-administration experience on dendritic spines in the medial and orbital prefrontal cortex. Cereb Cortex 15:341–348

    Article  PubMed  Google Scholar 

  • Cunningham CL, Tull LE, Rindal KE, Meyer PJ (2002) Distal and proximal pre-exposure to ethanol in the place conditioning task: tolerance to aversive effect, sensitization to activating effect, but no change in rewarding effect. Psychopharmacology 160:414–424

    Article  CAS  PubMed  Google Scholar 

  • Donny EC, Caggiula AR, Mielke MM, Jacobs KS, Rose C, Sved AF (1998) Acquisition of nicotine self- administration in rats: the effects of dose, feeding schedule, and drug contingency. Psychopharmacology 136:83–90

    Article  CAS  PubMed  Google Scholar 

  • Donny EC, Chaudhri N, Caggiula AR, Evans-Martin FF, Booth S, Gharib MA, Clements LA, Sved AF (2003) Operant responding for a visual reinforcer in rats is enhanced by noncontingent nicotine: implications for nicotine self-administration and reinforcement. Psychopharmacology 169:68–76

    Article  CAS  PubMed  Google Scholar 

  • Epstein DH, Preston KL, Stewart J, Shaham Y (2006) Toward a model of drug relapse: an assessment of the validity of the reinstatement procedure. Psychopharmacology 189:1–16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Everitt BJ, Robbins TW (2016) Drug addiction: updating actions to habits to compulsions ten years on. Annu Rev Psychol 67:23–50

    Article  PubMed  Google Scholar 

  • Fidler TL, Oberlin BG, Struthers AM, Cunningham CL (2009) Schedule of passive ethanol exposure affects subsequent intragastric ethanol self-infusion. Alcohol Clin Exp Res 33:1909–1923

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Flagel SB, Akil H, Robinson TE (2009) Individual differences in the attribution of incentive salience to reward-related cues: implications for addiction. Neuropharmacology 56(Suppl 1):139–148

    Article  CAS  PubMed  Google Scholar 

  • Flagel SB, Clark JJ, Robinson TE, Mayo L, Czuj A, Willuhn I, Akers CA, Clinton SM, Phillips PE, Akil H (2011) A selective role for dopamine in stimulus–reward learning. Nature 469:53–57

    Article  CAS  PubMed  Google Scholar 

  • Flagel SB, Watson SJ, Robinson TE, Akil H (2007) Individual differences in the propensity to approach signals vs goals promote different adaptations in the dopamine system of rats. Psychopharmacology 191:599–607

    Article  CAS  PubMed  Google Scholar 

  • Fowler CD, Kenny PJ (2014) Nicotine aversion: neurobiological mechanisms and relevance to tobacco dependence vulnerability. Neuropharmacology 76 Pt B:533–544

    Article  PubMed  Google Scholar 

  • Gamaleddin I, Wertheim C, Zhu AZ, Coen KM, Vemuri K, Makryannis A, Goldberg SR, Le Foll B (2012) Cannabinoid receptor stimulation increases motivation for nicotine and nicotine seeking. Addict Biol 17:47–61

    Article  CAS  PubMed  Google Scholar 

  • Goldberg SR, Spealman RD (1983) Suppression of behavior by intravenous injections of nicotine or by electric shocks in squirrel monkeys: effects of chlordiazepoxide and mecamylamine. J Pharmacol Exp Ther 224:334–340

    CAS  PubMed  Google Scholar 

  • Guy EG, Fletcher PJ (2013) Nicotine-induced enhancement of responding for conditioned reinforcement in rats: role of prior nicotine exposure and alpha4beta2 nicotinic receptors. Psychopharmacology 225:429–440

    Article  CAS  PubMed  Google Scholar 

  • Guy EG, Fletcher PJ (2014) The effects of nicotine exposure during Pavlovian conditioning in rats on several measures of incentive motivation for a conditioned stimulus paired with water. Psychopharmacology 231:2261–2271

    Article  CAS  PubMed  Google Scholar 

  • Hauser SR, Getachew B, Oster SM, Dhaher R, Ding ZM, Bell RL, McBride WJ, Rodd ZA (2012) Nicotine modulates alcohol-seeking and relapse by alcohol-preferring (P) rats in a time-dependent manner. Alcohol Clin Exp Res 36:43–54

    Article  CAS  PubMed  Google Scholar 

  • Hearst E, Jenkins HM (1974) Sign tracking: the stimulus-reinforcer relation and directed action. Proceedings of the Psychonomic Society, Austin, TX

  • King CP, Palmer AA, Woods LC, Hawk LW, Richards JB, Meyer, PJ (2016) Premature responding is associated with approach to a food cue in male and female heterogeneous stock rats. Psychopharmacology (Berl).

  • Krank MD (2003) Pavlovian conditioning with ethanol: sign-tracking (autoshaping), conditioned incentive, and ethanol self-administration. Alcohol Clin Exp Res 27:1592–1598

    Article  CAS  PubMed  Google Scholar 

  • Krank MD, O'Neill S, Squarey K, Jacob J (2008) Goal- and signal-directed incentive: conditioned approach, seeking, and consumption established with unsweetened alcohol in rats. Psychopharmacology 196:397–405

    Article  CAS  PubMed  Google Scholar 

  • Liu X, Caggiula AR, Palmatier MI, Donny EC, Sved AF (2008) Cue-induced reinstatement of nicotine-seeking behavior in rats: effect of bupropion, persistence over repeated tests, and its dependence on training dose. Psychopharmacology 196:365–375

    Article  CAS  PubMed  Google Scholar 

  • Lloyd DR, Gancarz AM, Ashrafioun L, Kausch MA, Richards JB (2012) Habituation and the reinforcing effectiveness of visual stimuli. Behav Process 91:184–191

    Article  Google Scholar 

  • Lloyd DR, Hausknecht KA, Richards JB (2014a) Nicotine and methamphetamine disrupt habituation of sensory reinforcer effectiveness in male rats. Exp Clin Psychopharmacol 22:166–175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lloyd DR, Medina DJ, Hawk LW, Fosco WD, Richards JB (2014b) Habituation of reinforcer effectiveness. Front Integr Neurosci 7:107

    Article  PubMed  PubMed Central  Google Scholar 

  • Lovic V, Saunders BT, Yager LM, Robinson TE (2011) Rats prone to attribute incentive salience to reward cues are also prone to impulsive action. Behav Brain Res 223:255–261

    Article  PubMed  PubMed Central  Google Scholar 

  • Lu L, Grimm JW, Hope BT, Shaham Y (2004) Incubation of cocaine craving after withdrawal: a review of preclinical data. Neuropharmacology 47(Suppl 1):214–226

    Article  CAS  PubMed  Google Scholar 

  • Matta SG, Balfour DJ, Benowitz NL, Boyd RT, Buccafusco JJ, Caggiula AR, Craig CR, Collins AC, Damaj MI, Donny EC, Gardiner PS, Grady SR, Heberlein U, Leonard SS, Levin ED, Lukas RJ, Markou A, Marks MJ, McCallum SE, Parameswaran N, Perkins KA, Picciotto MR, Quik M, Rose JE, Rothenfluh A, Schafer WR, Stolerman IP, Tyndale RF, Wehner JM, Zirger JM (2007) Guidelines on nicotine dose selection for in vivo research. Psychopharmacology 190:269–319

    Article  CAS  PubMed  Google Scholar 

  • Meyer PJ, Cogan ES, Robinson TE (2014) The form of a conditioned stimulus can influence the degree to which it acquires incentive motivational properties. PLoS One 9:e98163

    Article  PubMed  PubMed Central  Google Scholar 

  • Meyer PJ, King CP, Ferrario CR (2015) Motivational processes underlying substance abuse disorder. Current topics in behavioral neurosciences.

  • Meyer PJ, Lovic V, Saunders BT, Yager LM, Flagel SB, Morrow JD, Robinson TE (2012a) Quantifying individual variation in the propensity to attribute incentive salience to reward cues. PLoS One 7:e38987

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Meyer PJ, Ma ST, Robinson TE (2012b) A cocaine cue is more preferred and evokes more frequency- modulated 50-kHz ultrasonic vocalizations in rats prone to attribute incentive salience to a food cue. Psychopharmacology 219:999–1009

    Article  CAS  PubMed  Google Scholar 

  • Milton AL, Everitt BJ (2010) The psychological and neurochemical mechanisms of drug memory reconsolidation: implications for the treatment of addiction. Eur J Neurosci 31:2308–2319

    Article  PubMed  Google Scholar 

  • Nasser HM, Y-w C, Fiscella K, Calu DJ (2015) Individual variability in behavioral flexibility predicts sign-tracking tendency. Front Behav Neurosci 9

  • Olausson P, Jentsch JD, Taylor JR (2004a) Nicotine enhances responding with conditioned reinforcement. Psychopharmacology 171:173–178

    Article  CAS  PubMed  Google Scholar 

  • Olausson P, Jentsch JD, Taylor JR (2004b) Repeated nicotine exposure enhances responding with conditioned reinforcement. Psychopharmacology 173:98–104

    Article  CAS  PubMed  Google Scholar 

  • Palmatier MI, Evans-Martin FF, Hoffman A, Caggiula AR, Chaudhri N, Donny EC, Liu X, Booth S, Gharib M, Craven L, Sved AF (2006) Dissociating the primary reinforcing and reinforcement-enhancing effects of nicotine using a rat self-administration paradigm with concurrently available drug and environmental reinforcers. Psychopharmacology 184:391–400

    Article  CAS  PubMed  Google Scholar 

  • Palmatier MI, Kellicut MR, Brianna Sheppard A, Brown RW, Robinson DL (2014) The incentive amplifying effects of nicotine are reduced by selective and non-selective dopamine antagonists in rats. Pharmacol Biochem Behav 126:50–62

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Palmatier MI, Marks KR, Jones SA, Freeman KS, Wissman KM, Sheppard AB (2013) The effect of nicotine on sign-tracking and goal-tracking in a Pavlovian conditioned approach paradigm in rats. Psychopharmacology 226:247–259

    Article  CAS  PubMed  Google Scholar 

  • Palmatier MI, Matteson GL, Black JJ, Liu X, Caggiula AR, Craven L, Donny EC, Sved AF (2007) The reinforcement enhancing effects of nicotine depend on the incentive value of non-drug reinforcers and increase with repeated drug injections. Drug Alcohol Depend 89:52–59

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Paolone G, Angelakos CC, Meyer PJ, Robinson TE, Sarter M (2013) Cholinergic control over attention in rats prone to attribute incentive salience to reward cues. J Neurosci 33:8321–8335

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Piazza PV, Deroche-Gamonet V (2013) A multistep general theory of transition to addiction. Psychopharmacology 229:387–413

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Podlesnik CA, Jimenez-Gomez C, Woods JH (2010) A choice procedure to assess the aversive effects of drugs in rodents. J Exp Anal Behav 93:203–223

    Article  PubMed  PubMed Central  Google Scholar 

  • Robinson TE, Flagel SB (2009) Dissociating the predictive and incentive motivational properties of reward- related cues through the study of individual differences. Biol Psychiatry 65:869–873

    Article  PubMed  Google Scholar 

  • Robinson TE, Yager LM, Cogan ES, Saunders BT (2014) On the motivational properties of reward cues: individual differences. Neuropharmacology 76, Part B:450–459

    Article  Google Scholar 

  • Rodd ZA, Bell RL, McQueen VK, Davids MR, Hsu CC, Murphy JM, Li TK, Lumeng L, McBride WJ (2005) Chronic ethanol drinking by alcohol-preferring rats increases the sensitivity of the posterior ventral tegmental area to the reinforcing effects of ethanol. Alcohol Clin Exp Res 29:358–366

    Article  CAS  PubMed  Google Scholar 

  • Rose JE, Behm FM, Westman EC, Johnson M (2000) Dissociating nicotine and nonnicotine components of cigarette smoking. Pharmacol Biochem Behav 67:71–81

    Article  CAS  PubMed  Google Scholar 

  • Saunders BT, Robinson TE (2010) A cocaine cue acts as an incentive stimulus in some but not others: implications for addiction. Biol Psychiatry 67:730–736

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saunders BT, Robinson TE (2012) The role of dopamine in the accumbens core in the expression of Pavlovian-conditioned responses. Eur J Neurosci 36:2521–2532

    Article  PubMed  PubMed Central  Google Scholar 

  • Schramm-Sapyta NL, DiFeliceantonio AG, Foscue E, Glowacz S, Haseeb N, Wang N, Zhou C, Kuhn CM (2010) Aversive effects of ethanol in adolescent versus adult rats: potential causes and implication for future drinking. Alcohol Clin Exp Res 34:2061–2069

    Article  PubMed  PubMed Central  Google Scholar 

  • Sciascia JM, Mendoza J, Chaudhri N (2014) Blocking dopamine d1-like receptors attenuates context-induced renewal of pavlovian-conditioned alcohol-seeking in rats. Alcohol Clin Exp Res 38:418–427

    Article  CAS  PubMed  Google Scholar 

  • Shaham Y, Stewart J (1996) Effects of opioid and dopamine receptor antagonists on relapse induced by stress and re-exposure to heroin in rats. Psychopharmacology 125:385–391

    Article  CAS  PubMed  Google Scholar 

  • Simms JA, Steensland P, Medina B, Abernathy KE, Chandler LJ, Wise R, Bartlett SE (2008) Intermittent access to 20 % ethanol induces high ethanol consumption in Long-Evans and Wistar rats. Alcohol Clin Exp Res 32:1816–1823

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Srey CS, Maddux JM, Chaudhri N (2015) The attribution of incentive salience to Pavlovian alcohol cues: a shift from goal-tracking to sign-tracking. Front Behav Neurosci 9:54

    Article  PubMed  PubMed Central  Google Scholar 

  • Tiffany ST (1990) A cognitive model of drug urges and drug-use behavior: role of automatic and nonautomatic processes. Psychol Rev 97:147–168

    Article  CAS  PubMed  Google Scholar 

  • Tiffany ST (1999) Cognitive concepts of craving. Alcohol Res Health 23:215–224

    CAS  PubMed  Google Scholar 

  • Tomie A, Aguado AS, Pohorecky LA, Benjamin D (1998a) Ethanol induces impulsive-like responding in a delay-of-reward operant choice procedure: impulsivity predicts autoshaping. Psychopharmacology 139:376–382

    Article  CAS  PubMed  Google Scholar 

  • Tomie A, Cunha C, Mosakowski EM, Quartarolo NM, Pohorecky LA, Benjamin D (1998b) Effects of ethanol on Pavlovian autoshaping in rats. Psychopharmacology 139:154–159

    Article  CAS  PubMed  Google Scholar 

  • van der Kooy D, O'Shaughnessy M, Mucha RF, Kalant H (1983) Motivational properties of ethanol in naive rats as studied by place conditioning. Pharmacol Biochem Behav 19:441–445

    Article  PubMed  Google Scholar 

  • Yager LM, Pitchers KK, Flagel SB, Robinson TE (2015) Individual variation in the motivational and neurobiological effects of an opioid cue. Neuropsychopharmacology 40:1269–1277

    Article  CAS  PubMed  Google Scholar 

  • Yager LM, Robinson TE (2010) Cue-induced reinstatement of food seeking in rats that differ in their propensity to attribute incentive salience to food cues. Behav Brain Res 214:30–34

    Article  PubMed  PubMed Central  Google Scholar 

  • Yager LM, Robinson TE (2015) Individual variation in the motivational properties of a nicotine cue: sign- trackers vs. goal-trackers. Psychopharmacology 232:3149–3160

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors would like to thank Michael Demyan and Adam Rutz for their excellent technical support and Dr. Carrie Ferrario for her comments on an earlier version of the manuscript. This research was supported by a grant from the Office of the Director, National Institutes of Health, and the National Institute on Alcohol Abuse and Alcoholism (R01AA024112).

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Correspondence to Paul J. Meyer.

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All procedures were approved by the University at Buffalo Institutional Animal Care and Use Committee.

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Versaggi, C.L., King, C.P. & Meyer, P.J. The tendency to sign-track predicts cue-induced reinstatement during nicotine self-administration, and is enhanced by nicotine but not ethanol. Psychopharmacology 233, 2985–2997 (2016). https://doi.org/10.1007/s00213-016-4341-7

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