Behavioral Mechanisms Underlying Nicotine Reinforcement

Part of the Current Topics in Behavioral Neurosciences book series (CTBN, volume 24)


Cigarette smoking is the leading cause of preventable deaths worldwide, and nicotine, the primary psychoactive constituent in tobacco, drives sustained use. The behavioral actions of nicotine are complex and extend well beyond the actions of the drug as a primary reinforcer. Stimuli that are consistently paired with nicotine can, through associative learning, take on reinforcing properties as conditioned stimuli. These conditioned stimuli can then impact the rate and probability of behavior and even function as conditioning reinforcers that maintain behavior in the absence of nicotine. Nicotine can also act as a conditioned stimulus (CS), predicting the delivery of other reinforcers, which may allow nicotine to acquire value as a conditioned reinforcer. These associative effects, establishing non-nicotine stimuli as conditioned stimuli with discriminative stimulus and conditioned reinforcing properties as well as establishing nicotine as a CS, are predicted by basic conditioning principles. However, nicotine can also act non-associatively. Nicotine directly enhances the reinforcing efficacy of other reinforcing stimuli in the environment, an effect that does not require a temporal or predictive relationship between nicotine and either the stimulus or the behavior. Hence, the reinforcing actions of nicotine stem both from the primary reinforcing actions of the drug (and the subsequent associative learning effects) as well as the reinforcement enhancement action of nicotine which is non-associative in nature. Gaining a better understanding of how nicotine impacts behavior will allow for maximally effective tobacco control efforts aimed at reducing the harm associated with tobacco use by reducing and/or treating its addictiveness.


Reinforcement Reward Operant Self-administration Nicotine Conditioning 



Research reported in this publication was supported by the National Institute on Drug Abuse (R01 DA010464) and FDA Center for Tobacco Products (CTP) (U54 DA031659). The funding source had no other role other than financial support. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or the Food and Drug Administration.


  1. Abelson PH (1995) Flaws in risk assessments. Science 270:215PubMedGoogle Scholar
  2. Adriani W, Spijker S, Deroche-Gamonet V, Laviola G, Le Moal M, Smit AB, Piazza PV (2003) Evidence for enhanced neurobehavioral vulnerability to nicotine during periadolescence in rats. J Neurosci 23:4712–4716PubMedGoogle Scholar
  3. Adriani W, Deroche-Gamonet V, Le Moal M, Laviola G, Piazza PVV (2006) Preexposure during or following adolescence differently affects nicotine-rewarding properties in adult rats. Psychopharmacology 184:382–390PubMedGoogle Scholar
  4. Amit Z, Brown Z, Rockman G (1977) Possible involvement of acetaldehyde, norepinephrine and their tetrahydroisoquinoline derivatives in the regulation of ethanol self-administration. Drug Alcohol Depend 2:495–500PubMedGoogle Scholar
  5. Ator NA, Griffiths RR (2003) Principles of drug abuse liability assessment in laboratory animals. Drug Alcohol Depend 70:S55–S72PubMedGoogle Scholar
  6. Attwood AS, Penton-Voak IS, Munafo MR (2009) Effects of acute nicotine administration on ratings of attractiveness of facial cues. Nicotine Tob Res 11:44–48PubMedGoogle Scholar
  7. Bardo MT, Green TA, Crooks PA, Dwoskin LP (1999) Nornicotine is self-administered intravenously by rats. Psychopharmacology 146:290–296PubMedGoogle Scholar
  8. Barr RS, Pizzagalli DA, Culhane MA, Goff DC, Evins AE (2008) A single dose of nicotine enhances reward responsiveness in nonsmokers: implications for development of dependence. Biol Psychiatry 63:1061–1065PubMedCentralPubMedGoogle Scholar
  9. Barret ST, Bevins RA (2013) Nicotine enhances operant responding for qualitatively distinct reinforcers under maintenance and extinction conditions. Pharmacol Biochem Behav 114–115:9–15PubMedGoogle Scholar
  10. Becker JB, Hu M (2008) Sex differences in drug abuse. Front Neuroendocrinol 29:36–47PubMedCentralPubMedGoogle Scholar
  11. Belluzzi JD, Lee AG, Oliff HS, Leslie FM (2004) Age-dependent effects of nicotine on locomotor activity and conditioned place preference in rats. Psychopharmacology 174:389–395PubMedGoogle Scholar
  12. Belluzzi JD, Wang R, Leslie FM (2005) Acetaldehyde enhances acquisition of nicotine self-administration in adolescent rats. Neuropsychopharmacology 30:705–712PubMedGoogle Scholar
  13. Beninger RJ, Hanson DR, Phillips AG (1980) The acquisition of responding with conditioned reinforcement: effects of cocaine, (+)-amphetamine and pipradrol. Br J Pharmacol 1:149–154Google Scholar
  14. Benowitz NL (1990) Pharmacokinetic considerations in understanding nicotine dependence. In: The biology of nicotine dependence, Ciba Foundation Symposium, Wiley, New York Google Scholar
  15. Benowitz NL, Hatsukami D (1998) Gender differences in the pharmacology of nicotine addiction. Addict Biol 3:383–404Google Scholar
  16. Berchtold NC, Cribbs DH, Coleman PD, Rogers J, Head E, Kim R, Beach T, Miller C, Troncoso J, Trojanowski JQ (2008) Gene expression changes in the course of normal brain aging are sexually dimorphic. Proc Nat Acad Sci 105:15605–15610PubMedCentralPubMedGoogle Scholar
  17. Berlin I, Said S, Spreux-Varoquaux O, Olivares R, Launay JM, Puech AJ (1995) Monoamine oxidase A and B activities in heavy smokers. Biol Psychiatry 38:756–761PubMedGoogle Scholar
  18. Berridge KC, Robinson TE (2003) Parsing reward. Trends Neurosci 26:507–513Google Scholar
  19. Besheer J, Palmatier MI, Metschke DM, Bevins, RA (2004) Nicotine as a signal for the presence or absence of sucrose reward: a Pavlovian drug appetitive conditioning preparation in rats. Psychopharmacology 172:108–117Google Scholar
  20. Bevins RA (2009) Altering the motivational function of nicotine through conditioning processes. Nebr Symp Motiv 55:111–129PubMedCentralPubMedGoogle Scholar
  21. Bouton ME (2011) Learning and the persistence of appetite: extinction and the motivation to eat and overeat. Physiol Behav 103:51–58PubMedGoogle Scholar
  22. Brady KT, Randall CL (1999) Gender differences in substance use disorders. Psychiatr Clin North Am 22:241–252PubMedGoogle Scholar
  23. Breslau N, Peterson EL (1996) Smoking cessation in young adults: age at initiation of cigarette smoking and other suspected influences. Am J Public Health 86:214–220PubMedCentralPubMedGoogle Scholar
  24. Brielmaier JM, McDonald CG, Smith RF (2007) Immediate and long-term behavioral effects of a single nicotine injection in adolescent and adult rats. Neurotoxicol Teratol 29:74–80PubMedGoogle Scholar
  25. Brown Z, Amit Z, Rockman G (1979) Intraventricular self-administration of acetaldehyde, but not ethanol, in naive laboratory rats. Psychopharmacology 64:271–276PubMedGoogle Scholar
  26. Busto U, Sellers EM (1986) Pharmacokinetic determinants of drug abuse and dependence. A conceptual perspective. Clin Pharmacokinet 11:144–153PubMedGoogle Scholar
  27. Caggiula AR, Donny EC, White AR, Chaudhri N, Booth S, Gharib MA, Sved AF (2001) Cue dependency of nicotine self-administration and smoking. Pharmacol Biochem Behav 70:515–530PubMedGoogle Scholar
  28. Caggiula AR, Donny EC, Chaudhri N, Perkins KA, Evans-Martin FF, Sved AF (2002a) Importance of nonpharmacological factors in nicotine self-administration. Physiol Behav 77:683–687PubMedGoogle Scholar
  29. Caggiula AR, Donny EC, White AR, Chaudhri N, Booth S, Gharib MA, Sved AF (2002b) Environmental stimuli promote the acquisition of nicotine self-administration in rats. Psychopharmacology 163:230–237PubMedGoogle Scholar
  30. Caggiula AR, Donny EC, Palmatier MI, Liu X, Chaudhri N, Sved AF (2009) The role of nicotine in smoking: a dual-reinforcement model. Nebr Symp Motiv 55:91–109PubMedCentralPubMedGoogle Scholar
  31. Caine SB, Collins GT, Thomsen M, Wright C, Lanier RK, Mello NK (2014) Nicotine-like behavioral effects of the minor tobacco alkaloids nornicotine, anabasine, and anatabine in male rodents. Exp Clin Psychopharmacol 22:9–22PubMedGoogle Scholar
  32. Carroll ME, Lynch WJ, Roth ME, Morgan AD, Cosgrove KP (2004) Sex and estrogen influence drug abuse. Trends Pharmacol Sci 25:273–279PubMedGoogle Scholar
  33. CDC (2010) Cigarette use among high school students-United States, 1991–2009. Morb Mortal Wkly Rep (MMWR) 59:797Google Scholar
  34. CDC (2012) Current cigarette smoking among adults-United States, 2011. Morb Mortal Wkly Rep (MMWR) 61:889–894Google Scholar
  35. Chambers RA, Taylor JR, Potenza MN (2003) Developmental neurocircuitry of motivation in adolescence: a critical period of addiction vulnerability. Am J Psychiatry 160:1041–1052PubMedCentralPubMedGoogle Scholar
  36. Chaudhri N, Caggiula AR, Donny EC, Booth S, Gharib MA, Craven LA, Perkins KA (2005) Sex differences in the contribution of nicotine and nonpharmacological stimuli to nicotine self-administration in rats. Psychopharmacology 180:258–266PubMedGoogle Scholar
  37. Chaudhri N, Caggiula AR, Donny EC, Booth S, Gharib M, Craven L, 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 189:27–36PubMedGoogle Scholar
  38. 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 184:353–366PubMedGoogle Scholar
  39. Chaudhri N, Caggiula AR, Donny EC, Booth S, Gharib M, Craven L, Sved SF (2007) Self-administered and noncontingent nicotine enhance reinforced operant responding in rats: impact of nicotine dose and reinforcement schedule. Psychopharmacology 190:353–362PubMedCentralPubMedGoogle Scholar
  40. Chen H, Matta SG, Sharp BM (2007) Acquisition of nicotine self-administration in adolescent rats given prolonged access to the drug. Neuropsychopharmacology 32:700–709PubMedGoogle Scholar
  41. Cheskin LJ, Hess JM, Henningfield J, Gorelick DA (2005) Calorie restriction increases cigarette use in adult smokers. Psychopharmacology 179:430–436PubMedGoogle Scholar
  42. Choi K, Fabian L, Mottey N, Corbett A, Forster J (2012) Young adults’ favorable perceptions of snus, dissolvable tobacco products, and electronic cigarettes: findings from a focus group study. Am J Public Health 102:2088–2093PubMedCentralPubMedGoogle Scholar
  43. Clemens KJ, Caillé S, Stinus L, Cador M (2009) The addition of five minor tobacco alkaloids increases nicotine-induced hyperactivity, sensitization and intravenous self-administration in rats. Int J Neuropsychopharmacol 12:1355–1366PubMedGoogle Scholar
  44. Cohen A, Koob GF, George O (2012) Robust escalation of nicotine intake with extended access to nicotine self-administration and intermittent periods of abstinence. Neuropsychopharmacology 37:2153–2160Google Scholar
  45. Cohen C, Perrault G, Griebel G, Soubrie P (2005) Nicotine-associated cues maintain nicotine-seeking behavior in rats several weeks after nicotine withdrawal: reversal by the cannabinoid (CB1) receptor antagonist, rimonabant (SR141716). Neuropsychopharmacology 30:145–155PubMedGoogle Scholar
  46. Conklin CA, Tiffany S (2002a) Cue-exposure treatment: time for change. Addiction 97:1219–1221PubMedGoogle Scholar
  47. Conklin CA, Tiffany ST (2002b) Applying extinction research and theory to cue-exposure addiction treatments. Addiction 97:155–167PubMedGoogle Scholar
  48. Conklin CA, Perkins KA, Robin N, McClernon FG, Salkeld RP (2010) Bringing real world into the laboratory: person smoking and nonsmoking environments. Drug Alcohol Depend 111:58–63PubMedCentralPubMedGoogle Scholar
  49. Correa M, Salamone JD, Segovia KN, Pardo M, Longoni R, Spina L, Peana AT, Vinci S, Acquas E (2012) Piecing together the puzzle of acetaldehyde as a neuroactive agent. Neurosci Biobehav Rev 36:404–430PubMedGoogle Scholar
  50. Corrigall WA (1999) Nicotine self-administration in animals as a dependence model. Nicotine Tob Res 1:11–20PubMedGoogle Scholar
  51. Corrigall WA, Coen KM (1989) Nicotine maintains robust self-administration in rats on a limited-access schedule. Psychopharmacology 99:473–478PubMedGoogle Scholar
  52. Costello MR, Reynaga DD, Mojica CY, Zaveri NT, Belluzzi JD, Leslie FM (2014) Comparison of the reinforcing properties of nicotine and cigarette smoke extract in rats. Neuropsychopharmacol 39:1843–1851Google Scholar
  53. Crooks PA, Li M, Dwoskin LP (1997) Metabolites of nicotine in rat brain after peripheral nicotine administration cotinine, nornicotine, and norcotinine. Drug Metab Dispos 25:47–54PubMedGoogle Scholar
  54. Dawkins LPJ, West R, Powell J, Pickering A (2007) A double-blind placebo-controlled experimental study of nicotine: II–Effects on response inhibition and executive functioning. Psychopharmacology 190:457–467PubMedGoogle Scholar
  55. Deng XS, Deitrich RA (2008) Putative role of brain acetaldehyde in ethanol addiction. Current drug abuse reviews 1:3–8PubMedCentralPubMedGoogle Scholar
  56. DeNoble VJ, Mele PC (1983) Behavioral pharmacology annual report. Philip Morris Tobacco Resolution. Bates no. 20605661. Available at
  57. Donny EC, Jones M (2009) Prolonged exposure to denicotinized cigarettes with or without transdermal nicotine. Drug Alcohol Depend 104:23–33PubMedCentralPubMedGoogle Scholar
  58. Donny EC, Caggiula AR, Knopf S, Brown C (1995) Nicotine self-administration in rats. Psychopharmacology 122:390–394PubMedGoogle Scholar
  59. 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 136:83–90PubMedGoogle Scholar
  60. Donny EC, Caggiula AR, Mielke MM, Booth S, Gharib MA, Hoffman A, McCallum SE (1999) Nicotine self-administration in rats on a progressive ratio schedule of reinforcement. Psychopharmacology 147:135–142PubMedGoogle Scholar
  61. Donny EC, Caggiula AR, Rowell PP, Gharib MA, Maldovan V, Booth S, McCallum S (2000) Nicotine self-administration in rats: estrous cycle effects, sex differences and nicotinic receptor binding. Psychopharmacology 151:392–405PubMedGoogle Scholar
  62. Donny EC, Chaudhri N, Caggiula AR, Evans-Martin FF, Booth S, Gharib MA, Sved AF (2003) Operant responding for a visual reinforcer in rats is enhanced by noncontingent nicotine: implications for nicotine self-administration and reinforcement. Psychopharmacology 169:68–76PubMedGoogle Scholar
  63. Donny EC, Houtsmuller E, Stitzer ML (2007) Smoking in the absence of nicotine: behavioral, subjective and physiological effects over 11 days. Addiction 102:324–334PubMedGoogle Scholar
  64. Donny EC, Caggiula AR, Weaver MT, Levin ME, Sved AF (2011) The reinforcement-enhancing effects of nicotine: implications for the relationship between smoking, eating and weight. Physiol Behav 104:143–148PubMedCentralPubMedGoogle Scholar
  65. Duffy PH, Feuers R, Hart RW (1990) Effect of chronic caloric restriction on the circadian regulation of physiological and behavioral variables in old male B6C3F1 mice. Chronobiol Int 7:291–303PubMedGoogle Scholar
  66. Farre M, Cami J (1991) Pharmacokinetic considerations in abuse liability evaluation. Br J Addict 86:1601–1606PubMedGoogle Scholar
  67. Feltenstein MW, Ghee SM, See RE (2012) Nicotine self-administration and reinstatement of nicotine-seeking in male and female rats. Drug Alcohol Depend 121:240–246PubMedCentralPubMedGoogle Scholar
  68. Flagel SB, Watson SJ, Akil H, Robinson TE (2008) Individual differences in the attribution of incentive salience to a reward-related cue: influence on cocaine sensitization. Behav Brain Res 186:48–56PubMedCentralPubMedGoogle Scholar
  69. Fowler CD, Kenny PJ (2011) Intravenous nicotine self-administration and cue-induced reinstatement in mice: effects of nicotine dose, rate of drug infusion and prior instrumental training. Neuropharmacology 61:687–698PubMedCentralPubMedGoogle Scholar
  70. Fowler HARRY (1971) Implications of sensory reinforcement. The nature of reinforcement, Academic Press, New York, 151–195Google Scholar
  71. Fowler JS, Volkow ND, Wang G-J, Pappas N, Logan J, Shea C, Alexoff D, MacGregor RR, Schlyer DJ, Zezulkova I (1996a) Brain monoamine oxidase a inhibition in cigarette smokers. Proc Natl Acad Sci USA 93:14065–14069PubMedCentralPubMedGoogle Scholar
  72. Fowler J, Volkow N, Wang G-J, Pappas N, Logan J, MacGregor R, Alexoff D, Shea C, Schlyer D, Wolf A (1996b) Inhibition of monoamine oxidase B in the brains of smokers. Nature 379:733–736PubMedGoogle Scholar
  73. Goldberg SR, Spealman RD, Risner ME, Henningfield JE (1983) Control of behavior by intravenous nicotine injections in laboratory animals. Pharmacol Biochem Behav 19:1011–1020PubMedGoogle Scholar
  74. Grebenstein P, Burroughs D, Zhang Y, LeSage MG (2013) Sex differences in nicotine self-administration in rats during progressive unit dose reduction: implications for nicotine regulation policy. Pharmacol Biochem Behav 114–115:70–81PubMedGoogle Scholar
  75. Guillem K, Vouillac C, Azar MR, Parsons LH, Koob GF, Cador M, Stinus L (2005) Monoamine oxidase inhibition dramatically increases the motivation to self-administer nicotine in rats. J Neurosci 25:8593–8600PubMedGoogle Scholar
  76. Hall BJ, Wells C, Allenby C, Lin MY, Hao I, Marshall L, Levin ED (2014) Differential effects of non-nicotine tobacco constituent compounds on nicotine self-administration in rats. Pharmacol Biochem Behav 120:103–108PubMedGoogle Scholar
  77. Harrison AA, Gasparini F, Marlou A (2002) Nicotine potentiation of brain stimulation reward reversed by DH beta E and SCH 23390, but not my eticlopride, LY 314582, or MPEP in rats. Psychopharmacology 160:56–66PubMedGoogle Scholar
  78. Harrington GM (1963) Stimulus intensity stimulus satiation and optimum stimulation with light-contingent bar-press. Psychological Reports 13:107–111Google Scholar
  79. Harvey DM, Yasar S, Heishman SJ, Panlilio LV, Henningfield JE, Goldberg SR (2004) Nicotine serves as an effective reinforcer of intravenous drug-taking behavior in human cigarette smokers. Psychopharmacology 175:134–142PubMedGoogle Scholar
  80. Henningfield JE, Goldberg SR (1983) Nicotine as a reinforcer in human subjects and laboratory animals. Pharmacol Biochem Behav 19:989–992PubMedGoogle Scholar
  81. Hoffman AC, Evans SE (2013) Abuse potential of non-nicotine tobacco smoke components: acetaldehyde, nornicotine, cotinine, and anabasine. Nicotine Tob Res 15:622–632PubMedGoogle Scholar
  82. Houlgate PR, Dhingra KS, Nash SJ, Evans WH (1989) Determination of formaldehyde and acetaldehyde in mainstream cigarette smoke by high-performance liquid chromatography. Analyst 114:355–360PubMedGoogle Scholar
  83. Huang H-Y, Hsieh S-H (2007) Analyses of tobacco alkaloids by cation-selective exhaustive injection sweeping microemulsion electrokinetic chromatography. J Chromatogr A 1164:313–319PubMedGoogle Scholar
  84. Jensvold MF, Hamilton JA, Halbreich U (1996) Future research directions: methodological considerations for advancing gender-sensitive pharmacology. American Psychiatric Association, Arlington, VA, USA, pp 415–430Google Scholar
  85. Johnson MW, Bickel WK, Kirshenbaum AP (2004) Substitutes for tobacco smoking: a behavioral economic analysis of nicotine gum, denicotinized cigarettes, and nicotine-containing cigarettes. Drug Alcohol Depend 74:253–264PubMedGoogle Scholar
  86. Juliano LM, Donny EC, Houtsmuller EJ, Stitzer ML (2006) Experimental evidence for a causal relationship between smoking lapse and relapse. J Abnorm Psychol 115:166–173PubMedGoogle Scholar
  87. Kenny PJ, Markou A (2006) Nicotine self-administration acutely activates brain reward systems and induces a long-lasting increase in reward sensitivity. Neuropsychopharmacology 31:1203–1211PubMedGoogle Scholar
  88. Kim JYS, Fendrich M (2002) Gender differences in juvenile arrestees’ drug use, self-reported dependence, and perceived need for treatment. Psychiatric Services 53:70–75PubMedGoogle Scholar
  89. Kota D, Martin BR, Robinson SE, Damaj MI (2007) Nicotine dependence and reward differ between adolescent and adult male mice. J Pharmacol Exp Ther 322:399–407PubMedGoogle Scholar
  90. Kotz D, Brown J, West R (2014) ‘Real-world’ effectiveness of smoking cessation treatments: a population study. Addiction 109:491–499PubMedGoogle Scholar
  91. Kyerematen G, Owens G, Chattopadhyay B, Vesell E (1988) Sexual dimorphism of nicotine metabolism and distribution in the rat. Studies in vivo and in vitro. Drug Metab Dispos 16:823–828PubMedGoogle Scholar
  92. Lang WJ, Latiff AA, McQueen A, Singer G (1977) Self administration of nicotine with and without a food delivery schedule. Pharmcol Biochem Behav 7:65–70Google Scholar
  93. Lanza ST, Donny EC, Collins LM, Balster RL (2004) Analyzing the acquisition of drug self-administration using growth curve models. Drug Alcohol Depend 75:11–21PubMedGoogle Scholar
  94. Lazev AB, Herzog TA, Brandon TH (1999) Classical conditions of environmental cues to cigarette smoking. Clinical Trial. Exp Clin Psychopharmacol 7:56–63PubMedGoogle Scholar
  95. Le Foll B, Goldberg SR (2005) Control of the reinforcing effects of nicotine by associated environmental stimuli in animals and humans. Trends Pharmacol Sci 26:287–293PubMedGoogle Scholar
  96. LeSage MG, Burroughs D, Dufek M, Keyler DE, Pentel PR (2004) Reinstatement of nicotine self-administration in rats by presentation of nicotine-paired stimuli, but not nicotine priming. Pharmacol Biochem Behav 79:507–513PubMedGoogle Scholar
  97. Leslie FM, Mojica CY, Reynaga DD (2013) Nicotinic receptors in addiction pathways. Mol Pharmacol 83:753–758PubMedGoogle Scholar
  98. Levin ED, Rezvani AH, Montoya D, Rose JE, Swartzwelder HS (2003) Adolescent-onset nicotine self-administration modeled in female rats. Psychopharmacology 169:141–149PubMedGoogle Scholar
  99. Levin ED, Lawrence SS, Petro A, Horton K, Rezvani AH, Seidler FJ, Slotkin TA (2007) Adolescent vs. adult-onset nicotine self-administration in male rats: duration of effect and differential nicotinic receptor correlates. Neurotoxicol Teratol 29:458–465PubMedCentralPubMedGoogle Scholar
  100. Levin ED, Slade S, Wells C, Cauley M, Petro A, Vendittelli A, Johnson M, Williams P, Horton K, Rezvani AH (2011) Threshold of adulthood for the onset of nicotine self-administration in male and female rats. Behav Brain Res 225:473–481PubMedCentralPubMedGoogle Scholar
  101. Levin ME, Weaver MT, Palmatier MI, Caggiula AR, Sved AF, Donny EC (2012) Varenicline dose dependently enhances responding for nonpharmacological reinforcers and attenuates the reinforcement-enhancing effects of nicotine. Nicotine Tob Res 14:299–305PubMedCentralPubMedGoogle Scholar
  102. Li S, Zou S, Coen K, Funk D, Shram MJ, Le AD (2014) Sex differences in yohimbine-induced increases in the reinforcing efficacy of nicotine in adolescent rats. Addict Biol 19:156–164PubMedGoogle Scholar
  103. Liu X, Caggiula AR, Yee SK, Nobuta H, Sved AF, Pechnick RN, Poland RE (2007) Mecamylamine attenuates cue-induced reinstatement of nicotine-seeking behavior in rats. Neuropsychopharmacology 32:710–718PubMedCentralPubMedGoogle Scholar
  104. 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 196:365–375PubMedCentralPubMedGoogle Scholar
  105. Liu X, Jernigen C, Gharib M, Booth S, Caggiula AR, Sved AF (2010) Effects of dopamine antagonists on drug cue-induced reinstatement of nicotine-seeking behavior in rats. Behav Pharmacol 21:153–160PubMedCentralPubMedGoogle Scholar
  106. Loftipour Arnold SMM, Hogenkamp DJ, Gee KW, Belluzzi JD, Leslie FM (2011) The monoamine oxidase (MAO) inhibitor tranylcypromine enhances nicotine self-administration in rats through a mechanism independent of MAO inhibition. Neuropharm 61:95–104Google Scholar
  107. Lynch WJ (2006) Sex differences in vulnerability to drug self-administration. Exp Clin Psychopharmacol 14:34–41PubMedGoogle Scholar
  108. Lynch WJ (2009) Sex and ovarian hormones influence vulnerability and motivation for nicotine during adolescence in rats. Pharmacol Biochem Behav 94:43–50PubMedCentralPubMedGoogle Scholar
  109. Lynch WJ, Roth ME, Carroll ME (2002) Biological basis of sex differences in drug abuse: preclinical and clinical studies. Psychopharmacology 164:121–137PubMedGoogle Scholar
  110. Markou A, Paterson NE (2009) Multiple motivational forces contribute to nicotine dependence. In: Bevins RA, Caggiula AR (eds) Nebraska Symposium on Motivation: The motivational impact of nicotine and its role in tobacco use, vol 55. Springer Science + Business Media, New York, pp 65–89Google Scholar
  111. Matta SG, Balfour DJ, Benowitz NL, Boyd RT, Buccafusco JJ, Caggiula AR, Zirger JM (2007) Guidelines on nicotine dose selection for in vivo research. Psychopharmacology 190:269–319PubMedGoogle Scholar
  112. McColl S, Sellers EM (2006) Research design strategies to evaluate the impact of formulations on abuse liability. Drug Alcohol Depend 83(Suppl. 1):S52–S62PubMedGoogle Scholar
  113. McKee SA, Maciejewski PK, Falba T, Mazure CM (2003) Sex differences in the effects of stressful life events on changes in smoking status. Addiction 98:847–855PubMedGoogle Scholar
  114. Melis M, Enrico P, Peana AT, Diana M (2007) Acetaldehyde mediates alcohol activation of the mesolimbic dopamine system. Eur J Neurosci 26:2824–2833PubMedGoogle Scholar
  115. Mello NK, Fivel PA, Kohut SJ, Caine SB (2014) Anatabine significantly decreases nicotine self-administration. Exp Clin Psychopharmacol 22:1–8Google Scholar
  116. Meyer PJ, Ma ST, Robinson TE (2011) 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 219:999–1009PubMedCentralPubMedGoogle Scholar
  117. Myers WD, Ng KT, Singer G (1982) Intravenous self-administration of acetaldehyde in the rat as a function of schedule, food deprivation and photoperiod. Pharmacol Biochem Behav 17:807–811PubMedGoogle Scholar
  118. Myers WD, Ng KT, Singer G (1984a) Effects of naloxone and buprenorphine on intravenous acetaldehyde self-injection in rats. Physiol Behav 33:449–455PubMedGoogle Scholar
  119. Myers W, Ng K, Singer G (1984b) Ethanol preference in rats with a prior history of acetaldehyde self-administration. Cell Mol Life Sci 40:1008–1010Google Scholar
  120. Natividad LA, Torres OV, Friedman TC, O’Dell LE (2013) Adolescence is a period of development characterized by short-and long-term vulnerability to the rewarding effects of nicotine and reduced sensitivity to the anorectic effects of this drug. Behav Brain Res 257:275–285PubMedCentralPubMedGoogle Scholar
  121. O’Dell LE, Torres OV (2014) A mechanistic hypothesis of the factors that enhance vulnerability to nicotine use in females. Neuropharmacology 76:566–580PubMedGoogle Scholar
  122. O’Dell LE, Chen SA, Smith RT, Specio SE, Balster RL, Paterson NE, Koob GF (2007) Extended access to nicotine self-administration leads to dependence: Circadian measures, withdrawal measures, and extinction behavior in rats. J Pharmacol Exp Ther 320:180–193PubMedGoogle Scholar
  123. O’Hara P, Portser SA, Anderson BP (1989) The influence of menstrual cycle changes on the tobacco withdrawal syndrome in women. Addict Behav 14:595–600PubMedGoogle Scholar
  124. Palmatier MI, Evans-Martin FF, Hoffman A, Caggiula AR, Chaudhri N, Donny EC, 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 184:391–400PubMedGoogle Scholar
  125. Palmatier MI, Liu X, Matteson GL, Donny EC, Caggiula AR, Sved AF (2007) Conditioned reinforcement in rats established with self-administered nicotine and enhanced by noncontingent nicotine. Psychopharmacology 195:235–243PubMedCentralPubMedGoogle Scholar
  126. Palmatier MI, Liu X, Donny EC, Caggiula AR, Sved AF (2008) Metabotropic glutamate five receptor (mGluR5) antagonists decrease nicotine seeking, but do not affect the reinforcement enhancing effects of nicotine. Neuropsychopharmacology 33:2139–2147PubMedCentralPubMedGoogle Scholar
  127. Palmatier MI, Levin ME, Mays KL, Donny EC, Caggiula AR, Sved AF (2009) Bupropion and nicotine enhance responding for nondrug reinforcers via dissociable pharmacological mechanisms in rats. Psychopharmacology 207:381–390PubMedCentralPubMedGoogle Scholar
  128. Palmatier MI, O’Brien LC, Hall MJ (2012) The role of conditioning history and reinforcer strength in the reinforcement enhancing effects of nicotine in rats. Psychopharmacology 219:1119–1131Google Scholar
  129. Paterson NE, Markou A (2004) Prolonged nicotine dependence associated with extended access to nicotine self-administration in rats. Psychopharmacology 173:64–72PubMedGoogle Scholar
  130. Pavlov IP (1927) Conditioned reflexes. An investigation of the physiological activity of the cerebral cortex. Oxford University Press, OxfordGoogle Scholar
  131. Peana AT, Enrico P, Assaretti AR, Pulighe E, Muggironi G, Nieddu M, Piga A, Lintas A, Diana M (2008) Key role of ethanol-derived acetaldehyde in the motivational properties induced by intragastric ethanol: a conditioned place preference study in the rat. Alcohol Clin Exp Res 32:249–258PubMedGoogle Scholar
  132. Peana AT, Muggironi G, Diana M (2010) Acetaldehyde-reinforcing effects: a study on oral self-administration behavior. Frontiers in Psychiatry 1:23PubMedCentralPubMedGoogle Scholar
  133. Peana AT, Muggironi G, Fois GR, Zinellu M, Vinci S, Acquas E (2011) Effect of opioid receptor blockade on acetaldehyde self-administration and ERK phosphorylation in the rat nucleus accumbens. Alcohol 45:773–783PubMedGoogle Scholar
  134. Peartree NA, Sanabria F, Thiel KJ, Weber SM, Cheung TH, Neisewander JL (2012) A new criterion for acquisition of nicotine self-administration in rats. Drug Alcohol Depend 124:63–69PubMedCentralPubMedGoogle Scholar
  135. Perkins KA (2009) Does smoking cue‐induced craving tell us anything important about nicotine dependence? Addiction 104:1610–1616Google Scholar
  136. Perkins KA (2009) Sex differences in nicotine reinforcement and reward: influences on the persistence of tobacco smoking. Nebr Symp Motiv 55:143–169PubMedGoogle Scholar
  137. Perkins KA, Sexton JE, Reynolds WA, Grobe JE, Fonte C, Stiller RL (1994) Comparison of acute subjective and heart rate effects of nicotine intake via tobacco smoking versus nasal spray. Pharmacol Biochem Behav 47:295–299Google Scholar
  138. Perkins KA, Karelitz JL (2013a) Influence of reinforcer magnitude and nicotine amount on smoking’s acute reinforcement enhancing effects. Drug Alcohol Depend 133:167–171PubMedCentralPubMedGoogle Scholar
  139. Perkins KA, Karelitz JL (2013b) Reinforcement enhancing effects of nicotine via smoking. Psychopharmacology 228:479–486PubMedCentralPubMedGoogle Scholar
  140. Perkins KA, Donny E, Caggiula AR (1999) Sex differences in nicotine effects and self-administration: review of human and animal evidence. Nicotine Tob Res 1:301–315PubMedGoogle Scholar
  141. Perkins KA, Gerlach D, Vender J, Meeker J, Hutchison S, Grobe J (2001) Sex differences in the subjective and reinforcing effects of visual and olfactory cigarette smoke stimuli. Nicotine Tob Res 3:141–150PubMedGoogle Scholar
  142. Perkins KA, Jacobs L, Sanders M, Caggiula AR (2002) Sex differences in the subjective and reinforcing effects of cigarette nicotine dose. Psychopharmacology 163:194–201PubMedGoogle Scholar
  143. Perkins KA, Karelitz JL, Giedgowd GE, Conklin CA (2013) Negative mood effects on craving to smoke in women versus men. Addict Behav 38:1527–1531PubMedCentralPubMedGoogle Scholar
  144. Picciotto MR, Caldarone BJ, Brunzell DH, Zachariou V, Stevens TR, King SL (2001) Neuronal nicotinic acetylcholine receptor subunit knockout mice: physiological and behavioral phenotypes and possible clinical implications. Pharmacol Ther 92:89–108PubMedGoogle Scholar
  145. Quertemont E, De Witte P (2001) Conditioned stimulus preference after acetaldehyde but not ethanol injections. Pharmacol Biochem Behav 68:449–454PubMedGoogle Scholar
  146. Rescorla RA, Solomon RL (1967) Two-process learning theory: relationships between Pavlovian conditioning and instrumental learning. Psychol Rev 74:151–182PubMedGoogle Scholar
  147. Robbins TW, Koob GF (1978) Pipradrol enhances reinforcing properties of stimuli paired with brain stimulation. Pharmacol Biochem Behav 8:219–222PubMedGoogle Scholar
  148. Robinson TE, Berridge KC (2000) The psychology and neurobiology of addiction: an incentive-sensitization view. Addiction 95:S91–S117PubMedGoogle Scholar
  149. Robinson TE, Yager LM, Cogan ES, Saunders BT (2014) On the motivational properties of reward cues: individual differences. Neuropharmacology 76:450–459PubMedGoogle Scholar
  150. Rodd-Henricks ZA, Melendez RI, Zaffaroni A, Goldstein A, McBride WJ, Li T-K (2002) The reinforcing effects of acetaldehyde in the posterior ventral tegmental area of alcohol-preferring rats. Pharmacol Biochem Behav 72:55–64PubMedGoogle Scholar
  151. Rose JE, Behm FM, Westman EC, Coleman RE (1999) Arterial nicotine kinetics during cigarette smoking and intravenous nicotine administration: implications for addiction. Drug Alcohol Depend 56:99–107PubMedGoogle Scholar
  152. Rose JE, Behm FM, Westman EC, Johnson M (2000) Dissociating nicotine and nonnicotine components of cigarette smoking. Pharmacol Biochem Behav 67:71–81PubMedGoogle Scholar
  153. Russell MAH, Feyerabend C (1978) Cigarette smoking: a dependence on high-nicotine boli. Drug Metab Rev 8:29–57PubMedGoogle Scholar
  154. Russell JC, Epling WF, Pierce D, Amy RM, Boer DP (1987) Induction of voluntary prolonged running by rats. J Appl Physiol 63:2549–2553PubMedGoogle Scholar
  155. Samaha A-N, Robinson TE (2005) Why does the rapid delivery of drugs to the brain promote addiction? Trends Pharmacol Sci 26:82–87PubMedGoogle Scholar
  156. Saunders BT, Robinson TE (2011) Individual variation in the motivational properties of cocaine. Neuropsychopharmacology 36:1668–1676PubMedCentralPubMedGoogle Scholar
  157. Sayette MA, Tiffany ST (2013) Peak-provoked craving deserves a seat at the research table. Addiction 108:1030–1031PubMedGoogle Scholar
  158. Schassburger RL, Rupprecht LE, Smith TT, Buffalari DM, Thiels E, Donny EC, Sved AF (2013) Nicotine enhances the rewarding properties of sucrose. Paper presented at the Society for Neuroscience, San Diego, CaliforniaGoogle Scholar
  159. Schnoll RA, Patterson F, Lerman C (2007) Treating tobacco dependence in women. J Women’s Health 16:1211–1218Google Scholar
  160. Shram MJ, Funk D, Li Z, Lê AD (2008a) Nicotine self-administration, extinction responding and reinstatement in adolescent and adult male rats: evidence against a biological vulnerability to nicotine addiction during adolescence. Neuropsychopharmacology 33:739–748PubMedGoogle Scholar
  161. Shram MJ, Li Z, Lê AD (2008b) Age differences in the spontaneous acquisition of nicotine self-administration in male Wistar and Long-Evans rats. Psychopharmacology 197:45–58PubMedGoogle Scholar
  162. Siegel S (1988) Drug anticipation and the treatment of dependence. NIDA Res Monogr 84:1–24PubMedGoogle Scholar
  163. Singer G, Simpson F, Lang WJ (1978) Schedule induced self injections of nicotine with recovered body weight. Pharmacol Biochem Behav 9:387–389PubMedGoogle Scholar
  164. Skinner BF (1953) Science and Human Behavior. Macmillan, New YorkGoogle Scholar
  165. Smith B, Amit Z, Splawinsky J (1984) Conditioned place preference induced by intraventricular infusions of acetaldehyde. Alcohol 1:193–195PubMedGoogle Scholar
  166. Smith TT, Levin ME, Schassburger RL, Buffalari DM, Sved AF, Donny EC (2013) Gradual and immediate nicotine reduction result in similar low-dose nicotine self-administration. Nicotine Tob Res 15:1918–1925PubMedCentralPubMedGoogle Scholar
  167. Smith TT, Schassburgher RL, Rupprecht LE, Buffalari DM, Sved AF, Donny EC (2014a) Effects of tranylcypromine, an irreversible monoamine oxidase (MAO) inhibitor, on nicotine self-administration in rats. Paper presentation at the annual meeting of the association for behavior analysis international, Chicago, IllinoisGoogle Scholar
  168. Smith TT, Schassburger RL, Buffalari DM, Sved AF, Donny EC (2014b) Low dose nicotine self-administration is reduced in adult male rats naïve to high doses of nicotine: implications for nicotine product standards. Exp Clin Psychopharmacol.
  169. Sofuoglu M, Yoo S, Hill KP, Mooney M (2008) Self-administration of intravenous nicotine in male and female cigarette smokers. Neuropsychopharmacology 33:715–720PubMedGoogle Scholar
  170. Sorge RE, Clarke PB (2009) Rats self-administer intravenous nicotine delivered in a novel smoking-relevant procedure: effects of dopamine antagonists. J Pharmacol Exp Ther 330:633–640PubMedGoogle Scholar
  171. Sorge RE, Pierre VJ, Clarke PB (2009) Facilitation of intravenous nicotine self-administration in rats by a motivationally neutral sensory stimulus. Psychopharmacology 207:191–200PubMedGoogle Scholar
  172. Speakman JR, Mitchel SE (2011) Caloric Restriction. Mol Aspects Med 32:159–221PubMedGoogle Scholar
  173. Spear LP (2000) The adolescent brain and age-related behavioral manifestations. Neurosci Biobehav Rev 24:417–463PubMedGoogle Scholar
  174. Spina L, Longoni R, Vinci S, Ibba F, Peana AT, Muggironi G, Spiga S, Acquas E (2010) Role of dopamine D1 receptors and extracellular signal regulated kinase in the motivational properties of acetaldehyde as assessed by place preference conditioning. Alcohol Clin Exp Res 34:607–616PubMedGoogle Scholar
  175. Stolerman IP (1989) Discriminative stimulus effects of nicotine in rats trained under different schedules of reinforcement. Psychopharmacology 97:131–138Google Scholar
  176. Stolerman IP (1999) Inter-species consistency in the behavioural pharmacology of nicotine dependence. Behav Pharmacol 10:559–580PubMedGoogle Scholar
  177. Stolerman IP, Jarvis M (1995) The scientific case that nicotine is addictive. Psychopharmacology 117:2–10PubMedGoogle Scholar
  178. Takayama S, Uyeno E (1985) Intravenous self-administration of ethanol and acetaldehyde by rats. Japan J Psychopharmacol 5:329–334Google Scholar
  179. Tiffany ST (1990) A cognitive model of drug urges and drug-use behavior: role of automatic and nonautomatic processes. Psychol Rev 97:147–168PubMedGoogle Scholar
  180. Torres OV, Tejeda HA, Natividad LA, O’Dell LE (2008) Enhanced vulnerability to the rewarding effects of nicotine during the adolescent period of development. Pharmacol Biochem Behav 90:658–663PubMedCentralPubMedGoogle Scholar
  181. USDHHS (1988) Office of the Surgeon General DHHS Publication no. (CDC): 88-8406.0. The health consequences of smoking: nicotine addiction: a report of the surgeon general. Center for Health Promotion and Education. Office on Smoking and Health United States. Public Health ServiceGoogle Scholar
  182. USDHHS (2012) Preventing tobacco use among youth and young adults: a report of the Surgeon General. US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, Atlanta, GA, 3Google Scholar
  183. Vastola BJ, Douglas LA, Varlinskaya EI, Spear LP (2002) Nicotine-induced conditioned place preference in adolescent and adult rats. Physiol Behav 77:107–114PubMedGoogle Scholar
  184. Villegier AS, Lotfipour S, Belluzzi JD, Leslie FM (2007a) Involvement of alpha1-adrenergic receptors in tranylcypromine enhancement of nicotine self-administration in rat. Psychopharmacology 193:457–465PubMedGoogle Scholar
  185. Villegier AS, Lotfipour S, McQuown SC, Belluzzi JD, Leslie FM (2007b) Tranylcypromine enhancement of nicotine self-administration. Neuropharmacology 52:1415–1425PubMedGoogle Scholar
  186. Wakasa Y, Takada K, Yanagita T (1995) Reinforcing effect as a function of infusion speed in intravenous self-administration of nicotine in rhesus monkeys. Japan J Psychopharmacol 15:53–59Google Scholar
  187. Wertz JM, Sayette MA (2001) A review of the effects of perceived drug use opportunity of self-reported urge. Exp Clin Psychopharmacol 9:3–13PubMedCentralPubMedGoogle Scholar
  188. Wing VC, Shoaib M (2008) Contextual stimuli modulate extinction and reinstatement in rodents self-administering intravenous nicotine. Psychopharmacology 200:357–365PubMedGoogle Scholar
  189. Wing VC, Shoaib M (2013) Effect of infusion rate on intravenous nicotine self-administration in rats. Behav Pharmacol 24:517–522PubMedGoogle Scholar
  190. Wray JM, Godleski SA, Tiffany ST (2011) Cue-reactivity in the natural environment of cigarette smokers: the impact of photographic and in vivo smoking stimuli. Psychol Addict Behav 25:733–737PubMedCentralPubMedGoogle Scholar
  191. Xie J, Yin J, Sun S, Xie F, Zhang X, Guo Y (2009) Extraction and derivatization in single drop coupled to MALDI-FTICR-MS for selective determination of small molecule aldehydes in single puff smoke. Anal Chim Acta 638:198–201PubMedGoogle Scholar
  192. Xu J, Azizian A, Monterosso J, Domier CP, Brody AL, London ED, Fong TW (2008) Gender effects on mood and cigarette craving during early abstinence and resumption of smoking. Nicotine Tob Res 10:1653–1661PubMedCentralPubMedGoogle Scholar
  193. 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 214:30–34PubMedCentralPubMedGoogle Scholar
  194. Yan Y, Pushparaj A, Gamaleddin I, Steiner RC, Picciotto MR, Roder J, Le Foll B (2012) Nicotine-taking and nicotine-seeking in C57Bl/6 J mice without prior operant training or food restriction. Behav Brain Res 230:34–39PubMedCentralPubMedGoogle Scholar
  195. Zou S, Funk D, Shram MJ, Le AD (2014) Effects of stressors on the reinforcing efficacy of nicotine in adolescent and adult rats. Psychopharmacology 231:1601–1614PubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Department of NeuroscienceUniversity of PittsburghPittsburghUSA
  2. 2.Department of PsychologyUniversity of PittsburghPittsburghUSA

Personalised recommendations