Psychopharmacology

, Volume 208, Issue 1, pp 143–158 | Cite as

Tobacco smoke exposure induces nicotine dependence in rats

  • Elysia Small
  • Hina P. Shah
  • Jake J. Davenport
  • Jacqueline E. Geier
  • Kate R. Yavarovich
  • Hidetaka Yamada
  • Sreedharan N. Sabarinath
  • Hartmut Derendorf
  • James R. Pauly
  • Mark S. Gold
  • Adrie W. Bruijnzeel
Original Investigation

Abstract

Rationale

Tobacco smoke contains nicotine and many other compounds that act in concert on the brain reward system. Therefore, animal models are needed that allow the investigation of chronic exposure to the full spectrum of tobacco smoke constituents.

Objectives

The aim of these studies was to investigate if exposure to tobacco smoke leads to nicotine dependence in rats.

Methods

The intracranial self-stimulation procedure was used to assess the negative affective aspects of nicotine withdrawal. Somatic signs were recorded from a checklist of nicotine abstinence signs. Nicotine self-administration sessions were conducted to investigate if tobacco smoke exposure affects the motivation to self-administer nicotine. Nicotinic receptor autoradiography was used to investigate if exposure to tobacco smoke affects central α7 nicotinic acetylcholine receptor (nAChR) and non-α7 nAChR levels (primarily α4β2 nAChRs).

Results

The nAChR antagonist mecamylamine dose-dependently elevated the brain reward thresholds of the rats exposed to tobacco smoke and did not affect the brain reward thresholds of the untreated control rats. Furthermore, mecamylamine induced more somatic withdrawal signs in the smoke-exposed rats than in the control rats. Nicotine self-administration was decreased 1 day after the last tobacco smoke exposure sessions and was returned to control levels 5 days later. Tobacco smoke exposure increased the α7 nAChR density in the CA2/3 area and the stratum oriens and increased the non-α7 nAChR density in the dentate gyrus.

Conclusion

Tobacco smoke exposure leads to nicotine dependence as indicated by precipitated affective and somatic withdrawal signs and induces an upregulation of nAChRs in the hippocampus.

Keywords

Tobacco Nicotine Dependence Withdrawal Rats 

References

  1. American Psychiatric Association (2000) Diagnostic and statistical manual of mental disorders, 4th edn. American Psychiatric Press, Washington Text revision editionGoogle Scholar
  2. Anderson KL, Pinkerton KE, Uyeminami D, Simons CT, Carstens MI, Carstens E (2004) Antinociception induced by chronic exposure of rats to cigarette smoke. Neurosci Lett 366:86–91CrossRefPubMedGoogle Scholar
  3. Aricioglu F, Altunbas H (2003) Harmane induces anxiolysis and antidepressant-like effects in rats. Ann NY Acad Sci 1009:196–201CrossRefPubMedGoogle Scholar
  4. Bardo MT, Green TA, Crooks PA, Dwoskin LP (1999) Nornicotine is self-administered intravenously by rats. Psychopharmacology (Berl) 146:290–296CrossRefGoogle Scholar
  5. Belluzzi JD, Wang R, Leslie FM (2005) Acetaldehyde enhances acquisition of nicotine self-administration in adolescent rats. Neuropsychopharmacology 30:705–712CrossRefPubMedGoogle Scholar
  6. Benowitz NL (1988) Drug therapy. Pharmacologic aspects of cigarette smoking and nicotine addition. N Engl J Med 319:1318–1330PubMedCrossRefGoogle Scholar
  7. Benwell ME, Balfour DJ, Anderson JM (1988) Evidence that tobacco smoking increases the density of (−)-[3H]nicotine binding sites in human brain. J Neurochem 50:1243–1247CrossRefPubMedGoogle Scholar
  8. Breese CR, Adams C, Logel J, Drebing C, Rollins Y, Barnhart M, Sullivan B, Demasters BK, Freedman R, Leonard S (1997) Comparison of the regional expression of nicotinic acetylcholine receptor alpha7 mRNA and [125I]-alpha-bungarotoxin binding in human postmortem brain. J Comp Neurol 387:385–398CrossRefPubMedGoogle Scholar
  9. Breese CR, Lee MJ, Adams CE, Sullivan B, Logel J, Gillen KM, Marks MJ, Collins AC, Leonard S (2000) Abnormal regulation of high affinity nicotinic receptors in subjects with schizophrenia. Neuropsychopharmacology 23:351–364CrossRefPubMedGoogle Scholar
  10. Brown ZW, Amit Z, Rockman GE (1979) Intraventricular self-administration of acetaldehyde, but not ethanol, in naive laboratory rats. Psychopharmacology (Berl) 64:271–276CrossRefGoogle Scholar
  11. Bruijnzeel AW, Markou A (2003) Characterization of the effects of bupropion on the reinforcing properties of nicotine and food in rats. Synapse 50:20–28CrossRefPubMedGoogle Scholar
  12. Bruijnzeel AW, Markou A (2004) Adaptations in cholinergic transmission in the ventral tegmental area associated with the affective signs of nicotine withdrawal in rats. Neuropharmacology 47:572–579CrossRefPubMedGoogle Scholar
  13. Bruijnzeel AW, Lewis B, Bajpai LK, Morey TE, Dennis DM, Gold M (2006) Severe deficit in brain reward function associated with fentanyl withdrawal in rats. Biol Psychiatry 59:477–480CrossRefPubMedGoogle Scholar
  14. Bruijnzeel AW, Zislis G, Wilson C, Gold MS (2007) Antagonism of CRF receptors prevents the deficit in brain reward function associated with precipitated nicotine withdrawal in rats. Neuropsychopharmacology 32:955–963CrossRefPubMedGoogle Scholar
  15. Coen KM, Adamson KL, Corrigall WA (2009) Medication-related pharmacological manipulations of nicotine self-administration in the rat maintained on fixed- and progressive-ratio schedules of reinforcement. Psychopharmacology (Berl) 201:557–568CrossRefGoogle Scholar
  16. Corrigall WA, Coen KM (1989) Nicotine maintains robust self-administration in rats on a limited-access schedule. Psychopharmacology (Berl) 99:473–478CrossRefGoogle Scholar
  17. Corrigall WA, Coen KM, Adamson KL (1994) Self-administered nicotine activates the mesolimbic dopamine system through the ventral tegmental area. Brain Res 653:278–284CrossRefPubMedGoogle Scholar
  18. Crooks PA, Dwoskin LP (1997) Contribution of CNS nicotine metabolites to the neuropharmacological effects of nicotine and tobacco smoking. Biochem Pharmacol 54:743–753CrossRefPubMedGoogle Scholar
  19. Cryan JF, Bruijnzeel AW, Skjei KL, Markou A (2003) Bupropion enhances brain reward function and reverses the affective and somatic aspects of nicotine withdrawal in the rat. Psychopharmacology (Berl) 168:347–358CrossRefGoogle Scholar
  20. Dani JA, Heinemann S (1996) Molecular and cellular aspects of nicotine abuse. Neuron 16:905–908CrossRefPubMedGoogle Scholar
  21. Debruyne D, Sobrio F, Hinschberger A, Camsonne R, Coquerel A, Barre L (2003) Short-term pharmacokinetics and brain distribution of mecamylamine as a preliminary to carbon-11 labeling for nicotinic receptor investigation. J Pharm Sci 92:1051–1057CrossRefPubMedGoogle Scholar
  22. Donny EC, Caggiula AR, Mielke MM, Booth S, Gharib MA, Hoffman A, Maldovan V, Shupenko C, McCallum SE (1999) Nicotine self-administration in rats on a progressive ratio schedule of reinforcement. Psychopharmacology (Berl) 147:135–142CrossRefGoogle Scholar
  23. Eisenberg MJ, Filion KB, Yavin D, Belisle P, Mottillo S, Joseph L, Gervais A, O'Loughlin J, Paradis G, Rinfret S, Pilote L (2008) Pharmacotherapies for smoking cessation: a meta-analysis of randomized controlled trials. CMAJ 179:135–144PubMedGoogle Scholar
  24. Epping-Jordan MP, Watkins SS, Koob GF, Markou A (1998) Dramatic decreases in brain reward function during nicotine withdrawal. Nature 393:76–79CrossRefPubMedGoogle Scholar
  25. Farzin D, Mansouri N (2006) Antidepressant-like effect of harmane and other beta-carbolines in the mouse forced swim test. Eur Neuropsychopharmacol 16:324–328CrossRefPubMedGoogle Scholar
  26. Foulds J, Stapleton JA, Bell N, Swettenham J, Jarvis MJ, Russell MA (1997) Mood and physiological effects of subcutaneous nicotine in smokers and never-smokers. Drug Alcohol Depend 44:105–115CrossRefPubMedGoogle Scholar
  27. Fowler JS, Volkow ND, Wang GJ, Pappas N, Logan J, Shea C, Alexoff D, MacGregor RR, Schlyer DJ, Zezulkova I, Wolf AP (1996) Brain monoamine oxidase A inhibition in cigarette smokers. Proc Natl Acad Sci USA 93:14065–14069CrossRefPubMedGoogle Scholar
  28. Fowler JS, Volkow ND, Wang GJ, Pappas N, Logan J, MacGregor R, Alexoff D, Wolf AP, Warner D, Cilento R, Zezulkova I (1998) Neuropharmacological actions of cigarette smoke: brain monoamine oxidase B (MAO B) inhibition. J Addict Dis 17:23–34CrossRefPubMedGoogle Scholar
  29. Fowler JS, Logan J, Wang GJ, Volkow ND (2003) Monoamine oxidase and cigarette smoking. Neurotoxicology 24:75–82CrossRefPubMedGoogle Scholar
  30. Ghosheh O, Dwoskin LP, Li WK, Crooks PA (1999) Residence times and half-lives of nicotine metabolites in rat brain after acute peripheral administration of [2'-(14)C]nicotine. Drug Metab Dispos 27:1448–1455PubMedGoogle Scholar
  31. Grunberg NE (1985) Nicotine, cigarette smoking, and body weight. Br J Addict 80:369–377CrossRefPubMedGoogle Scholar
  32. Grunberg NE, Bowen DJ, Morse DE (1984) Effects of nicotine on body weight and food consumption in rats. Psychopharmacology (Berl) 83:93–98CrossRefGoogle Scholar
  33. Harrison AA, Parsons LH, Koob GF, Markou A (1999) RU 24969, a 5-HT1A/1B agonist, elevates brain stimulation reward thresholds: an effect reversed by GR 127935, a 5-HT1B/1D antagonist. Psychopharmacology (Berl) 141:242–250CrossRefGoogle Scholar
  34. Harrison AA, Liem YT, Markou A (2001) Fluoxetine combined with a serotonin-1A receptor antagonist reversed reward deficits observed during nicotine and amphetamine withdrawal in rats. Neuropsychopharmacology 25:55–71CrossRefPubMedGoogle Scholar
  35. Harrison AA, Gasparini F, Markou A (2002) Nicotine potentiation of brain stimulation reward reversed by DH beta E and SCH 23390, but not by eticlopride, LY 314582 or MPEP in rats. Psychopharmacology (Berl) 160:56–66CrossRefGoogle Scholar
  36. Herraiz T, Chaparro C (2005) Human monoamine oxidase is inhibited by tobacco smoke: beta-carboline alkaloids act as potent and reversible inhibitors. Biochem Biophys Res Commun 326:378–386CrossRefPubMedGoogle Scholar
  37. Houghtling RA, Davila-Garcia MI, Kellar KJ (1995) Characterization of (+/−)(−)[3H]epibatidine binding to nicotinic cholinergic receptors in rat and human brain. Mol Pharmacol 48:280–287PubMedGoogle Scholar
  38. Kem WR, Mahnir VM, Papke RL, Lingle CJ (1997) Anabaseine is a potent agonist on muscle and neuronal alpha-bungarotoxin-sensitive nicotinic receptors. J Pharmacol Exp Ther 283:979–992PubMedGoogle Scholar
  39. Kenny PJ, Paterson NE, Boutrel B, Semenova S, Harrison AA, Gasparini F, Koob GF, Skoubis PD, Markou A (2003) Metabotropic glutamate 5 receptor antagonist MPEP decreased nicotine and cocaine self-administration but not nicotine and cocaine-induced facilitation of brain reward function in rats. Ann NY Acad Sci 1003:415–418CrossRefPubMedGoogle Scholar
  40. Kornetsky C, Esposito RU (1979) Euphorigenic drugs: effects on the reward pathways of the brain. Fed Proc 38:2473–2476PubMedGoogle Scholar
  41. Kyerematen GA, Taylor LH, deBethizy JD, Vesell ES (1988) Pharmacokinetics of nicotine and 12 metabolites in the rat. Application of a new radiometric high performance liquid chromatography assay. Drug Metab Dispos 16:125–129PubMedGoogle Scholar
  42. Lawson GM, Hurt RD, Dale LC, Offord KP, Croghan IT, Schroeder DR, Jiang NS (1998) Application of serum nicotine and plasma cotinine concentrations to assessment of nicotine replacement in light, moderate, and heavy smokers undergoing transdermal therapy. J Clin Pharmacol 38:502–509PubMedGoogle Scholar
  43. Maciuk A, Moaddel R, Haginaka J, Wainer IW (2008) Screening of tobacco smoke condensate for nicotinic acetylcholine receptor ligands using cellular membrane affinity chromatography columns and missing peak chromatography. J Pharm Biomed Anal 48:238–246CrossRefPubMedGoogle Scholar
  44. Malin DH, Lake JR, Newlin-Maultsby P, Roberts LK, Lanier JG, Carter VA, Cunningham JS, Wilson OB (1992) Rodent model of nicotine abstinence syndrome. Pharmacol Biochem Behav 43:779–784CrossRefPubMedGoogle Scholar
  45. Markou A, Koob GF (1992) Construct validity of a self-stimulation threshold paradigm: effects of reward and performance manipulations. Physiol Behav 51:111–119CrossRefPubMedGoogle Scholar
  46. Marks MJ, Burch JB, Collins AC (1983) Effects of chronic nicotine infusion on tolerance development and nicotinic receptors. J Pharmacol Exp Ther 226:817–825PubMedGoogle Scholar
  47. McGehee DS, Role LW (1995) Physiological diversity of nicotinic acetylcholine receptors expressed by vertebrate neurons. Annu Rev Physiol 57:521–546CrossRefPubMedGoogle Scholar
  48. Mineur YS, Picciotto MR (2008) Genetics of nicotinic acetylcholine receptors: relevance to nicotine addiction. Biochem Pharmacol 75:323–333CrossRefPubMedGoogle Scholar
  49. Molinari EJ, Delbono O, Messi ML, Renganathan M, Arneric SP, Sullivan JP, Gopalakrishnan M (1998) Up-regulation of human alpha7 nicotinic receptors by chronic treatment with activator and antagonist ligands. Eur J Pharmacol 347:131–139CrossRefPubMedGoogle Scholar
  50. 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 17:807–811CrossRefPubMedGoogle Scholar
  51. Nguyen HN, Rasmussen BA, Perry DC (2003) Subtype-selective up-regulation by chronic nicotine of high-affinity nicotinic receptors in rat brain demonstrated by receptor autoradiography. J Pharmacol Exp Ther 307:1090–1097CrossRefPubMedGoogle Scholar
  52. O'Dell LE, Bruijnzeel AW, Smith RT, Parsons LH, Merves ML, Goldberger BA, Richardson HN, Koob GF, Markou A (2006) Diminished nicotine withdrawal in adolescent rats: implications for vulnerability to addiction. Psychopharmacology (Berl) 186:612–619CrossRefGoogle Scholar
  53. Okoli CT, Kelly T, Hahn EJ (2007) Secondhand smoke and nicotine exposure: a brief review. Addict Behav 32:1977–1988CrossRefPubMedGoogle Scholar
  54. Paterson NE, Myers C, Markou A (2000) Effects of repeated withdrawal from continuous amphetamine administration on brain reward function in rats. Psychopharmacology (Berl) 152:440–446CrossRefGoogle Scholar
  55. Pauly JR, Marks MJ, Gross SD, Collins AC (1991) An autoradiographic analysis of cholinergic receptors in mouse brain after chronic nicotine treatment. J Pharmacol Exp Ther 258:1127–1136PubMedGoogle Scholar
  56. Perkins KA, Grobe JE, Caggiula A, Wilson AS, Stiller RL (1997) Acute reinforcing effects of low-dose nicotine nasal spray in humans. Pharmacol Biochem Behav 56:235–241CrossRefPubMedGoogle Scholar
  57. Perry DC, Kellar KJ (1995) [3H]epibatidine labels nicotinic receptors in rat brain: an autoradiographic study. J Pharmacol Exp Ther 275:1030–1034PubMedGoogle Scholar
  58. Perry DC, Davila-Garcia MI, Stockmeier CA, Kellar KJ (1999) Increased nicotinic receptors in brains from smokers: membrane binding and autoradiography studies. J Pharmacol Exp Ther 289:1545–1552PubMedGoogle Scholar
  59. Rasmussen BA, Perry DC (2006) An autoradiographic analysis of [125I]alpha-bungarotoxin binding in rat brain after chronic nicotine exposure. Neurosci Lett 404:9–14CrossRefPubMedGoogle Scholar
  60. Rylkova D, Boissoneault J, Isaac S, Prado M, Shah HP, Bruijnzeel AW (2008) Effects of NPY and the specific Y1 receptor agonist [D-His(26)]-NPY on the deficit in brain reward function and somatic signs associated with nicotine withdrawal in rats. Neuropeptides 42:215–227CrossRefPubMedGoogle Scholar
  61. Schechter MD, Cook PG (1976) Nicotine-induced weight loss in rats without an effect on appetite. Eur J Pharmacol 38:63–69CrossRefPubMedGoogle Scholar
  62. Schulteis G, Markou A, Cole M, Koob GF (1995) Decreased brain reward produced by ethanol withdrawal. Proc Natl Acad Sci USA 92:5880–5884CrossRefPubMedGoogle Scholar
  63. Schwid SR, Hirvonen MD, Keesey RE (1992) Nicotine effects on body weight: a regulatory perspective. Am J Clin Nutr 55:878–884PubMedGoogle Scholar
  64. Smith BR, Amit Z, Splawinsky J (1984) Conditioned place preference induced by intraventricular infusions of acetaldehyde. Alcohol 1:193–195CrossRefPubMedGoogle Scholar
  65. Smith KR, Pinkerton KE, Watanabe T, Pedersen TL, Ma SJ, Hammock BD (2005) Attenuation of tobacco smoke-induced lung inflammation by treatment with a soluble epoxide hydrolase inhibitor. Proc Natl Acad Sci USA 102:2186–2191CrossRefPubMedGoogle Scholar
  66. Sparks JA, Pauly JR (1999) Effects of continuous oral nicotine administration on brain nicotinic receptors and responsiveness to nicotine in C57Bl/6 mice. Psychopharmacology (Berl) 141:145–153CrossRefGoogle Scholar
  67. Stolerman IP, Jarvis MJ (1995) The scientific case that nicotine is addictive. Psychopharmacology (Berl) 117:2–10CrossRefGoogle Scholar
  68. Talhout R, Opperhuizen A, van Amsterdam JG (2007) Role of acetaldehyde in tobacco smoke addiction. Eur Neuropsychopharmacol 17:627–636CrossRefPubMedGoogle Scholar
  69. Teague SV, Pinkerton KE, Goldsmith M, Gebremichael A, Chang S, Jenkins RA, Moneyhun JH (1994) A sidestream cigarette smoke generation and exposure system for environmental tobacco smoke studies. Inhalation Toxicology 6:79–93CrossRefGoogle Scholar
  70. Totsuka Y, Ushiyama H, Ishihara J, Sinha R, Goto S, Sugimura T, Wakabayashi K (1999) Quantification of the co-mutagenic beta-carbolines, norharman and harman, in cigarette smoke condensates and cooked foods. Cancer Lett 143:139–143CrossRefPubMedGoogle Scholar
  71. Trauth JA, Seidler FJ, Slotkin TA (2000) An animal model of adolescent nicotine exposure: effects on gene expression and macromolecular constituents in rat brain regions. Brain Res 867:29–39CrossRefPubMedGoogle Scholar
  72. Wall MA, Johnson J, Jacob P, Benowitz NL (1988) Cotinine in the serum, saliva, and urine of nonsmokers, passive smokers, and active smokers. Am J Public Health 78:699–701CrossRefPubMedGoogle Scholar
  73. Wall A, Gong ZH, Johnson AE, Meyerson B, Zhang X (2000) Cross-tolerance in drug response and differential changes in central nicotinic and N-methyl-D-aspartate receptor binding following chronic treatment with either (+)- or (−)-nicotine. Psychopharmacology (Berl) 148:186–195CrossRefGoogle Scholar
  74. Watkins SS, Epping-Jordan MP, Koob GF, Markou A (1999) Blockade of nicotine self-administration with nicotinic antagonists in rats. Pharmacol Biochem Behav 62:743–751CrossRefPubMedGoogle Scholar
  75. Wise RA, Munn E (1995) Withdrawal from chronic amphetamine elevates baseline intracranial self-stimulation thresholds. Psychopharmacology (Berl) 117:130–136CrossRefGoogle Scholar
  76. Yates SL, Bencherif M, Fluhler EN, Lippiello PM (1995) Up-regulation of nicotinic acetylcholine receptors following chronic exposure of rats to mainstream cigarette smoke or alpha 4 beta 2 receptors to nicotine. Biochem Pharmacol 50:2001–2008CrossRefPubMedGoogle Scholar
  77. Zhang X, Gong ZH, Nordberg A (1994) Effects of chronic treatment with (+)- and (−)-nicotine on nicotinic acetylcholine receptors and N-methyl-D-aspartate receptors in rat brain. Brain Res 644:32–39CrossRefPubMedGoogle Scholar
  78. Zhang X, Tian JY, Svensson AL, Gong ZH, Meyerson B, Nordberg A (2002) Chronic treatments with tacrine and (−)-nicotine induce different changes of nicotinic and muscarinic acetylcholine receptors in the brain of aged rat. J Neural Transm 109:377–392CrossRefPubMedGoogle Scholar
  79. Zhong CY, Zhou YM, Douglas GC, Witschi H, Pinkerton KE (2005) MAPK/AP-1 signal pathway in tobacco smoke-induced cell proliferation and squamous metaplasia in the lungs of rats. Carcinogenesis 26:2187–2195CrossRefPubMedGoogle Scholar
  80. Zislis G, Desai TV, Prado M, Shah HP, Bruijnzeel AW (2007) Effects of the CRF receptor antagonist D-Phe CRF(12–41) and the alpha2-adrenergic receptor agonist clonidine on stress-induced reinstatement of nicotine-seeking behavior in rats. Neuropharmacology 58:958–966CrossRefGoogle Scholar
  81. Zoli M, Lena C, Picciotto MR, Changeux JP (1998) Identification of four classes of brain nicotinic receptors using beta2 mutant mice. J Neurosci 18:4461–4472PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Elysia Small
    • 1
  • Hina P. Shah
    • 1
  • Jake J. Davenport
    • 1
  • Jacqueline E. Geier
    • 1
  • Kate R. Yavarovich
    • 1
  • Hidetaka Yamada
    • 1
  • Sreedharan N. Sabarinath
    • 2
  • Hartmut Derendorf
    • 2
  • James R. Pauly
    • 3
  • Mark S. Gold
    • 1
  • Adrie W. Bruijnzeel
    • 1
  1. 1.Department of Psychiatry, College of Medicine, McKnight Brain InstituteUniversity of FloridaGainesvilleUSA
  2. 2.Department of Pharmaceutics, College of PharmacyUniversity of FloridaGainesvilleUSA
  3. 3.Department of Pharmaceutical Sciences, College of PharmacyUniversity of KentuckyLexingtonUSA

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