In vivo Brain Imaging of Human Exposure to Nicotine and Tobacco

  • Anil Sharma
  • Arthur L. Brody
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 192)


While most cigarette smokers endorse a desire to quit smoking, only 14–49% will achieve abstinence after 6 months or more of treatment. A greater understanding of the effects of smoking on brain function may result in improved pharmacological and behavioral interventions for this condition. Research groups have examined the effects of acute and chronic nicotine/cigarette exposure on brain activity using functional imaging; the purpose of this chapter is to synthesize findings from such studies and present a coherent model of brain function in smokers. Responses to acute administration of nicotine/smoking include reduced global brain activity; activation of the prefrontal cortex, thalamus, and visual system; activation of the thalamus and visual cortex during visual cognitive tasks; and increased dopamine (DA) concentration in the ventral striatum/nucleus accumbens. Responses to chronic nicotine/cigarette exposure include decreased monoamine ox-idase (MAO) A and B activity in the basal ganglia and a reduction in α4β2 nicotinic acetylcholine receptor (nAChR) availability in the thalamus and putamen (accompanied by an overall upregulation of these receptors). These findings indicate that smoking enhances neurotransmission through cortico–basal ganglia–thalamic circuits by direct stimulation of nAChRs, indirect stimulation via DA release or MAO inhibition, or a combination of these and possibly other factors. Activation of this circuitry may be responsible for the effects of smoking seen in tobacco-dependent smokers, such as improvements in attentional performance, mood, anxiety, and irritability.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Alexander GE, Crutcher MD, DeLong MR (1990) Basal ganglia-thalamocortical circuits: parallel substrates for motor, oculomotor, “prefrontal” and “limbic” functions. Prog Brain Res 85: 119–146PubMedGoogle Scholar
  2. Bahk JY, Li SP, Park MS, Kim MO (2002) Dopamine D-1 and D-2 receptor mRNA up-regulation in the caudate-putamen and nucleus accumbens of rat brains by smoking. Prog Neuropsychophar-macol Biol Psychiatry 26:1095–1104Google Scholar
  3. Baker RR, Massey ED, Smith G (2004) An overview of the effects of tobacco ingredients on smoke chemistry and toxicity. Food Chem Toxicol 42(Suppl):S53–S83PubMedGoogle Scholar
  4. Balluz L, Ahluwalia IB, Murphy W, Mokdad A, Giles W, Harris VB (2004) Surveillance for certain health behaviors among selected local areas–United States, Behavioral Risk Factor Surveillance System, 2002. MMWR Surveill Summ 53:1–100PubMedGoogle Scholar
  5. Barrett SP, Boileau I, Okker J, Pihl RO, Dagher A (2004) The hedonic response to cigarette smoking is proportional to dopamine release in the human striatum as measured by positron emission tomography and [11C]raclopride. Synapse 54:65–71PubMedGoogle Scholar
  6. Bartal M (2001) Health effects of tobacco use and exposure. Monaldi Arch Chest Dis 56:545–554PubMedGoogle Scholar
  7. Bell SL, Taylor RC, Singleton EG, Henningfield JE, Heishman SJ (1999) Smoking after nicotine deprivation enhances cognitive performance and decreases tobacco craving in drug abusers. Nicotine Tob Res 1:45–52PubMedGoogle Scholar
  8. Benwell ME, Balfour DJK, Anderson JM (1988) Evidence that tobacco smoking increases the density of (−)-[3H]nicotine binding sites in human brain. J Neurochem 50:1243–1247PubMedGoogle Scholar
  9. Berlin I, Anthenelli RM (2001) Monoamine oxidases and tobacco smoking. Int J Neuropsy-chopharmacol 4:33–42Google Scholar
  10. Blaha CD, Allen LF, Das S, Inglis WL, Latimer MP, Vincent SR, Winn P (1996) Modulation of dopamine efflux in the nucleus accumbens after cholinergic stimulation of the ventral tegmen-tal area in intact, pedunculopontine tegmental nucleus-lesioned, and laterodorsal tegmental nucleus-lesioned rats. J Neurosci 16:714–722PubMedGoogle Scholar
  11. Breese CR, Marks MJ, Logel J, Adams CE, Sullivan B, Collins AC, Leonard S (1997) Effect of smoking history on [3H]nicotine binding in human postmortem brain. J Pharmacol Exp Ther 282:7–13PubMedGoogle Scholar
  12. Brody AL, Mandelkern MA, London ED, Childress AR, Bota RG, Ho ML, Lee GS, Saxena S, Baxter LR, Madsen D, Jarvik ME (2002) Brain metabolic changes during cigarette craving. Arch Gen Psychiatry 59:1162–1172PubMedGoogle Scholar
  13. Brody AL, Mandelkern MA, Lee G, Smith E, Sadeghi M, Saxena S, Jarvik ME, London ED (2004a) Attenuation of cue-induced cigarette craving and anterior cingulate cortex activation in bupropion-treated smokers: a preliminary study. Psych Res Neuroimaging 130:269–281Google Scholar
  14. Brody AL, Olmstead RE, London ED, Farahi J, Meyer JH, Grossman P, Lee GS, Huang J, Hahn EL, Mandelkern MA (2004b) Smoking-induced ventral striatum dopamine release. Am J Psychiatry 161:1211–1218Google Scholar
  15. Brody AL, Mandelkern MA, London ED, Olmstead RE, Farahi J, Scheibal D, Jou J, Allen V, Tiongson E, Chefer SI, Koren AO, Mukhin AG (2006) Cigarette smoking saturates brain alpha 4 beta 2 nicotinic acetylcholine receptors. Arch Gen Psychiatry 63:907–915PubMedGoogle Scholar
  16. Brody AL, Mandelkern MA, Olmstead RE, Jou J, Tiongson E, Allen V, Scheibal D, London ED, Monterosso JR, Tiffany ST, Korb A, Gan JJ, Cohen MS (2007) Neural substrates of resisting craving during cigarette cue exposure. Biol Psychiatry 62:642–651PubMedGoogle Scholar
  17. Broussolle EP, Wong D, Fanelli RJ, London ED (1989) In vivo specific binding of [3H]-nicotine in the mouse brain. Life Sci 44:1123–1132PubMedGoogle Scholar
  18. Carter BL, Tiffany ST (1999) Meta-analysis of cue-reactivity in addiction research. Addiction 94:327–340PubMedGoogle Scholar
  19. Carter CS, Botvinick MM, Cohen JD (1999) The contribution of the anterior cingulate cortex to executive processes in cognition. Rev Neurosci 10:49–57PubMedGoogle Scholar
  20. Chefer SI, Horti AG, Lee K, Koren A, Jones DW, Gorey J, Links JM, Mukhin AG, Weinberger DR, London ED (1998) In vivo imaging of brain nicotinic receptors with 5-[123I]iodo-A-85380 using single photon emission computed tomography. Life Sci 63:PL355–PL360PubMedGoogle Scholar
  21. Chefer SI, Horti AG, Koren AO, Gündrisch D, Links JM, Kurian V, Dannals RF, Mukhin AG, London ED (1999) 2-[18F]F-A-83580: a PET radioligand for α4β2 nicotinic acetylcholine receptors. Neuroreport 10:2715–2721PubMedGoogle Scholar
  22. Chefer SI, London ED, Koren AO, Pavlova OA, Kurian V, Kimes AS, Horti AG, Mukhin AG (2003) Graphical analysis of 2-[F-18]FA binding to nicotinic acetylcholine receptors in rhesus monkey brain. Synapse 48:25–34PubMedGoogle Scholar
  23. Chua P, Krams M, Toni I, Passingham R, Dolan R (1999) A functional anatomy of anticipatory anxiety. Neuroimage 9:563–571PubMedGoogle Scholar
  24. Cimino M, Marini P, Fornasari D, Cattabeni F, Clementi F (1992) Distribution of nicotinic receptors in cynomolgus monkey brain and ganglia: localization of alpha 3 subunit mRNA, alpha-bungarotoxin and nicotine binding sites. Neuroscience 51:77–86PubMedGoogle Scholar
  25. Clarke PBS (2004) Nicotinic modulation of thalamocortical neurotransmission. Acetylcholine in the cerebral cortex. Prog Brain Res 145:253–260PubMedGoogle Scholar
  26. Clarke PBS, Pert C, Pert A (1984) Autoradiographic distribution of nicotine receptors in rat brain. Brain Res 323:390–395PubMedGoogle Scholar
  27. Cohen C, Pickworth WB, Henningfield JE (1991) Cigarette smoking and addiction. Clin Chest Med 12:701–710PubMedGoogle Scholar
  28. Connelly MS, Littleton JM (1983) Lack of stereoselectivity in ability of nicotine to release dopamine from rat synaptosomal preparations. J Neurochem 41:1297–1302PubMedGoogle Scholar
  29. Corrigall WA, Franklin KB, Coen KM, Clarke PB (1992) The mesolimbic dopaminergic system is implicated in the reinforcing effects of nicotine. Psychopharmacology 107:285–289PubMedGoogle Scholar
  30. Corrigall WA, Coen KM, Adamson KL (1994) Self-administered nicotine activates the mesolimbic dopamine system through the ventral tegmental area. Brain Res 653:278–284PubMedGoogle Scholar
  31. Court JA, Martin-Ruiz C, Graham A, Perry E (2000) Nicotinic receptors in human brain: topography and pathology. J Chem Neuroanat 20:281–298PubMedGoogle Scholar
  32. Cousins MS, Roberts DC, de Wit H (2002) GABA(B) receptor agonists for the treatment of drug addiction: a review of recent findings. Drug Alcohol Depend 65:209–220PubMedGoogle Scholar
  33. Critchley HD, Mathias CJ, Dolan RJ (2001) Neural activity in the human brain relating to uncertainty and arousal during anticipation. Neuroimage 13:S392Google Scholar
  34. Cruickshank JM, Neildwyer G, Dorrance DE, Hayes Y, Patel S (1989) Acute effects of smoking on blood-pressure and cerebral blood-flow. J Hum Hypertension 3:443–449Google Scholar
  35. Dagher A, Bleicher C, Aston JAD, Gunn RN, Clarke PBS, Cumming P (2001) Reduced dopamine D1 receptor binding in the ventral striatum of cigarette smokers. Synapse 42:48–53PubMedGoogle Scholar
  36. Damsma G, Day J, Fibiger HC (1989) Lack of tolerance to nicotine-induced dopamine release in the nucleus accumbens. Eur J Pharmacol 168:363–368PubMedGoogle Scholar
  37. Dávila-García MI, Musachio J, Perry D, Xiao Y, Horti A, London E, Dannals RF, Kellar K (1997) [125I]IPH, an epibatidine analog, binds with high affinity to neuronal nicotinic cholinergic receptors. J Pharmacol Exp Ther 282:445–451PubMedGoogle Scholar
  38. Davila-Garcia MI, Houghtling RA, Qasba SS, Kellar KJ (1999) Nicotinic receptor binding sites in rat primary neuronal cells in culture: characterization and their regulation by chronic nicotine. Mol Brain Res 66:14–23PubMedGoogle Scholar
  39. Dewey SL, Brodie JD, Gerasimov M, Horan B, Gardner EL, Ashby CRJ (1999) A pharmacologic strategy for the treatment of nicotine addiction. Synapse 31:76–86PubMedGoogle Scholar
  40. Di Chiara G, Imperato A (1988) Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci USA 85:5274–5278PubMedGoogle Scholar
  41. Ding YS, Volkow ND, Logan J, Garza V, Pappas N, King P, Fowler JS (2000) Occupancy of brain nicotinic acetylcholine receptors by nicotine doses equivalent to those obtained when smoking a cigarette. Synapse 35: 234–237PubMedGoogle Scholar
  42. Domino EF, Minoshima S, Guthrie S, Ohl L, Ni L, Koeppe RA, Zubieta JK (2000a) Nicotine effects on regional cerebral blood flow in awake, resting tobacco smokers. Synapse 38: 313–321Google Scholar
  43. Domino EF, Minoshima S, Guthrie SK, Ohl L, Ni L, Koeppe RA, Cross DJ, Zubieta J (2000b) Effects of nicotine on regional cerebral glucose metabolism in awake resting tobacco smokers. Neuroscience 101:277–282Google Scholar
  44. Drevets WC, Price JL, Simpson JR, Jr., Todd RD, Reich T, Vannier M, Raichle ME (1997) Sub-genual prefrontal cortex abnormalities in mood disorders. Nature 386:824–827PubMedGoogle Scholar
  45. Due DL, Huettel SA, Hall WG, Rubin DC (2002) Activation in mesolimbic and visuospatial neural circuits elicited by smoking cues: evidence from functional magnetic resonance imaging. Am J Psychiatry 159:954–960PubMedGoogle Scholar
  46. Duncan J, Owen AM (2000) Common regions of the human frontal lobe recruited by diverse cognitive demands. Trends Neurosci 23:475–483PubMedGoogle Scholar
  47. Ernst M, Heishman SJ, Spurgeon L, London ED (2001a) Smoking history and nicotine effects on cognitive performance. Neuropsychopharmacology 25:313–319Google Scholar
  48. Ernst M, Matochik JA, Heishman SJ, Van Horn JD, Jons PH, Henningfield JE, London ED (2001b) Effect of nicotine on brain activation during performance of a working memory task. Proc Natl Acad Sci USA 98:4728–4733Google Scholar
  49. Fallon JH, Keator DB, Mbogori J, Turner J, Potkin SG (2004) Hostility differentiates the brain metabolic effects of nicotine. Brain Res Cogn Brain Res 18:142–148PubMedGoogle Scholar
  50. Fiore MC, Bailey WC, Cohen SJ, Dorfman SF, Goldstein MG, Gritz ER, Heyman RB, Jaen CR, Kottke TE, Lando HA, Mecklenburg RE, Mullen PD, Nett LM, Robinson L, Stitzer ML, Tommasello AC, Villejo L, Wewers ME (2000) Treating tobacco use and dependence. Clinical Practice Guideline, U.S. Department of Health and Human Services. Public Health Service, Rockville, MDGoogle Scholar
  51. Fowler JS, Volkow ND, Logan J, Wang GJ, MacGregor RR, Schyler D, Wolf AP, Pappas N, Alexoff D, Shea C (1994) Slow recovery of human brain MAO B after L-deprenyl (Selege-line) withdrawal. Synapse 18:86–93PubMedGoogle Scholar
  52. Fowler JS, Volkow ND, Wang GJ, Pappas N, Logan J, MacGregor R, Alexoff D, Shea C, Schlyer D, Wolf AP, Warner D, Zezulkova I, Cilento R (1996a) Inhibition of monoamine oxidase B in the brains of smokers. Nature 379:733–736Google Scholar
  53. Fowler JS, Volkow ND, Wang GJ, Pappas N, Logan J, Shea C, Alexoff D, MacGregor RR, Schlyer DJ, Zezulkova I, Wolf AP (1996b) Brain monoamine oxidase A inhibition in cigarette smokers. Proc Natl Acad Sci USA 93:14065–14069Google Scholar
  54. Fowler JS, Volkow ND, Logan J, Pappas N, King P, MacGregor R, Shea C, Garza V, Gatley SJ (1998a) An acute dose of nicotine does not inhibit MAO B in baboon brain in vivo. Life Sci 63:L19–L23Google Scholar
  55. Fowler JS, Volkow ND, Wang GJ, Pappas N, Logan J, MacGregor R, Alexoff D, Wolf AP, Warner D, Cilento R, Zezulkova I (1998b) Neuropharmacological actions of cigarette smoke: brain monoamine oxidase B (MAO B) inhibition. J Addict Dis 17:23–34Google Scholar
  56. Fowler JS, Wang GJ, Volkow ND, Franceschi D, Logan J, Pappas N, Shea C, MacGregor RR, Garza V (1999) Smoking a single cigarette does not produce a measurable reduction in brain MAO B in non-smokers. Nicotine Tob Res 1:325–329PubMedGoogle Scholar
  57. Fowler JS, Wang GJ, Volkow ND, Franceschi D, Logan J, Pappas N, Shea C, MacGregor RR, Garza V (2000) Maintenance of brain monoamine oxidase B inhibition in smokers after overnight cigarette abstinence. Am J Psychiatry 157:1864–1866PubMedGoogle Scholar
  58. Fowler JS, Logan J, Wang GJ, Volkow ND (2003a) Monoamine oxidase and cigarette smoking. Neurotoxicology 24:75–82Google Scholar
  59. Fowler JS, Logan J, Wang GJ, Volkow ND, Telang F, Zhu W, Franceschi D, Pappas N, Ferrieri R, Shea C, Garza V, Xu YW, Schlyer D, Gatley SJ, Ding YS, Alexoff D, Warner D, Netusil N, Carter P, Jayne M, King P, Vaska P (2003b) Low monoamine oxidase B in peripheral organs in smokers. Proc Natl Acad Sci USA 100:11600–11605Google Scholar
  60. Fowler JS, Logan J, Wang GJ, Volkow ND, Telang F, Zhu W, Franceschi D, Shea C, Garza V, Xu Y, Ding YS, Alexoff D, Warner D, Netusil N, Carter P, Jayne M, King P, Vaska P (2005) Comparison of monoamine oxidase a in peripheral organs in nonsmokers and smokers. J Nucl Med 46:1414–1420PubMedGoogle Scholar
  61. Fowles J, Dybing E (2003) Application of toxicological risk assessment principles to the chemical constituents of cigarette smoke. Tob Control 12:424–430PubMedGoogle Scholar
  62. Fujita M, Seibyl JP, Vaupel DB, Tamagnan G, Early M, Zoghbi SS, Baldwin RM, Horti AG, Koren AO, Mukhin AG, Khan S, Bozkurt A, Kimes AS, London ED, Innis RB (2002) Whole-body biodistribution, radiation absorbed dose, and brain SPET imaging with [123I]5-I-A-85380 in healthy human subjects. Eur J Nucl Med Mol Imaging 29:183–190PubMedGoogle Scholar
  63. Fujita M, Ichise M, van Dyck CH, Zoghbi SS, Tamagnan G, Mukhin AG, Bozkurt A, Seneca N, Tipre D, DeNucci CC, Iida H, Vaupel DB, Horti AG, Koren AO, Kimes AS, London ED, Seibyl JP, Baldwin RM, Innis RB (2003) Quantification of nicotinic acetylcholine receptors in human brain using [I-123]5-I-A-85380 SPET. Eur J Nucl Med Mol Imaging 30:1620–1629PubMedGoogle Scholar
  64. Ghatan PH, Ingvar M, Eriksson L, Stone-Elander S, Serrander M, Ekberg K, Wahren J (1998) Cerebral effects of nicotine during cognition in smokers and non-smokers. Psychopharmacology 136:179–189PubMedGoogle Scholar
  65. Gioanni Y, Rougeot C, Clarke PB, Lepouse C, Thierry AM, Vidal C (1999) Nicotinic receptors in the rat prefrontal cortex: increase in glutamate release and facilitation of mediodorsal thalamo-cortical transmission. Eur J Neurosci 11:18–30PubMedGoogle Scholar
  66. Goldman-Rakic PS, Leranth C, Williams SM, Mons N, Geffard M (1989) Dopamine synaptic complex with pyramidal neurons in primate cerebral cortex. Proc Natl Acad Sci USA 86: 9015–9019PubMedGoogle Scholar
  67. Goldstein RZ, Volkow ND (2002) Drug addiction and its underlying neurobiological basis: neu-roimaging evidence for the involvement of the frontal cortex. Am J Psychiatry 159:1642–1652PubMedGoogle Scholar
  68. Groenewegen HJ, Galis-de Graaf Y, Smeets WJAJ (1999) Integration and segregation of limbic cortico-striatal loops at the thalamic level: an experimental tracing study in rats. J Chem Neu-roanat 16:167–185Google Scholar
  69. Gross TM, Jarvik ME, Rosenblatt MR (1993) Nicotine abstinence produces content-specific Stroop interference. Psychopharmacology 110:333–336PubMedGoogle Scholar
  70. Haber SN, Fudge JL (1997) The primate substantia nigra and VTA: integrative circuitry and function. Crit Rev Neurobiol 11:323–342PubMedGoogle Scholar
  71. Hatsukami D, Fletcher L, Morgan S, Keenan R, Amble P (1989) The effects of varying cigarette deprivation duration on cognitive and performance tasks. J Subst Abuse 1:407–416PubMedGoogle Scholar
  72. Herrero MT, Barcia C, Navarro JM (2002) Functional anatomy of thalamus and basal ganglia. Childs Nervous Syst 18:386–404Google Scholar
  73. Hogg RC, Raggenbass M, Bertrand D (2003) Nicotinic acetylcholine receptors: from structure to brain function. Rev Physiol Biochem Pharmacol 147:1–46PubMedGoogle Scholar
  74. Holmes S, Zwar N, Jimenez-Ruiz CA, Ryan PJ, Browning D, Bergmann L, Johnston JA (2004) Bupropion as an aid to smoking cessation: a review of real-life effectiveness. Int J Clin Pract 58:285–291PubMedGoogle Scholar
  75. Horti AG, Scheffel U, Koren AO, Ravert HT, Mathews WB, Musachio JL, Finley PA, London ED, Dannals RF (1998) 2-[F-18]fluoro-A-85380, an in vivo tracer for the nicotinic acetylcholine receptors. Nucl Med Biol 25:599–603PubMedGoogle Scholar
  76. Horti AG, Koren AO, Lee KS, Mukhin AG, Vaupel DB, Kimes AS, Stratton M, London ED (1999) Radiosynthesis and preliminary evaluation of 5-[123/125I]iodo-3-(2(S)-azetidinylmethoxy)pyridine: a radioligand for nicotinic acetylcholine receptors. Nucl Med Biol 26:175–182PubMedGoogle Scholar
  77. Horti AG, Villemagne, VL (2006) The quest for Eldorado: development of radioligands for in vivo imaging of nicotinic acetylcholine receptors in human brain. Curr Pharm Des 12:3877–3900PubMedGoogle Scholar
  78. Hughes JR, Lesmes GR, Hatsukami DK, Richmond RL, Lichtenstein E, Jorenby DE, Broughton JO, Fortmann SP, Leischow SJ, McKenna JP, et al (1999) Are higher doses of nicotine replacement more effective for smoking cessation? Nic Tobacco Res 1:169–174Google Scholar
  79. Hurt RD, Sachs DP, Glover ED, Offord KP, Johnston JA, Dale LC, Khayrallah MA, Schroeder DR, Glover PN, Sullivan CR, Croghan IT, Sullivan PM (1997) A comparison of sustained-release bupropion and placebo for smoking cessation. NEJM 337:1195–1202PubMedGoogle Scholar
  80. Jacobsen LK, Gore JC, Skudlarski P, Lacadie CM, Jatlow P, Krystal JH (2002) Impact of intravenous nicotine on BOLD signal response to photic stimulation. Magn Reson Imaging 20: 141–145PubMedGoogle Scholar
  81. Jacobsen LK, D'Souza DC, Mencl WE, Pugh KR, Skudlarski P, Krystal JH (2004) Nicotine effects on brain function and functional connectivity in schizophrenia. Biol Psychiatry 55:850–858PubMedGoogle Scholar
  82. Jarvik ME, Madsen DC, Olmstead RE, Iwamoto-Schaap PN, Elins JL, Benowitz NL (2000) Nicotine blood levels and subjective craving for cigarettes. Pharmacol Biochem Behav 66:553–558PubMedGoogle Scholar
  83. Jorenby DE, Leischow SJ, Nides MA, Rennard SI, Johnston JA, Hughes AR, Smith SS, Muramoto ML, Daughton DM, Doan K, Fiore MC, Baker TB (1999) A controlled trial of sustained-release bupropion, a nicotine patch, or both for smoking cessation. NEJM 340:685–691PubMedGoogle Scholar
  84. Kenny PJ, Markou A (2001) Neurobiology of the nicotine withdrawal syndrome. Pharmacol Biochem Behav 70:531–549PubMedGoogle Scholar
  85. Killen JD, Fortmann SP, Davis L, Strausberg L, Varady A (1999) Do heavy smokers benefit from higher dose nicotine patch therapy? Exp Clin Psychopharm 7:226–233Google Scholar
  86. Killen JD, Fortmann SP, Schatzberg AF, Hayward C, Sussman L, Rothman M, Strausberg L, Varady A (2000) Nicotine patch and paroxetine for smoking cessation. J Consult Clin Psych 68:883–889Google Scholar
  87. Kimbrell TA, George MS, Parekh PI, Ketter TA, Podell DM, Danielson AL, Repella JD, Benson BE, Willis MW, Herscovitch P, Post RM (1999) Regional brain activity during transient self-induced anxiety and anger in healthy adults. Biol Psychiatry 46:454–465PubMedGoogle Scholar
  88. Kimes AS, Horti AG, London ED, Chefer SI, Contoreggi C, Ernst M, Friello P, Koren AO, Kurian V, Matochik JA, Pavlova O, Vaupel DB, Mukhin AG (2003) 2-[18F]F-A-85380: PET imaging of brain nicotinic acetylcholine receptors and whole body distribution in humans. FASEB J 17:1331–1333PubMedGoogle Scholar
  89. Klimek V, Zhu MY, Dilley G, Konick L, Overholser JC, Meltzer HY, May WL, Stockmeier CA, Ordway GA (2001) Effects of long-term cigarette smoking on the human locus coeruleus. Arch Gen Psychiatry 58:821–827PubMedGoogle Scholar
  90. Kodaira K, Fujishiro K, Wada T, Maie K, Satoi T, Tsukiyama E, Fukumoto T, Uchida T, Yamazaki S, Okamura T (1993) A study on cerebral nicotine receptor distribution, blood flow, oxygen consumption, and other metabolic activities–a study on the effects of smoking on carotid and cerebral artery blood flow. Yakubutsu Seishin Kodo 13:157–165PubMedGoogle Scholar
  91. Koob GF (1992) Drugs of abuse: anatomy, pharmacology and function of reward pathways. Trends Pharm Sci 13:177–184PubMedGoogle Scholar
  92. Koren AO, Horti AG, Mukhin AG, Gundisch D, Kimes AS, Dannals RF, London ED (1998) 2-, 5-, and 6-halo-3-(2(S)-azetidinylmethoxy)pyridines: synthesis, affinity for nicotinic acetylcholine receptors, and molecular modeling. J Med Chem 41:3690–3698PubMedGoogle Scholar
  93. Krause KH, Dresel SH, Krause J, Kung HF, Tatsch K, Ackenheil M (2002) Stimulant-like action of nicotine on striatal dopamine transporter in the brain of adults with attention deficit hyper-activity disorder. Int J Neuropsychopharmacol 5:111–113PubMedGoogle Scholar
  94. Kubota K, Yamaguchi T, Abe Y, Fujiwara T, Hatazawa J, Matsuzawa T (1983) Effects of smoking on regional cerebral blood-flow in neurologically normal subjects. Stroke 14:720–724PubMedGoogle Scholar
  95. Kubota K, Yamaguchi T, Fujiwara T, Matsuzawa T (1987) Effects of smoking on regional cerebral blood-flow in cerebral vascular-disease patients and normal subjects. Tohoku J Exp Med 151:261–268PubMedGoogle Scholar
  96. Kumari V, Gray JA, Ffytche DH, Mitterschiffthaler MT, Das M, Zachariah E, Vythelingum GN, Williams SCR, Simmons A, Sharma T (2003) Cognitive effects of nicotine in humans: an fMRI study. Neuroimage 19:1002–1013PubMedGoogle Scholar
  97. Lambe EK, Picciotto MR, Aghajanian GK (2003) Nicotine induces glutamate release from thala-mocortical terminals in prefrontal cortex. Neuropsychopharmacology 28:216–225PubMedGoogle Scholar
  98. Lanca AJ, Adamson KL, Coen KM, Chow BL, Corrigall WA (2000) The pedunculopontine tegmental nucleus and the role of cholinergic neurons in nicotine self-administration in the rat: a correlative neuroanatomical and behavioral study. Neuroscience 96:735–742PubMedGoogle Scholar
  99. Lawrence NS, Ross TJ, Stein EA (2002) Cognitive mechanisms of nicotine on visual attention. Neuron 36:539–548PubMedGoogle Scholar
  100. Leistikow BN, Martin DC, Milano CE (2000a) Estimates of smoking-attributable deaths at ages 15–54, motherless or fatherless youths, and resulting Social Security costs in the United States in 1994. Prev Med 30:353–360Google Scholar
  101. Leistikow BN, Martin DC, Milano CE (2000b) Fire injuries, disasters, and costs from cigarettes and cigarette lights: a global overview. Prev Med 31:91–99Google Scholar
  102. Leshner AI, Koob GF (1999) Drugs of abuse and the brain. Proc Assoc Am Phys 111:99–108PubMedGoogle Scholar
  103. Li SP, Kim KY, Kim JH, Kim JH, Park MS, Bahk JY, Kim MO (2004) Chronic nicotine and smoking treatment increases dopamine transporter mRNA expression in the rat midbrain. Neurosci Lett 363:29–32PubMedGoogle Scholar
  104. London ED, Waller SB, Wamsley JK (1985) Autoradiographic localization of [3H] nicotine binding sites in the rat brain. Neurosci Lett 53:179–184PubMedGoogle Scholar
  105. London ED, Connolly RJ, Szikszay M, Wamsley JK, Dam M (1988a) Effects of nicotine on local cerebral glucose-utilization in the rat. J Neurosci 8:3920–3928Google Scholar
  106. London ED, Dam M, Fanelli RJ (1988b) Nicotine enhances cerebral glucose utilization in central components of the rat visual system. Brain Res Bull 20:381–385Google Scholar
  107. London ED, Scheffel U, Kimes AS, Kellar KJ (1995) In vivo labeling of nicotinic acetylcholine receptors in brain with [3H]epibatidine. Eur J Pharmacol 278:R1–R2PubMedGoogle Scholar
  108. Lukas RJ (1998) Neuronal nicotinic acetylcholine receptors. In: Barrantes FJ (ed) The nicotinic acetylcholine receptor: current views and future trends. R.G. Landes, Georgetown, pp 145–173Google Scholar
  109. Mansvelder HD, Keath JR, McGehee DS (2002) Synaptic mechanisms underlie nicotine-induced excitability of brain reward areas. Neuron 33:905–919PubMedGoogle Scholar
  110. Marenco T, Bernstein S, Cumming P, Clarke PBS (2000) Effects of nicotine and chlorisondamine on cerebral glucose utilization in immobilized and freely-moving rats. Br J Pharmacol 129: 147–155PubMedGoogle Scholar
  111. Marenco S, Carson RE, Berman KF, Herscovitch P, Weinberger DR (2004) Nicotine-induced dopamine release in primates measured with [C-11]raclopride PET. Neuropsychopharmacology 29:259–268PubMedGoogle Scholar
  112. Marien M, Brien J, Jhamandas K (1983) Regional release of [3H]dopamine from rat brain in vitro: effects of opioids on release induced by potassium, nicotine, and L-glutamic acid. Can J Physiol Pharmacol 61:43–60PubMedGoogle Scholar
  113. McClernon FJ, Huettel SA, Rose JE (2005) Abstinence-induced changes in self-report craving correlate with event-related fMRI responses to smoking cues. Neuropsychopharmacology 301:940–1947Google Scholar
  114. Miller NS, Goldsmith RJ (2001) Craving for alcohol and drugs in animals and humans: biology and behavior. J Addict Dis 20:87–104PubMedGoogle Scholar
  115. Mokdad AH, Marks JS, Stroup DF, Gerberding JL (2004) Actual causes of death in the United States, 2000. JAMA 291:1238–1245PubMedGoogle Scholar
  116. Mukhin AG, Gundisch D, Horti AG, Koren AO, Tamagnan G, Kimes AS, Chambers J, Vaupel DB, King SL, Picciotto MR, Innis RB, London ED (2000) 5-Iodo-A-85380, an alpha 4 beta 2 subtype-selective ligand for nicotinic acetylcholine receptors. Mol Pharmacol 57:642–649PubMedGoogle Scholar
  117. Naito E, Kinomura S, Geyer S, Kawashima R, Roland PE, Zilles K (2000) Fast reaction to different sensory modalities activates common fields in the motor areas, but the anterior cingulate cortex is involved in the speed of reaction. J Neurophysiol 83:1701–1709PubMedGoogle Scholar
  118. Nakamura H, Tanaka A, Nomoto Y, Ueno Y, Nakayama Y (2000) Activation of fronto-limbic system in the human brain by cigarette smoking: evaluated by a CBF measurement. Keio J Med 49(Suppl 1):A122–A124PubMedGoogle Scholar
  119. Newhouse PA, Potter A, Singh A (2004) Effects of nicotinic stimulation on cognitive performance. Curr Opin Pharmacol 4:36–46PubMedGoogle Scholar
  120. Nisell M, Nomikos GG, Svensson TH (1994) Systemic nicotine-induced dopamine release in the rat nucleus accumbens is regulated by nicotinic receptors in the ventral tegmental area. Synapse 16:36–44PubMedGoogle Scholar
  121. Pabreza LA, Dhawan S, Kellar KJ (1991) [3H]Cytisine binding to nicotinic cholinergic receptors in brain. Mol Pharmacol 39:9–12PubMedGoogle Scholar
  122. Parrott AC (2003) Cigarette-derived nicotine is not a medicine. World J Biol Psychiatry 4:49–55PubMedGoogle Scholar
  123. Parrott AC, Kaye FJ (1999) Daily uplifts, hassles, stresses and cognitive failures: in cigarette smokers, abstaining smokers, and non-smokers. Behav Pharmacol 10:639–646PubMedGoogle Scholar
  124. Paterson D, Nordberg A (2000) Neuronal nicotinic receptors in the human brain. Prog Neurobiol 61:75–111PubMedGoogle Scholar
  125. Paulson OB (2002) Blood-brain barrier, brain metabolism and cerebral blood flow. Eur Neuropsy-chopharmacol 12:495–501Google Scholar
  126. Pauly JR, Stitzel JA, Marks MJ, Collins AC (1989) An autoradiographic analysis of cholinergic receptors in mouse brain. Brain Res Bull 22:453–459PubMedGoogle Scholar
  127. Pauly JR, Marks MJ, Robinson SF, van de Kamp JL, Collins AC (1996) Chronic nicotine and mecamylamine treatment increase brain nicotinic receptor binding without changing alpha 4 or beta 2 mRNA levels. J Pharmacol Exp Ther 278:361–369PubMedGoogle Scholar
  128. Perkins K, Sayette M, Conklin C, Caggiula A (2003) Placebo effects of tobacco smoking and other nicotine intake. Nicotine Tob Res 5:695–709PubMedGoogle Scholar
  129. Perry DC, Kellar KJ (1995) [3H]Epibatidine labels nicotinic receptors in rat brain: an autoradi-ographic study. J Pharmacol Exp Ther 285:1030–1034Google Scholar
  130. Pessoa L, Kastner S, Ungerleider LG (2003) Neuroimaging studies of attention: from modulation of sensory processing to top-down control. J Neurosci 23:3990–3998PubMedGoogle Scholar
  131. Peterson BS, Skudlarski P, Gatenby JC, Zhang HP, Anderson AW, Gore JC (1999) An fMRI study of Stroop word-color interference: evidence for cingulate subregions subserving multiple distributed attentional systems. Biol Psychiatry 45:1237–1258PubMedGoogle Scholar
  132. Picciotto MR, Corrigall WA (2002) Neuronal systems underlying behaviors related to nicotine addiction: neural circuits and molecular genetics. J Neurosci 22:3338–3341PubMedGoogle Scholar
  133. Pomper MG, Phillips, E, Fan, H, McCarthy, DJ, Keith, RA, Gordon, JC, Scheffel, U, Dannals, RF, Musachio, JL. (2005) Synthesis and biodistribution of radiolabeled alpha 7 nicotinic acetyl-choline receptor ligands. J Nucl Med 46:326–334PubMedGoogle Scholar
  134. Pontieri FE, Tanda G, Orzi F, Di Chiara G (1996) Effects of nicotine on the nucleus accumbens and similarity to those of addictive drugs. Nature 382:255–257PubMedGoogle Scholar
  135. Powell J, Dawkins L, Davis RE (2002) Smoking, reward responsiveness, and response inhibition: tests of an incentive motivational model. Biol Psychiatry 51:151–163PubMedGoogle Scholar
  136. Pritchard WS, Robinson JH, Guy TD (1992) Enhancement of continuous performance task reaction-time by smoking in nondeprived smokers. Psychopharmacology 108:437–442PubMedGoogle Scholar
  137. Rauch SL, Shin LM, Dougherty DD, Alpert NM, Orr SP, Lasko M, Macklin ML, Fischman AJ, Pitman RK (1999) Neural activation during sexual and competitive arousal in healthy men. Psychiatry Res Neuroimaging 91:1–10Google Scholar
  138. Rees G, Lavie N (2001) What can functional imaging reveal about the role of attention in visual awareness? Neuropsychologia 39:1343–1353PubMedGoogle Scholar
  139. Rogers RL, Meyer JS, Shaw TG, Mortel KF, Hardenberg JP, Zaid RR (1983) Cigarette-smoking decreases cerebral blood-flow suggesting increased risk for stroke. JAMA 250:2796–2800PubMedGoogle Scholar
  140. Rolls ET, Baylis LL (1994) Gustatory, olfactory, and visual convergence within the primate or-bitofrontal cortex. J Neurosci 14:5437–5452PubMedGoogle Scholar
  141. Rolls ET, Critchley HD, Browning A, Hernadi I (1998) The neurophysiology of taste and olfaction in primates, and umami flavor. Ann N Y Acad Sci 855:426–437PubMedGoogle Scholar
  142. Rose JE, Behm FM, Westman EC, Mathew RJ, London ED, Hawk TC, Turkington TG, Coleman RE (2003) PET studies of the influences of nicotine on neural systems in cigarette smokers. Am J Psychiatry 160:323–333PubMedGoogle Scholar
  143. Rose JE, Behm FM, Salley AN, Bates JE, Coleman RE, Hawk TC (2007) Regional brain activity correlates of nicotine dependence. Neuropsychopharmacology 32:2441–2452PubMedGoogle Scholar
  144. Rourke SB, Dupont RM, Grant I, Lehr PP, Lamoureux G, Halpern S, Yeung DW (1997) Reduction in cortical IMP-SPET tracer uptake with recent cigarette consumption in a young group of healthy males. San Diego HIV Neurobehavioral Research Center. Eur J Nucl Med 24:422–427PubMedGoogle Scholar
  145. Rowell PP, Carr LA, Garner AC (1987) Stimulation of [3H]dopamine release by nicotine in rat nucleus accumbens. J Neurochem 49:1449–1454PubMedGoogle Scholar
  146. Rusted JM, Caulfield D, King L, Goode A (2000) Moving out of the laboratory: does nicotine improve everyday attention? Behav Pharmacol 11:621–629PubMedGoogle Scholar
  147. Ryan RE, Ross SA, Drago J, Loiacono RE (2001) Dose-related neuroprotective effects of chronic nicotine in 6-hydroxydopamine treated rats, and loss of neuroprotection in alpha 4 nicotinic receptor subunit knockout mice. Br J Pharmacol 132:1650–1656PubMedGoogle Scholar
  148. Sakurai Y, Takano Y, Kohjimoto Y, Honda K, Kamiya HO (1982) Enhancement of [3H]dopamine release and its [3H]metabolites in rat striatum by nicotinic drugs. Brain Res 242:99–106PubMedGoogle Scholar
  149. Salokangas RK, Vilkman H, Ilonen T, Taiminen T, Bergman J, Haaparanta M, Solin O, Alanen A, Syvalahti E, Hietala J (2000) High levels of dopamine activity in the basal ganglia of cigarette smokers. Am J Psychiatry 157:632–634PubMedGoogle Scholar
  150. Schilstrom B, Fagerquist MV, Zhang X, Hertel P, Panagis G, Nomikos GG, Svensson TH (2000) Putative role of presynaptic alpha7* nicotinic receptors in nicotine stimulated increases of extracellular levels of glutamate and aspartate in the ventral tegmental area. Synapse 38:375–383PubMedGoogle Scholar
  151. Schuh KJ, Stitzer ML (1995) Desire to smoke during spaced smoking intervals. Psychopharmacology 120:289–295PubMedGoogle Scholar
  152. Sherman SM (2001) Thalamic relay functions. Prog Brain Res 134:51–69PubMedGoogle Scholar
  153. Shiffman S, Paty JA, Gnys M, Elash C, Kassel JD (1995) Nicotine withdrawal in chippers and regular smokers – subjective and cognitive effects. Health Psychol 14:301–309PubMedGoogle Scholar
  154. Shoaib M, Schindler CW, Goldberg SR, Pauly JR (1997) Behavioural and biochemical adaptations to nicotine in rats: influence of MK801, an NMDA receptor antagonist. Psychopharmacology 134:121–130PubMedGoogle Scholar
  155. Shoaib M, Lowe AS, Williams SCR (2004) Imaging localised dynamic changes in the nucleus accumbens following nicotine withdrawal in rats. Neuroimage 22:847–854PubMedGoogle Scholar
  156. Sihver W, Langstrom B, Nordberg A (2000) Ligands for in vivo imaging of nicotinic receptor subtypes in Alzheimer brain. Acta Neurol Scand 102:27–33Google Scholar
  157. Sillito AM, Jones HE (2002) Corticothalamic interactions in the transfer of visual information. Philos Trans R Soc Lond Ser B Biol Sci 357:1739–1752Google Scholar
  158. Smith EE, Jonides J (1999) Neuroscience – Storage and executive processes in the frontal lobes. Science 283:1657–1661PubMedGoogle Scholar
  159. Sommer MA (2003) The role of the thalamus in motor control. Curr Opin Neurobiol 13:663–670PubMedGoogle Scholar
  160. Staley JK, Krishnan-Sarin S, Zoghbi S, Tamagnan G, Fujita M, Seibyl JP, Maciejewski PK, O'Malley S, Innis RB (2001) Sex differences in [123I]beta-CIT SPECT measures of dopamine and serotonin transporter availability in healthy smokers and nonsmokers. Synapse 41:275–284PubMedGoogle Scholar
  161. Staley JK, Krishnan-Sarin S, Cosgrove KP, Krantzler E, Frohlich E, Perry E, Dubin JA, Estok K, Brenner E, Baldwin RM, Tamagnan GD, Seibyl JP, Jatlow P, Picciotto MR, London ED, O'Malley S, van Dyck CH (2006) Human tobacco smokers in early abstinence have higher levels of beta2* nicotinic acetylcholine receptors than nonsmokers. J Neurosci 34:8707–8714Google Scholar
  162. Stapleton JM, Gilson SF, Wong DF, Villemagne VL, Dannals RF, Grayson RF, Henningfield JE, London ED (2003a) Intravenous nicotine reduces cerebral glucose metabolism: a preliminary study. Neuropsychopharmacology 28:765–772Google Scholar
  163. Stapleton JM, Gilson SF, Wong DF, Villemagne VL, Dannals RF, Grayson RF, Henningfield JE, London ED (2003b) Intravenous nicotine reduces cerebral glucose metabolism: a preliminary study. Neuropsychopharmacology 28:765–772Google Scholar
  164. Stein E, Pankiewicz J, Harsch HH, Cho JK, Fuller SA, Hoffmann RG, Hawkins M, Rao S, Bandettini PA, Bloom AS (1998) Nicotine-induced limbic cortical activation in the human brain: a functional MRI study. Am J Psychiatry 155:1009–1015PubMedGoogle Scholar
  165. Sziraki I, Lipovac MN, Hashim A, Sershen H, Allen D, Cooper T, Czobor P, Lajtha A (2001) Differences in nicotine-induced dopamine release and nicotine pharmacokinetics between Lewis and Fischer 344 rats. Neurochem Res 26:609–617PubMedGoogle Scholar
  166. Terborg C, Birkner T, Schack B, Witte OW (2002) Acute effects of cigarette smoking on cerebral oxygenation and hemodynamics: a combined study with near-infrared spectroscopy and transcranial Doppler sonography. J Neurol Sci 205:71–75PubMedGoogle Scholar
  167. Thompson JC, Wilby G, Stough C (2002) The effects of transdermal nicotine on inspection time. Hum Psychopharmacol 17:157–161PubMedGoogle Scholar
  168. Tsukada H, Miyasato K, Kakiuchi T, Nishiyama S, Harada N, Domino EF (2002) Comparative effects of methamphetamine and nicotine on the striatal [C-11]raclopride binding in unanes-thetized monkeys. Synapse 45:207–212PubMedGoogle Scholar
  169. Valette H, Bottlaender M, Dolle F, Guenther I, Coulon C, Hinnen F, Fuseau C, Ottaviani M, Crouzel C (1998) Characterization of the nicotinic ligand 2-[F-18]fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine in vivo. Life Sci 64:L93–L97Google Scholar
  170. Valette H, Bottlaender M, Dolle F, Guenther I, Fuseau C, Coulon C, Ottaviani M, Crouzel C (1999) Imaging central nicotinic acetylcholine receptors in baboons with [F-18]fluoro-A-85380. J Nucl Med 40:1374–1380PubMedGoogle Scholar
  171. Valette H, Bottlaender M, Dolle F, Coulon C, Ottaviani M, Syrota A (2003) Long-lasting occupancy of central nicotinic acetylcholine receptors after smoking: a PET study in monkeys. J Neurochem 84:105–111PubMedGoogle Scholar
  172. Villemagne V, Horti A, Scheffel U, Ravert H, Finley P, Clough DJ, London E, Wagner H, Dannals RF (1997) Imaging nicotinic acetylcholine receptors with fluorine-18-FPH, an epi-batidine analog. J Nucl Med 38:1737–1741PubMedGoogle Scholar
  173. Westfall TC, Grant H, Perry H (1983) Release of dopamine and 5-hydroxytryptamine from rat stri-atal slices following activation of nicotinic cholinergic receptors. Gen Pharmacol 14: 321–325PubMedGoogle Scholar
  174. Wilson SJ, Sayette MA, Fiez JA (2004) Prefrontal responses to drug cues: a neurocognitive analysis. Nat Neurosci 7:211–214PubMedGoogle Scholar
  175. Yamamoto Y, Nishiyama Y, Monden T, Satoh K, Ohkawa M (2003) A study of the acute effect of smoking on cerebral blood flow using 99mTc-ECD SPET. Eur J Nucl Med Mol Imaging 30:612–614PubMedGoogle Scholar
  176. 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 50:2001–2008PubMedGoogle Scholar
  177. Yeomans J, Baptista M (1997) Both nicotinic and muscarinic receptors in ventral tegmental area contribute to brain-stimulation. Pharmacol Biochem Behav 57:915–921PubMedGoogle Scholar
  178. Yoshida M, Yokoo H, Tanaka T, Mizoguchi K, Emoto H, Ishii H, Tanaka M (1993) Facilitatory modulation of mesolimbic dopamine neuronal-activity by a mu-opioid agonist and nicotine as examined with in-vivo microdialysis. Brain Res 624:277–280PubMedGoogle Scholar
  179. 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 109:377–392PubMedGoogle Scholar
  180. Zubieta J, Lombardi U, Minoshima S, Guthrie S, Ni L, Ohl LE, Koeppe RA, Domino EF (2001) Regional cerebral blood flow effects of nicotine in overnight abstinent smokers. Biol Psychiatry 49:906–913PubMedGoogle Scholar
  181. Zubieta JK, Heitzeg MM, Xu Y, Koeppe RA, Ni L, Guthrie S, Domino EF (2005) Regional cerebral blood flow responses to smoking in tobacco smokers after overnight abstinence. Am J Psychiatry 162:567–577PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  • Anil Sharma
    • 1
  • Arthur L. Brody
    • 2
  1. 1.Department of Psychiatry and Biobehavioral Sciences, UCLA School of Medicine; Departments of Psychiatry and ResearchGreater Los Angeles VA Healthcare SystemLos AngelesUSA
  2. 2.Department of Psychiatry & Biobehavioral Sciences, UCLA School of Medicine; Departments of Psychiatry and ResearchGreater Los Angeles VA Healthcare SystemLos AngelesUSA

Personalised recommendations