Imaging Tobacco Smoking with PET and SPECT

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


Receptor imaging, including positron emission computed tomography (PET) and single photon emission computed tomography (SPECT), provides a way to measure chemicals of interest, such as receptors, and neurotransmitter fluctuations, in the living human brain. Imaging the neurochemical mechanisms involved in the maintenance and recovery from tobacco smoking has provided insights into critical smoking related brain adaptations. Nicotine, the primary addictive chemical in tobacco smoke, enters the brain, activates beta2-nicotinic acetylcholine receptors (β2*-nAChRs) and, like most drugs of abuse, elicits dopamine (DA) release in the ventral striatum. Both β2*-nAChRs and DA signaling are critical neurosubstrates underlying tobacco smoking behaviors and dependence and have been studied extensively with PET and SPECT brain imaging. We review the imaging literature on these topics and describe how brain imaging has helped inform the treatment of tobacco smoking.


Brain imaging  Smoking Nicotine Nicotinic acetylcholine receptors Dopamine PET SPECT 



Funding K02 DA031750 (Cosgrove) and K01 MH092681 (Esterlis).


  1. Abreu-Villaca Y, Seidler FJ, Qiao D, Tate CA, Cousins MM, Thillai I, Slotkin TA (2003) Short-term adolescent nicotine exposure has immediate and persistent effects on cholinergic systems: critical periods, patterns of exposure, dose thresholds. Neuropsychopharmacology 28:1935–1949PubMedCrossRefGoogle Scholar
  2. 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 54:65–71PubMedCrossRefGoogle Scholar
  3. Benwell M, Balfour D, Anderson J (1988) Evidence that tobacco smoking increases the density of (−)-[3H]nicotine binding site in human brain. J Neurochem 50:1243–1247PubMedCrossRefGoogle Scholar
  4. Breese C, Marks M, Logel J, Adams C, Sullivan B, Collins A, Leonard S (1997) Effect of smoking history on [3H]nicotine binding in human postmortem brain. J Pharmacol Exp Ther 282:7–13PubMedGoogle Scholar
  5. Breese C, Lee M, Adams C, Sullivan B, Logel J, Gillen K, Marks M, Collins A, Leonard S (2000) Abnormal regulation of high affinity nicotinic receptors in subjects with schizophrenia. Neuropsychopharmacology 23:351–364PubMedCrossRefGoogle Scholar
  6. Brody AL, Olmstead RE, London ED (2004) Smoking-induced ventral striatum dopamine release. Am J Psychiatry 161:1211–1218Google Scholar
  7. Brody AL, Mandelkern MA, London ED, Olmstead RE, Farahi J, Scheibal D, Jou J, Allen V, Tiongson E, Chefer SI, Koren AO, Mukhin AG (2006a) Cigarette smoking saturates brain alpha4 beta2 nicotinic acetylcholine receptors. Arch Gen Psychiatry 63:907–915PubMedCentralPubMedCrossRefGoogle Scholar
  8. Brody AL, Mandelkern MA, Olmstead RE, Scheibal D, Hahn E, Shiraga S, Zamora-Paja E, Farahi J, Saxena S, London ED, McCracken JT (2006b) Gene variants of brain dopamine pathways and smoking-induced dopamine release in the ventral caudate/nucleus accumbens. Arch Gen Psychiatry 63:808–816PubMedCentralPubMedCrossRefGoogle Scholar
  9. Brody AL, Mandelkern MA, Costello MR, Abrams AL, Scheibal D, Farahi J, London ED, Olmstead RE, Rose JE, Mukhin AG (2009) Brain nicotinic acetylcholine receptor occupancy: effect of smoking a denicotinized cigarette. Int J Neuropsychopharmacol 12:305–316Google Scholar
  10. Brody AL, London ED, Olmstead RE, Allen-Martinez Z, Shulenberger S, Costello MR, Abrams AL, Scheibal D, Farahi J, Shoptaw S, Mandelkern MA (2010) Smoking-induced change in intrasynaptic dopamine concentration: effect of treatment for tobacco dependence. Psychiatry Res 183:218–224PubMedCentralPubMedCrossRefGoogle Scholar
  11. Brody AL, Mandelkern MA, London ED, Khan A, Kozman D, Costello MR, Vellios EE, Archie MM, Bascom R, Mukhin AG (2012) Effect of secondhand smoke on occupancy of nicotinic acetylcholine receptors in brain. Arch Gen Psychiatry 68:953–960CrossRefGoogle Scholar
  12. Brody AL, Mukhin AG, La Charite J, Ta K, Farahi J, Sugar CA, Mamoun MS, Vellios E, Archie M, Kozman M, Phuong J, Arlorio F, Mandelkern MA (2013a) Up-regulation of nicotinic acetylcholine receptors in menthol cigarette smokers. Int J Neuropsychopharmacol 16:957–966PubMedCentralPubMedCrossRefGoogle Scholar
  13. Brody AL, Mukhin AG, Stephanie S, Mamoun MS, Kozman M, Phuong J, Neary M, Luu T, Mandelkern MA (2013b) Treatment for tobacco dependence: effect on brain nicotinic acetylcholine receptor density. Neuropsychopharmacology 38:1548–1556PubMedCentralPubMedCrossRefGoogle Scholar
  14. Brunzell DH, Boschen KE, Hendrick ES, Beardsley PM, McIntosh JM (2010) Alpha-conotoxin MII-sensitive nicotinic acetylcholine receptors in the nucleus accumbens shell regulate progressive ratio responding maintained by nicotine. Neuropsychopharmacology 35:665–673PubMedCentralPubMedCrossRefGoogle Scholar
  15. Collins A, Romm E, Wehner J (1990) Dissociation of the apparent relationship between nicotine tolerance and up-regulation of nicotinic receptors. Brain Res Bull 25:373–379PubMedCrossRefGoogle Scholar
  16. Cosgrove KP, Batis J, Bois F, Maciejewski PK, Esterlis I, Kloczynski T, Stiklus S, Krishnan-Sarin S, O’Malley S, Perry E, Tamagnan G, Seibyl JP, Staley JK (2009) beta2-Nicotinic acetylcholine receptor availability during acute and prolonged abstinence from tobacco smoking. Arch Gen Psychiatry 66:666–676PubMedCentralPubMedCrossRefGoogle Scholar
  17. Cosgrove KP, Esterlis I, McKee S, Bois F, Alagille D, Tamagnan GD, Seibyl JP, Krishnan-Sarin S, Staley JK (2010) Beta2* nicotinic acetylcholine receptors modulate pain sensitivity in acutely abstinent tobacco smokers. Nicotine Tob Res 12:535–539PubMedCentralPubMedCrossRefGoogle Scholar
  18. Cosgrove KP, Esterlis I, McKee SA, Bois F, Seibyl JP, Mazure CM, Krishnan-Sarin S, Staley JK, Picciotto MR, O’Malley SS (2012) Sex differences in availability of beta2*-nicotinic acetylcholine receptors in recently abstinent tobacco smokers. Arch Gen Psychiatry 69:418–427PubMedCentralPubMedCrossRefGoogle Scholar
  19. D’Souza D, Esterlis I, Carbuto M, Krasenics M, Seibyl J, Bois F, Pittman B, Ranganathan M, Cosgrove K, Staley J (2012) Lower β2*-nicotinic acetylcholine receptor availability in smokers with schizophrenia. Am J Psychiatry 169:326–334PubMedCrossRefGoogle Scholar
  20. 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 85:5274–5278PubMedCentralPubMedCrossRefGoogle Scholar
  21. Epping-Jordan M, Picciotto M, Changeux J, Pich EM (1999) Assessment of nicotinic acetylcholine receptor subunit contributions to nicotine self-administration in mutant mice. Psychopharmacology 147:25–26PubMedCrossRefGoogle Scholar
  22. Esterlis I, Mitsis EM, Batis JC, Bois F, Picciotto MR, Stiklus SM, Kloczynski T, Perry E, Seibyl JP, McKee S, Staley JK, Cosgrove KP (2011) Brain beta2*-nicotinic acetylcholine receptor occupancy after use of a nicotine inhaler. Int J Neuropsychopharmacol 14:389–398PubMedCentralPubMedCrossRefGoogle Scholar
  23. Esterlis I, Hannestad JO, Perkins E, Bois F, D’Souza DC, Tyndale RF, Seibyl JP, Hatsukami DM, Cosgrove KP, O’Malley SS (2013) Effect of a nicotine vaccine on nicotine binding to beta2*-nicotinic acetylcholine receptors in vivo in human tobacco smokers. Am J Psychiatry 170:399–407PubMedCentralPubMedCrossRefGoogle Scholar
  24. Girgis RR, Xu X, Miyake N, Easwaramoorthy B, Gunn RN, Rabiner EA, Abi-Dargham A, Slifstein M (2011) In vivo binding of antipsychotics to D(3) and D(2) receptors: a PET study in baboons with [(11)C]-(+)-PHNO. Neuropsychopharmacology 36:887–895PubMedCentralPubMedCrossRefGoogle Scholar
  25. Imperato A, Mulas A, DiChiara G (1986) Nicotine preferentially stimulates dopamine release n the limbic system of freely moving rats. Eur J Pharmacol 132:337–338PubMedCrossRefGoogle Scholar
  26. Kassiou M, Eberl S, Meikle S, Birrell A, Constable C, Fulham M, Wong D, Musachio J (2001) In vivo imaging of nicotinic receptor upregulation following chronic (−)-nicotine treatment in baboon using SPECT. Nuc Med Biol 28:165–175CrossRefGoogle Scholar
  27. Kim SJ, Sullivan JM, Wang S, Cosgrove KP, Morris ED (2014) Voxelwise lp-ntPET for detecting localized, transient dopamine release of unknown timing: sensitivity analysis and application to cigarette smoking in the PET scanner. Hum Brain Mapp 35:4876–4891PubMedCentralPubMedCrossRefGoogle Scholar
  28. Koranda JL, Cone JJ, McGehee DS, Roitman MF, Beeler JA, Zhuang X (2013) Nicotinic receptors regulate the dynamic range of dopamine release in vivo. J Neurophysiol 111:103–111PubMedCentralPubMedCrossRefGoogle Scholar
  29. Koylu E, Demirgoren S, London E, Pogun S (1997) Sex difference in up-regulation of nicotinic acetylcholine receptors in rat brain. Life Sci 61:PL185–PL190CrossRefGoogle Scholar
  30. Laruelle M (2000) Imaging synaptic neurotransmission with in vivo binding competition techniques: a critical review. J Cereb Blood Flow Metab 20:423–451PubMedCrossRefGoogle Scholar
  31. Le Foll B, Guranda M, Wilson AA, Houle S, Rusjan PM, Wing VC, Zawertailo L, Busto U, Selby P, Brody AL, George TP, Boileau I (2013) Elevation of dopamine induced by cigarette smoking: novel insights from a [(11)C]-(+)-PHNO PET study in humans. Neuropsychopharmacology 39:415–424PubMedCentralPubMedCrossRefGoogle Scholar
  32. Mamede M, Ishizu K, Ueda M, Mukai T, Iida Y, Kawashima H, Fukuyama H, Togashi K, Saji H (2007) Temporal change in human nicotinic acetylcholine receptor after smoking cessation: 5IA SPECT study. J Nucl Med 48:1829–1835PubMedCrossRefGoogle Scholar
  33. Marks MJ, Pauly JR, Gross SD, Deneris ES, Hermans-Borgmeyer I, Heinemann SF, Collins AC (1992) Nicotine binding and nicotinic receptor subunit RNA after chronic nicotine treatment. J Neurosci 12:2765–2784PubMedGoogle Scholar
  34. Marubio LM, del Mar Arroyo-Jimenez M, Cordero-Erausquin M, Lena C, Le Novere N, de Kerchove d’Exaerde A, Huchet M, Damaj MI, Changeux JP (1999) Reduced antinociception in mice lacking neuronal nicotinic receptor subunits. Nature 398:805–810Google Scholar
  35. Mochizuki T, Villemagne V, Scheffel U, Dannals R, Finley P, Zhan Y, Wagner H, Musachio J (1998) Nicotine induced up-regulation of nicotinic receptors in CD-1 mice demonstrated with an in vivo radiotracer: gender differences. Synapse 30:116–118PubMedCrossRefGoogle Scholar
  36. Montgomery AJ, Lingford-Hughes AR, Egerton A, Nutt DJ, Grasby PM (2007) The effect of nicotine on striatal dopamine release in man: a [11C]raclopride PET study. Synapse 61:637–645PubMedCrossRefGoogle Scholar
  37. Morris ED, Kim SJ, Sullivan JM, Wang S, Normandin MD, Constantinescu CC, Cosgrove KP (2013) Creating dynamic images of short-lived dopamine fluctuations with lp-ntPET: dopamine movies of cigarette smoking. J Vis Exp 78Google Scholar
  38. Mukhin AG, Kimes AS, Chefer SI, Matochik JA, Contoreggi CS, Horti AG, Vaupel DB, Pavlova O, Stein EA (2008) Greater nicotinic acetylcholine receptor density in smokers than in nonsmokers: a PET study with 2-18F-FA-85380. J Nucl Med 49:1628–1635PubMedCentralPubMedCrossRefGoogle Scholar
  39. Perkins KA (2009) Sex differences in nicotine reinforcement and reward: influences on the persistence of tobacco smoking. Nebr Symp Motiv 55:143–169PubMedCrossRefGoogle Scholar
  40. Perkins KA, Scott J (2008) Sex differences in long-term smoking cessation rates due to nicotine patch. Nicotine Tob Res 10:1245–1250PubMedCrossRefGoogle Scholar
  41. Perkins KA, Donny E, Caggiula AR (1999) Sex differences in nicotine effects and self-administration: review of human and animal evidence. Nicotine Tob Res 1:301–315PubMedCrossRefGoogle Scholar
  42. Picciotto M, Zoli M, Rimondin R, Lena C, Marubio L, Pich E, Fuxe K, Changeux J (1998) Acetycholine receptors containing the beta2 subunit are involved in the reinforcing properties of nicotine. Nature 391:173–177PubMedCrossRefGoogle Scholar
  43. Pietila K, Lahde T, Attila M, Ahtee L, Nordberg A (1998) Regulation of nicotinic receptors in the brain of mice withdrawn from chronic oral nicotine treatment. Naunyn-Schmiedeberg’s Arch Pharmacol 357:176–182CrossRefGoogle Scholar
  44. Rose JE, Mukhin AG, Lokitz SJ, Turkington TG, Herskovic J, Behm FM, Garg S, Garg PK (2010) Kinetics of brain nicotine accumulation in dependent and nondependent smokers assessed with PET and cigarettes containing 11C-nicotine. Proc Natl Acad Sci USA 107:5190–5195PubMedCentralPubMedCrossRefGoogle Scholar
  45. Scott DJ, Domino EF, Heitzeg MM, Koeppe RA, Ni L, Guthrie S, Zubieta JK (2007) Smoking modulation of mu-opioid and dopamine D2 receptor-mediated neurotransmission in humans. Neuropsychopharmacology 32:450–457PubMedCrossRefGoogle Scholar
  46. Srinivasan R, Pantoja R, Moss FJ, Mackey ED, Son CD, Miwa J, Lester HA (2010) Nicotine up-regulates alpha4beta2 nicotinic receptors and ER exit sites via stoichiometry-dependent chaperoning. J Gen Physiol 137:59–79CrossRefGoogle Scholar
  47. 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 26:8707–8714PubMedCrossRefGoogle Scholar
  48. Sullivan JM, Kim SJ, Cosgrove KP, Morris ED (2013) Limitations of SRTM, Logan graphical method, and equilibrium analysis for measuring transient dopamine release with [(11)C]raclopride PET. Am J Nucl Med Mol Imaging 3:247–260PubMedCentralPubMedGoogle Scholar
  49. Takahashi H, Fujimura Y, Hayashi M, Takano H, Kato M, Okubo Y, Kanno I, Ito H, Suhara T (2008) Enhanced dopamine release by nicotine in cigarette smokers: a double-blind, randomized, placebo-controlled pilot study. Int J Neuropsychopharmacol 11:413–417PubMedCrossRefGoogle Scholar
  50. Tritto T, McCallum SE, Waddle SA, Hutton SR, Paylor R, Collins AC, Marks MJ (2004) Null mutant analysis of responses to nicotine: deletion of beta2 nicotinic acetylcholine receptor subunit but not alpha7 subunit reduces sensitivity to nicotine-induced locomotor depression and hypothermia. Nicotine Tob Res 6:145–158PubMedCrossRefGoogle Scholar
  51. Tziortzi AC, Searle GE, Tzimopoulou S, Salinas C, Beaver JD, Jenkinson M, Laruelle M, Rabiner EA, Gunn RN (2011) Imaging dopamine receptors in humans with [11C]-(+)-PHNO: dissection of D3 signal and anatomy. Neuroimage 54:264–277PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Department of PsychiatryYale University School of MedicineNew HavenUSA
  2. 2.Department of Diagnostic RadiologyYale PET Center, Yale University School of MedicineNew HavenUSA
  3. 3.Department of Biomedical EngineeringYale PET Center, Yale University School of MedicineNew HavenUSA

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