Cigarette Smoking Saturates Brain α4β2 Nicotinic Acetylcholine Receptors | Lifestyle Behaviors | JAMA Psychiatry | JAMA Network
[Skip to Navigation]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address Please contact the publisher to request reinstatement.
Michaud  CMMurray  CJBloom  BR Burden of disease—implications for future research.  JAMA 2001;285535- 539PubMedGoogle ScholarCrossref
Ezzati  MLopez  AD Estimates of global mortality attributable to smoking in 2000.  Lancet 2003;362847- 852PubMedGoogle ScholarCrossref
Fiore  MCBailey  WCCohen  SJDorfman  SFGoldstein  MGGritz  ERHeyman  RBJaén  CRKottke  TELando  HAMecklenburg  REMullen  PDNett  LMRobinson  LStitzer  MLTommasello  ACVillejo  LWewers  ME Treating Tobacco Use and Dependence: Clinical Practice Guideline.  Rockville, Md US Dept of Health and Human Services, Public Health Service2000;
Ashenden  RSilagy  CWeller  D A systematic review of the effectiveness of promoting lifestyle change in general practice.  Fam Pract 1997;14160- 176PubMedGoogle ScholarCrossref
Jorenby  DELeischow  SJNides  MARennard  SIJohnston  JAHughes  ARSmith  SSMuramoto  MLDaughton  DMDoan  KFiore  MCBaker  TB A controlled trial of sustained-release bupropion, a nicotine patch, or both for smoking cessation.  N Engl J Med 1999;340685- 691PubMedGoogle ScholarCrossref
Henningfield  JEFant  RV Tobacco use as drug addiction: the scientific foundation.  Nicotine Tob Res 1999;1 ((suppl 2)) S31- S35PubMedGoogle ScholarCrossref
Cohen  CPickworth  WBHenningfield  JE Cigarette smoking and addiction.  Clin Chest Med 1991;12701- 710PubMedGoogle Scholar
Koob  GF Drugs of abuse: anatomy, pharmacology and function of reward pathways.  Trends Pharmacol Sci 1992;13177- 184PubMedGoogle ScholarCrossref
West  RShiffman  S Effect of oral nicotine dosing forms on cigarette withdrawal symptoms and craving.  Psychopharmacology (Berl) 2001;155115- 122PubMedGoogle ScholarCrossref
Newhouse  PAPotter  ASingh  A Effects of nicotinic stimulation on cognitive performance.  Curr Opin Pharmacol 2004;436- 46PubMedGoogle ScholarCrossref
Ernst  MHeishman  SJSpurgeon  LLondon  ED Smoking history and nicotine effects on cognitive performance.  Neuropsychopharmacology 2001;25313- 319PubMedGoogle ScholarCrossref
Mendrek  AMonterosso  JSimon  SLJarvik  MBrody  AOlmstead  RDomier  CPCohen  MSErnst  MLondon  ED Working memory in cigarette smokers: comparison to non-smokers and effects of abstinence.  Addict Behav 2006;31833- 844PubMedGoogle ScholarCrossref
Lukas  RJChangeux  JPLe Novere  NAlbuquerque  EXBalfour  DJBerg  DKBertrand  DChiappinelli  VAClarke  PBCollins  ACDani  JAGrady  SRKellar  KJLindstrom  JMMarks  MJQuik  MTaylor  PWWonnacott  S International Union of Pharmacology, XX: current status of the nomenclature for nicotinic acetylcholine receptors and their subunits.  Pharmacol Rev 1999;51397- 401PubMedGoogle Scholar
Di Chiara  GImperato  A Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats.  Proc Natl Acad Sci U S A 1988;855274- 5278PubMedGoogle ScholarCrossref
Pontieri  FETanda  GOrzi  FDi Chiara  G Effects of nicotine on the nucleus accumbens and similarity to those of addictive drugs.  Nature 1996;382255- 257PubMedGoogle ScholarCrossref
SzirakiLipovac  MNHashim  ASershen  HAllen  DCooper  TCzobor  PLajtha  A Differences in nicotine-induced dopamine release and nicotine pharmacokinetics between Lewis and Fischer 344 rats.  Neurochem Res 2001;26609- 617PubMedGoogle ScholarCrossref
Damsma  GDay  JFibiger  HC Lack of tolerance to nicotine-induced dopamine release in the nucleus accumbens.  Eur J Pharmacol 1989;168363- 368PubMedGoogle ScholarCrossref
Corrigall  WACoen  KMAdamson  KL Self-administered nicotine activates the mesolimbic dopamine system through the ventral tegmental area.  Brain Res 1994;653278- 284PubMedGoogle ScholarCrossref
Mansvelder  HDKeath  JRMcGehee  DS Synaptic mechanisms underlie nicotine-induced excitability of brain reward areas.  Neuron 2002;33905- 919PubMedGoogle ScholarCrossref
Leshner  AIKoob  GF Drugs of abuse and the brain.  Proc Assoc Am Physicians 1999;11199- 108PubMedGoogle ScholarCrossref
Tapper  ARMcKinney  SLNashmi  RSchwarz  JDeshpande  PLabarca  CWhiteaker  PMarks  MJCollins  ACLester  HA Nicotine activation of alpha4* receptors: sufficient for reward, tolerance, and sensitization.  Science 2004;3061029- 1032PubMedGoogle ScholarCrossref
Picciotto  MRZoli  MChangeux  JP Use of knock-out mice to determine the molecular basis for the actions of nicotine.  Nicotine Tob Res 1999;1 ((suppl 2)) S121- S125PubMedGoogle ScholarCrossref
Salminen  OMurphy  KLMcIntosh  JMDrago  JMarks  MJCollins  ACGrady  SR Subunit composition and pharmacology of two classes of striatal presynaptic nicotinic acetylcholine receptors mediating dopamine release in mice.  Mol Pharmacol 2004;651526- 1535PubMedGoogle ScholarCrossref
Liu  XKoren  AOYee  SKPechnick  RNPoland  RELondon  ED Self-administration of 5-iodo-A-85380, a beta 2-selective nicotinic receptor ligand, by operantly trained rats.  Neuroreport 2003;141503- 1505PubMedGoogle ScholarCrossref
Maskos  UMolles  BEPons  SBesson  MGuiard  BPGuilloux  JPEvrard  ACazala  PCormier  AMameli-Engvall  MDufour  NCloez-Tayarani  IBemelmans  APMallet  JGardier  AMDavid  VFaure  PGranon  SChangeux  JP Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors.  Nature 2005;436103- 107PubMedGoogle ScholarCrossref
Sihver  WNordberg  ALangstrom  BMukhin  AGKoren  AOKimes  ASLondon  ED Development of ligands for in vivo imaging of cerebral nicotinic receptors.  Behav Brain Res 2000;113143- 157PubMedGoogle ScholarCrossref
Benowitz  NLPorchet  HJacob  PI Pharmacokinetics, metabolism, and pharmacodynamics of nicotine. In:Wonnacott  SRussell  MAHStolerman  IPeds. Nicotine Psychopharmacology: Molecular, Cellular, and Behavioural Aspects. Oxford, England Oxford University Press1990;112- 157Google Scholar
Koren  AOHorti  AGMukhin  AGGundisch  DKimes  ASDannals  RFLondon  ED 2-, 5-, and 6-halo-3-(2(S)-azetidinylmethoxy)pyridines.  J Med Chem 1998;413690- 3698PubMedGoogle ScholarCrossref
Chefer  SILondon  EDKoren  AOPavlova  OAKurian  VKimes  ASHorti  AGMukhin  AG Graphical analysis of 2-[F-18]FA binding to nicotinic acetylcholine receptors in rhesus monkey brain.  Synapse 2003;4825- 34PubMedGoogle ScholarCrossref
Gallezot  JDBottlaender  MGregoire  MCRoumenov  DDeverre  JRCoulon  COttaviani  MDolle  FSyrota  AValette  H In vivo imaging of human cerebral nicotinic acetylcholine receptors with 2-18F-fluoro-A-85380 and PET.  J Nucl Med 2005;46240- 247PubMedGoogle Scholar
Valette  HBottlaender  MDolle  FCoulon  COttaviani  MSyrota  A Long-lasting occupancy of central nicotinic acetylcholine receptors after smoking: a PET study in monkeys.  J Neurochem 2003;84105- 111PubMedGoogle ScholarCrossref
Ding  YSVolkow  NDLogan  JGarza  VPappas  NKing  PFowler  JS Occupancy of brain nicotinic acetylcholine receptors by nicotine doses equivalent to those obtained when smoking a cigarette.  Synapse 2000;35234- 237PubMedGoogle ScholarCrossref
Obrzut  SLKoren  AOMandelkern  MABrody  ALHoh  CKLondon  ED Whole-body radiation dosimetry of 2-[18F]fluoro-A-85380 in human PET imaging studies.  Nucl Med Biol 2005;32869- 874Google ScholarCrossref
Mitkovski  SVillemagne  VLNovakovic  KEO'Keefe  GTochon-Danguy  HMulligan  RSDickinson  KLSaunder  TGregoire  MCBottlaender  MDolle  FRowe  CC Simplified quantification of nicotinic acetylcholine receptors with 2[18F]F-A-85380 PET.  Nucl Med Biol 2005;32585- 591PubMedGoogle ScholarCrossref
Kimes  ASHorti  AGLondon  EDChefer  SIContoreggi  CErnst  MFriello  PKoren  AOKurian  VMatochik  JAPavlova  OVaupel  DBMukhin  AG 2-[18F]F-A-85380: PET imaging of brain nicotinic acetylcholine receptors and whole body distribution in humans.  FASEB J 2003;171331- 1333PubMedGoogle Scholar
First  MBSpitzer  RLGibbon  MWilliams  JBW Structured Clinical Interview for DSM-IV Axis I Disorders–Patient Edition (SCID-I/P, version 2.0).  New York Biometrics Research Department, New York State Psychiatric Institute1995;
Fagerström  KO Measuring the degree of physical dependence to tobacco smoking with reference to individualization of treatment.  Addict Behav 1978;3235- 241PubMedGoogle ScholarCrossref
Heatherton  TFKozlowski  LTFrecker  RCFagerström  KO The Fagerström Test for Nicotine Dependence: a revision of the Fagerström Tolerance Questionnaire.  Br J Addict 1991;861119- 1127PubMedGoogle ScholarCrossref
Beck  ATWard  CHMendelson  MMock  JErbaugh  J An inventory for measuring depression.  Arch Gen Psychiatry 1961;4561- 571PubMedGoogle ScholarCrossref
Spielberger  C Manual for the State-Trait Anxiety Inventory.  Palo Alto, Calif Consulting Psychologists Press1983;
Shiffman  SMJarvik  ME Smoking withdrawal symptoms in two weeks of abstinence.  Psychopharmacology (Berl) 1976;5035- 39PubMedGoogle ScholarCrossref
Carson  RE PET physiological measurements using constant infusion.  Nucl Med Biol 2000;27657- 660PubMedGoogle ScholarCrossref
Carson  REChanning  MABlasberg  RGDunn  BBCohen  RMRice  KCHerscovitch  P Comparison of bolus and infusion methods for receptor quantitation.  J Cereb Blood Flow Metab 1993;1324- 42PubMedGoogle ScholarCrossref
US Federal Trade Commission, “Tar,” Nicotine, and Carbon Monoxide of the Smoke of 1294 Varieties of Domestic Cigarettes for the Year 1998.  Washington, DC US Federal Trade Commission2000;
Jacob  P  IIIWilson  MBenowitz  NL Improved gas chromatographic method for the determination of nicotine and cotinine in biologic fluids.  J Chromatogr 1981;22261- 70PubMedGoogle ScholarCrossref
Jarvik  MEMadsen  DCOlmstead  REIwamoto-Schaap  PNElins  JLBenowitz  NL Nicotine blood levels and subjective craving for cigarettes.  Pharmacol Biochem Behav 2000;66553- 558PubMedGoogle ScholarCrossref
Brody  ALMandelkern  MALondon  EDChildress  ARLee  GSBota  RGHo  MLSaxena  SBaxter  LR  JrMadsen  DJarvik  ME Brain metabolic changes during cigarette craving.  Arch Gen Psychiatry 2002;591162- 1172PubMedGoogle ScholarCrossref
Dhawan  VKazumata  KRobeson  WBelakhlef  AMargouleff  CChaly  TNakamura  TDahl  RMargouleff  DEidelberg  D Quantitative brain PET: comparison of 2D and 3D acquisitions on the GE Advance Scanner.  Clin Positron Imaging 1998;1135- 144PubMedGoogle ScholarCrossref
Doll  FDolci  LValette  HHinnen  FVaufrey  FGuenther  IFuseau  CCoulon  CBottlaender  MCrouzel  C Synthesis and nicotinic acetylcholine receptor in vivo binding properties of 2-fluoro-3-[2(S)-2-azetidinylmethoxypyridine.  J Med Chem 1999;422251- 2299PubMedGoogle ScholarCrossref
Woods  RPMazziotta  JCCherry  SR MRI-PET registration with automated algorithm.  J Comput Assist Tomogr 1993;17536- 546PubMedGoogle ScholarCrossref
London  EDWaller  SBWamsley  JK Autoradiographic localization of [3H]nicotine binding sites in the rat brain.  Neurosci Lett 1985;53179- 184PubMedGoogle ScholarCrossref
Villemagne  VLHorti  AScheffel  URavert  HTFinley  PClough  DJLondon  EDWagner  HN  JrDannals  RF Imaging nicotinic acetylcholine receptors with fluorine-18-FPH, an epibatidine analog.  J Nucl Med 1997;381737- 1741PubMedGoogle Scholar
Fujita  MIchise  Mvan Dyck  CHZoghbi  SSTamagnan  GMukhin  AGBozkurt  ASeneca  NTipre  DDeNucci  CCIida  HVaupel  DBHorti  AGKoren  AOKimes  ASLondon  EDSeibyl  JPBaldwin  RMInnis  RB Quantification of nicotinic acetylcholine receptors in human brain using [I-123]5-I-A-85380 SPET.  Eur J Nucl Med Mol Imaging 2003;301620- 1629PubMedGoogle ScholarCrossref
Valette  HBottlaender  MDolle  FGuenther  ICoulon  CHinnen  FFuseau  COttaviani  MCrouzel  C Characterization of the nicotinic ligand 2-[F-18]fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine in vivo.  Life Sci 1999;64PL93- PL97PubMedGoogle Scholar
Ichise  MMeyer  JHYonekura  Y An introduction to PET and SPECT neuroreceptor quantification models.  J Nucl Med 2001;42755- 763PubMedGoogle Scholar
Hukkanen  JJacob  P  IIIBenowitz  NL Metabolism and disposition kinetics of nicotine.  Pharmacol Rev 2005;5779- 115PubMedGoogle ScholarCrossref
Paradiso  KGSteinbach  JH Nicotine is highly effective at producing desensitization of rat alpha4beta2 neuronal nicotinic receptors.  J Physiol 2003;553857- 871PubMedGoogle ScholarCrossref
Quick  MWLester  RA Desensitization of neuronal nicotinic receptors.  J Neurobiol 2002;53457- 478PubMedGoogle ScholarCrossref
Benwell  MEBalfour  DJKAnderson  JM Evidence that tobacco smoking increases the density of (-)-[3H]nicotine binding sites in human brain.  J Neurochem 1988;501243- 1247PubMedGoogle ScholarCrossref
Breese  CRMarks  MJLogel  JAdams  CESullivan  BCollins  ACLeonard  S Effect of smoking history on [3H]nicotine binding in human postmortem brain.  J Pharmacol Exp Ther 1997;2827- 13PubMedGoogle Scholar
Rice  MECragg  SJ Nicotine amplifies reward-related dopamine signals in striatum.  Nat Neurosci 2004;7583- 584PubMedGoogle ScholarCrossref
Zhang  HSulzer  D Frequency-dependent modulation of dopamine release by nicotine.  Nat Neurosci 2004;7581- 582PubMedGoogle ScholarCrossref
Robinson  MLHoutsmuller  EJMoolchan  ETPickworth  WB Placebo cigarettes in smoking research.  Exp Clin Psychopharmacol 2000;8326- 332PubMedGoogle ScholarCrossref
Chefer  SIMukhin  AGHorti  AGKoren  ADPavlova  OIKurian  VStratton  MKimes  ASLondon  ED 2-[18F]-fluoro-a-85380. In: Proceedings of the International Conference on Mathematics and Engineering Techniques in Medicine and Biology2000;409- 415
Henningfield  JEStapleton  JMBenowitz  NLGrayson  RFLondon  ED Higher levels of nicotine in arterial than in venous blood after cigarette smoking.  Drug Alcohol Depend 1993;3323- 29PubMedGoogle ScholarCrossref
Luck  WNau  HHansen  RSteldinger  R Extent of nicotine and cotinine transfer to the human fetus, placenta and amniotic fluid of smoking mothers.  Dev Pharmacol Ther 1985;8384- 395PubMedGoogle Scholar
Becker  ABManfreda  JFerguson  ACDimich-Ward  HWatson  WTChan-Yeung  M Breast-feeding and environmental tobacco smoke exposure.  Arch Pediatr Adolesc Med 1999;153689- 691PubMedGoogle ScholarCrossref
Jarvis  MJRussell  MAFeyerabend  C Absorption of nicotine and carbon monoxide from passive smoking under natural conditions of exposure.  Thorax 1983;38829- 833PubMedGoogle ScholarCrossref
Jarvis  MJ Uptake of environmental tobacco smoke.  IARC Sci Publ 1987; ((87)) 43- 58PubMedGoogle Scholar
Original Article
August 2006

Cigarette Smoking Saturates Brain α4β2 Nicotinic Acetylcholine Receptors

Author Affiliations

Author Affiliations: Department of Psychiatry and Biobehavioral Sciences (Drs Brody and London, Mr Scheibal, and Mss Jou, Allen, and Tiongson), University of California, Los Angeles; Greater Los Angeles Veterans Affairs Healthcare System Positron Emission Tomography Center (Drs Brody, Mandelkern, London, Olmstead, and Farahi, Mr Scheibal, and Mss Jou, Allen, and Tiongson), Los Angeles; Department of Physics, University of California, Irvine (Dr Mandelkern); Intramural Research Program, Neuroimaging Research Branch, National Institute on Drug Abuse, Rockville, Md (Drs Chefer and Mukhin); and Institute for Neurodegenerative Disorders, New Haven, Conn (Dr Koren).

Arch Gen Psychiatry. 2006;63(8):907-914. doi:10.1001/archpsyc.63.8.907

Context  2-[18F]fluoro-3-(2(S)-azetidinylmethoxy) pyridine (2-F-A-85380, abbreviated as 2-FA) is a recently developed radioligand that allows for visualization of brain α4β2* nicotinic acetylcholine receptors (nAChRs) with positron emission tomography (PET) scanning in humans.

Objective  To determine the effect of cigarette smoking on α4β2* nAChR occupancy in tobacco-dependent smokers.

Design  Fourteen 2-FA PET scanning sessions were performed. During the PET scanning sessions, subjects smoked 1 of 5 amounts (none, 1 puff, 3 puffs, 1 full cigarette, or to satiety [2½ to 3 cigarettes]).

Setting  Academic brain imaging center.

Participants  Eleven tobacco-dependent smokers (paid volunteers).

Main Outcome Measure  Dose-dependent effect of smoking on occupancy of α4β2* nAChRs, as measured with 2-FA and PET in nAChR-rich brain regions.

Results  Smoking 0.13 (1 to 2 puffs) of a cigarette resulted in 50% occupancy of α4β2* nAChRs for 3.1 hours after smoking. Smoking a full cigarette (or more) resulted in more than 88% receptor occupancy and was accompanied by a reduction in cigarette craving. A venous plasma nicotine concentration of 0.87 ng/mL (roughly 1/25th of the level achieved in typical daily smokers) was associated with 50% occupancy of α4β2* nAChRs.

Conclusions  Cigarette smoking in amounts used by typical daily smokers leads to nearly complete occupancy of α4β2* nAChRs, indicating that tobacco-dependent smokers maintain α4β2* nAChR saturation throughout the day. Because prolonged binding of nicotine to α4β2* nAChRs is associated with desensitization of these receptors, the extent of receptor occupancy found herein suggests that smoking may lead to withdrawal alleviation by maintaining nAChRs in the desensitized state.