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Brain β2*-nicotinic acetylcholine receptor occupancy after use of a nicotine inhaler

  • Irina Esterlis (a1), Effie M. Mitsis (a2), Jeffery C. Batis (a3), Frederic Bois (a1), Marina R. Picciotto (a1), Stephanie M. Stiklus (a1), Tracy Kloczynski (a1), Edward Perry (a1), John P. Seibyl (a3), Sherry McKee (a1), Julie K. Staley (a1) (a4) and Kelly P. Cosgrove (a1)...

The Nicotrol® (Pfizer, USA) nicotine inhaler reduces craving by mimicking the behavioural component of cigarettes and delivering controlled doses of nicotine, which binds to the beta-2 subunit-containing nicotinic acetylcholine receptors (β2*-nAChRs). Previous studies examined β2*-nAChR occupancy after administration of regular and low-nicotine cigarettes. Here, we measured occupancy of β2*-nAChRs after administration of nicotine via inhaler, and the relationship between occupancy and changes in craving for tobacco smoking and withdrawal symptoms. Tobacco smokers participated in [123I]5-IA-85380 SPECT studies with either a nicotine inhaler (n=9) or tobacco cigarette (n=4) challenge. [123I]5-IA was administered as a bolus plus constant infusion. After equilibrium was achieved, three 30-min baseline scans were collected, and subjects either used the nicotine inhaler or a regular cigarette, and up to six additional scans were obtained. Receptor occupancy was determined based on the Lassen plot method. Craving for tobacco smoking and withdrawal symptoms were evaluated pre- and post-challenge. Use of the nicotine inhaler produced an average 55.9±6.4% occupancy of β2*-nAChRs 2–5 h post-challenge, whereas use of a cigarette produced significantly higher receptor occupancy (F=10.6, p=0.009) with an average 67.6±14.1% occupancy 1.5–5 h post-challenge. There was a significant decrease in withdrawal symptoms post-nicotine inhaler use (F=6.13, p=0.04). These results demonstrate significant differences in occupancy of β2*-nAChRs by nicotine after use of the inhaler vs. a cigarette and confirm the ability of the nicotine inhaler to relieve withdrawal symptoms.

Corresponding author
Address for correspondence: I. Esterlis, Ph.D., Yale University and VACHS, 950 Campbell Ave, 116A6, West Haven, CT 06516, USA. Tel.: 203-932-5711 (ext. 3109)Fax: 203-937-3897Email:
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N Benowitz (1999). Nicotine addiction. Primary Care 26, 611631.

M Bergstrom , A Nordberg , E Lunell , G Aton , (1995). Regional disposition of inhaled 11C-vapor in the human airways as visualized by positron emission tomography. Clinical Pharmacological Therapy 57, 309317.

A Brody , M Mandelkern , M Costello , A Abrams , (2009). Brain nicotinic cetylcholine receptor occupancy: effect of smoking a denicotinized cigarette. International Journal of Neuropsychopharmacology 12, 305316.

A Brody , M Mandelkern , E London , R Olmstead , (2006). Cigarette smoking saturates brain alpha 4 beta 2 nicotinic acetylcholine receptors. Archives of General Psychiatry 63, 907915.

B Caldwell , S Dickson , C Burgess , R Siebers , (2009). A pilot study of nicotine delivery to smokers from a metered-dose inhaler. Nicotine and Tobacco Research 11, 342347.

V Cunningham , E Rabiner , M Slifstein , M Laruelle , RN Gunn (2010). Measuring drug occupancy in the absence of a reference region: the Lassen plot re-visited. Journal of Cerebral Blood Flow and Metabolism 30, 4650.

C Endres , R Carson (1998). Assessment of dynamic neurotransmitter changes with bolus or infusion delivery of neuroreceptor ligands. Journal of Cerebral Blood Flow and Metabolism 18, 11961210.

M Epping-Jordan , M Picciotto , J Changeux , EM Pich (1999). Assessment of nicotinic acetylcholine receptor subunit contributions to nicotine self-administration in mutant mice. Psychopharmacology 147, 2526.

I Esterlis , K Cosgrove , (2010). Quantification of smoking induced occupancy of β2-nicotinic acetylcholine receptors: estimation of nondisplaceable binding. Journal of Nuclear Medicine 51, 12261233.

M Fujita , G Tamagnan , SS Zoghbi , MS Al-Tikriti , (2010). Measurement of alpha4beta2 nicotinic acetylcholine receptors with [123I]5-I-A-85380 SPECT. Journal of Nuclear Medicine 41, 15521560.

S Gourlay , N Benowitz (1997). Arteriovenous differences in plasma concentration of nicotine and catecholamines and related cardiovascular effects after smoking, nicotine nasal spray and intravenous nicotine. Clinical Pharmacological Therapy 62, 453463.

M Hariharan , T VanNoord , JF Greden (1988). A high-performance liquid-chromatographic method for routine simultaneous determination of nicotine and cotinine in plasma. Clinical Chemistry 34, 724729.

D Hatsukami , J Hughes , R Pickens , D Svikis (1984). Tobacco withdrawal symptoms: An experimental analysis. Psychopharmacology 84, 231236.

T Heatherton , L Kozlowski , R Frecker , K Fagerstrom (1991). The Fagerstrom test for nicotine dependence: a revision of the Fagerstrom tolerance questionnaire. British Journal of Addiction 86, 11191127.

J Henningfield , J Stapletom , N Benowitz , R Grayson , (1993). Higher levels of nicotine in arterial than in venous blood after cigarette smoking. Drug and Alcohol Dependence 33, 2329.

R Innis , V Cunningham , J Delforge , M Fujita , (2007). Consensus nomenclature for in vivo imaging of reversibly binding radioligands. Journal of Cerebral Blood Flow and Metabolism 27, 15331539.

A Kahlil , S Steyn , N Castagnoli (2000). Isolation and characterization of monoamine oxidase inhibitor from tobacco leaves. Chemistry Research and Toxicology 13, 3135.

E Lunell , M Bergström , G Antoni , B Långström , A Nordberg (1996). Nicotine deposition and body distribution from a nicotine inhaler and a cigarette studied with positron emission tomography. Clinical Pharmacology and Therapeutics 59, 593594.

H Mansvelder , J Keath , D McGehee (2002). Synaptic mechanisms underlie nicotine induced excitability of brain reward areas. Neuron 33, 905919.

U Maskos , B Molles , S Pons , M Besson , (2005). Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors. Nature 436, 103107.

D Meyers , J Neuberger (2008). Cardiovascular effect of bans on smoking in public places. American Journal of Cardiology 102, 14211424.

D Monchuk , M Rousu , J Shogren , J Nonnemaker , (2007). Decomposing the value of cigarettes using experimental auctions. Nicotine and Tobacco Research 9, 9399.

E Nestler (2005). Is there a common molecular pathway for addiction? Nature Neuroscience. 8, 14451449.

M Rice , S Cragg (2004). Nicotine amplifies reward-related dopamine signals in striatum. Nature Neuroscience 7, 583584.

J Roll , S Higgins , G Badger (1996). An experimental comparison of three different schedules of reinforcement of drug abstinence using cigarette smoking as an exemplar. Journal of Applied Behavior Analysis 29, 495504.

J Rose , F Behm (2004). Extinguishing the rewarding value of smoke cues: Pharmacological and behavioral treatments. Nicotine and Tobacco Research 6, 523532.

N Schneider , C Cortner , J Gould , MKR Olmstead (2008). Comparison of craving and withdrawal among four combination nicotine treatments. Human Psychopharmacology 23, 513517.

N Schneider , R Olmstead , M Franzon , E Lunell (2001). The Nicotine Inhaler: Clinical pharmacokinetics and comparison with other nicotine treatments. Clinical Pharmacokinetics 40, 661684.

N Schneider , S Terrace , M Koury , S Patel , (2005). Comparison of three nicotine treatments: initial reactions and preferences with guided use. Psychopharmacology (Berlin) 182, 545550.

M Sofuoglu , M Mouratidis , S Yoo , KCT Kosten (2005). Effects of tiagabine in combination with intravenous nicotine in overnight abstinent smokers. Psychopharmacology (Berlin) 181, 504510.

J Staley , S Krishnan-Sarin , K Cosgrove , E Krantzler , (2006). Human tobacco smokers in early abstinence have higher levels of beta2-nicotinic acetylcholine receptors than nonsmokers. Journal of Neuroscience 26, 87078714.

M Stitzer , G Bigelow (1985). Contingent reinforcement for reduced breath carbon monoxide levels: target-specific effects on cigarette smoking. Addictive Behavior 10, 345349.

M Stitzer , C Rand , G Bigelow , A Mead (1986). Contingent payment procedures for smoking reduction and cessation. Journal of Applied Behavioral Analysis 19, 197202.

I Stolerman , M Shoaib (1991). The neurobiology of tobacco addiction. Trends in Pharmacological Science 12, 467473.

S Tiffany , D Drobes (1991). The development and initial validation of a questionnaire on smoking urges. British Journal of Addictions 86, 14671476.

P Tønnesen (2009). Smoking cessation: How compelling is the evidence? A review. Health Policy 91 (Suppl. 1), S15S25.

D Vaupel , A Mukhin , A Kimes , A Horti , (1998). In vivo studies with [125I]5-IA 85380, a nicotinic acetylcholine receptor radioligand. NeuroReport 9, 23112317.

H Zhang , D Sulzer (2004). Frequency-dependent modulation of dopamine release by nicotine. Nature Neuroscience 7, 581582.

S Zoghbi , G Tamagnan , M Fujita , R Baldwin , (2001). Measurement of plasma metabolites of (S)-5-[123I]iodo-3-(2-azetidinylmethoxy) pyridine (5-IA-85380), a nicotinic acetylcholine receptor imaging agent, in non-human primates. Nuclear Medicine and Biology 28, 9196.

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The International Journal of Neuropsychopharmacology
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