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The Journal of Neuroscience, August 23, 2006, 26(34):8707-8714; doi:10.1523/JNEUROSCI.0546-06.2006

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Neurobiology of Disease
Human Tobacco Smokers in Early Abstinence Have Higher Levels of ₂* Nicotinic Acetylcholine Receptors than Nonsmokers

Julie K. Staley,^1,3 Suchitra Krishnan-Sarin,¹ Kelly P. Cosgrove,^1,3 Erica Krantzler,^1,3 Erin Frohlich,^1,3 Edward Perry,^1,3 Joel A. Dubin,¹ Kristina Estok,^1,3 Eric Brenner,^1,3 Ronald M. Baldwin,^1,3 Gilles D. Tamagnan,^1,3,4 John P. Seibyl,^1,4 Peter Jatlow,^1,2 Marina R. Picciotto,¹ Edythe D. London,⁵ Stephanie O'Malley,¹ and Christopher H. van Dyck¹

¹Departments of Psychiatry and ²Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut 06511, ³Veterans Administration Connecticut Healthcare System, West Haven, Connecticut 06516, ⁴Institute for Neurodegenerative Disorders, New Haven, Connecticut 06510, and ⁵Departments of Psychiatry and Biobehavioral Sciences, and Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90024

Correspondence should be addressed to Dr. Julie K. Staley, Department of Psychiatry, Yale University and Veterans Administration Connecticut Hospital System 116A2, 950 Campbell Avenue, West Haven, CT 06516. Email: julie.staley{at}yale.edu

Nicotine, the addictive chemical in tobacco smoke, initiates its actions in brain through nicotinic acetylcholine receptors (nAChRs). In particular, nAChRs containing ₂-subunits (₂*-nAChRs) the most prevalent subtype, mediate the reinforcing properties of nicotine. We hypothesized that abnormal numbers of ₂*-nAChRs during early abstinence contribute to the perpetuation of addiction to tobacco smoking. Using molecular imaging, specifically single-photon emission computed tomography with the nAChR agonist radiotracer [¹²³I]5-IA-85380 ([¹²³I]5-IA), we imaged ₂*-nAChR availability in human smokers. First, using nonhuman primates treated chronically with nicotine, we estimated the time interval necessary for smokers to abstain from smoking so that residual nicotine would not interfere with [¹²³I]5-IA binding to the ₂*-nAChR as 7 d. Thus, we imaged human smokers at 6.8 ± 1.9 d (mean ± SD) of abstinence. Abstinence was confirmed by daily assessments of urinary cotinine and expired carbon monoxide levels. In smokers, [¹²³I]5-IA uptake was significantly higher throughout the cerebral cortex (26–36%) and in the striatum (27%) than in nonsmokers, suggesting higher ₂*-nAChR in recently abstinent smokers. ₂*-nAChR availability in recently abstinent smokers correlated with the days since last cigarette and the urge to smoke to relieve withdrawal symptoms but not the severity of nicotine dependence, severity of nicotine withdrawal, or the desire to smoke. Higher brain ₂*-nAChR during early abstinence indicates that, when smokers quit smoking, they do so in the face of a significant increase in the receptors normally activated by nicotine. Greater ₂*-nAChR availability during early abstinence may impact the ability of smokers to maintain abstinence.

Key words: brain; nicotine; nicotinic acetylcholine receptor; human; smokers; addiction; thalamus

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Received Feb. 6, 2006; revised June 16, 2006; accepted July 5, 2006.

Correspondence should be addressed to Dr. Julie K. Staley, Department of Psychiatry, Yale University and Veterans Administration Connecticut Hospital System 116A2, 950 Campbell Avenue, West Haven, CT 06516. Email: julie.staley{at}yale.edu

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