Temporal Change in Human Nicotinic Acetylcholine Receptor After Smoking Cessation: 5IA SPECT Study

Abstract

Nicotinic acetylcholine receptors (nAChRs) are of great interest because they are implicated in various brain functions. They also are thought to play an important role in nicotine addiction of smokers. Chronic (2)-nicotine, a nAChR agonist, treatment in mice and rats elicits a dose-dependent increase in nAChRs in the brain. Upregulation of nAChRs in postmortem human brains of smokers has also been reported. However, changes in nAChRs after cigarette smoking cessation in humans are poorly understood. The aim of this study was to detect the dynamic changes of nAChRs after smoking and smoking cessation in the brains of living subjects. Methods: We performed 5-123 Iiodo-A-85380 ( 123 I-5IA) SPECT on nonsmokers and smokers (n 5 16) who had quit smoking for 4 h, 10 d, and 21 d and calculated and compared distribution volumes (Vt) of 123 I-5IA. Results: The binding potential of nAChRs (Vt of 123 I-5IA) in the brains of smokers decreased by 33.5% 6 10.5% after 4 h of smoking cessation, increased by 25.7% 6 9.2% after 10 d of smoking cessation, and decreased to the level of nonsmokers after 21 d of smoking cessation. Conclusion: Because the upregulation of the nAChRs of the smokers after chronic exposure of the nicotine was downregulated to the nonsmokers' level by around 21 d after smoking cessation, the upregulation is a temporary effect. The decrease in nicotinic receptors to nonsmoker levels may be the breaking point during the nicotine withdrawal period.

Treatment for Tobacco Dependence: Effect on Brain Nicotinic Acetylcholine Receptor Density

“…No associations between a 4 b 2 * nAChR densities and treatment type were found, but significant associations were discovered between the extent of a 4 b 2 * nAChR density reduction and the amount of decreased cigarette usage. These results indicate that a 4 b 2 * nAChR density is strongly linked to the number of cigarettes smoked per day, but not to the treatment type being administered, and are consistent with our previous study of untreated smokers (Brody et al, 2013) and other studies linking nicotine (Marks et al, 2011;Yates et al, 1995;Zhang et al, 2002) and cigarette smoke (Mamede et al, 2007;Mukhin et al, 2008;Staley et al, 2006;Wullner et al, 2008) exposure with upregulation of a 4 b 2 * nAChRs in brain regions other than the thalamus. Because education about the biological effects of smoking and quitting smoking are standard parts of smoking-cessation psychotherapy (Fiore et al, 2008), the additional information found here could prove useful in treatment of smokers by letting them know that brain receptor changes found with regular smoking tend toward normalization with smoking reduction and cessation.…”

“…ROIs were the prefrontal cortex, brainstem, and cerebellum, which were chosen for three reasons. First and most importantly, previous reports indicate that these ROIs (and most brain regions other than the thalamus) have upregulation of nAChR densities in cigarette smokers (Brody et al, 2013;Mamede et al, 2007;Mukhin et al, 2008;Staley et al, 2006;Wullner et al, 2008). Second, these ROIs have a range of 2-FA-binding levels from moderate to high (Brody et al, 2006;Brody et al, 2013;Kimes et al, 2008;Mukhin et al, 2008), which eliminates the issues of examining the highest nAChR density region (thalamus) as an experimental variable (because it does not have upregulation of nAChRs in smokers), and ROIs with very low nAChR density (eg, corpus callosum), which may have very small differences between groups or conditions.…”

“…In follow-up scanning, nAChR upregulation in smokers was found to normalize to levels of non-smokers when participants were given contingency management to maintain abstinence for roughly 3 (Mamede et al, 2007) to 12 (Cosgrove et al, 2009) weeks. However, to our knowledge, no one has yet reported the effects of commonly used, standard first-line treatments for cigarette smoking on nAChR density.…”

“…Previous brain imaging studies of human smokers, including a recent one by our group, have used positron emission tomography (PET) or single photon emission computed tomography to demonstrate upregulation of nAChRs in smokers compared with non-smoking controls in brain regions other than the thalamus (Brody et al, 2013;Cosgrove et al, 2009;Mamede et al, 2007;Mukhin et al, 2008;Staley et al, 2006;Wullner et al, 2008). In follow-up scanning, nAChR upregulation in smokers was found to normalize to levels of non-smokers when participants were given contingency management to maintain abstinence for roughly 3 (Mamede et al, 2007) to 12 (Cosgrove et al, 2009) weeks.…”

Differential contribution of genetic variation in multiple brain nicotinic cholinergic receptors to nicotine dependence: recent progress and emerging open questions

“…177 Upregulation following smoking cessation is time dependent, and 3 weeks later nAChRs were downregulated to the levels of nonsmokers. 178 The possible contribution of nAChR upregulation to the pathophysiology of ND is not fully understood, but is believed to be mediated by midbrain DA release. Vezina et al 168 have proposed that nicotine exposure produces temporary nAChR upregulation, leading to augmentation of midbrain dopaminergic neuron excitation and the induction of long-term potentiation.…”