Abstract
The cholinergic system is a critical mediator of cognition in animals. People who smoke cigarettes exhibit cognitive deficits, especially during quit attempts. Few studies jointly examine the cholinergic system and cognition in people while trying to quit smoking. We used positron emission tomography (PET) brain imaging with the β2-subunit containing nicotinic acetylcholine receptor (β2*-nAChR) partial agonist radioligand (-)-[18F]flubatine and the acetylcholinesterase inhibitor physostigmine to jointly examine the cholinergic system, smoking status, and cognition. (-)-[18F]Flubatine scans and cognitive data were acquired from twenty people who recently stopped smoking cigarettes (aged 38 ± 11 years; 6 female, 14 male; abstinent 7 ± 1 days) and 27 people who never smoked cigarettes (aged 29 ± 8 years; 11 female, 16 male). A subset of fifteen recently abstinent smokers and 21 never smokers received a mid-scan physostigmine challenge to increase acetylcholine levels. Regional volume of distribution (VT) was estimated with equilibrium analysis at “baseline” and post-physostigmine. Participants completed a cognitive battery prior to (-)-[18F]flubatine injection and physostigmine administration assessing executive function (Groton Maze Learning test), verbal learning (International Shopping List test), and working memory (One Back test). Physostigmine significantly decreased cortical (-)-[18F]flubatine VT, consistent with increased cortical acetylcholine levels reducing the number of β2*-nAChR sites available for (-)-[18F]flubatine binding, at comparable magnitudes across groups (p values < 0.05). A larger magnitude of physostigmine-induced decrease in (-)-[18F]flubatine VT was significantly associated with worse executive function in people who recently stopped smoking (p values < 0.05). These findings underscore the role of the cholinergic system in early smoking cessation and highlight the importance of neuroscience-informed treatment strategies.
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Acknowledgements
We thank the Yale PET Centre and research assistants Elizabeth Yanac and Ryan Cool for scan management and MRI analysis. We thank Dr. Nii Addy, Dr. Richard Carson, and Dr. Stephanie O’Malley for their insightful scientific contributions.
Funding
This work was supported by the National Institute on Drug Abuse (Grants R01 DA038832, K02 DA031750) and the National Institute on Alcohol Abuse and Alcoholism (Grant K01 AA024788). KCC and SRB were also supported by the National Institute of Neurological Disorders and Stroke (Grant T32 NS041228) and the National Institute on Drug Abuse (Grant K23 DA045957), respectively.
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KPC designed the study. KCC, ATH, JA, BL, SRB, GAA, DM, and KPC supervised recruitment and participation of human volunteers. SRB, GAA, and DM were study physicians. MK, MZ, and YH were study radiochemists. ATH performed image analysis. KCC analyzed clinical data and performed statistical analyses of imaging and clinical data. KCC and KPC drafted the initial manuscript. All authors contributed to editing this article.
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Calakos, K.C., Hillmer, A.T., Anderson, J.M. et al. Cholinergic system adaptations are associated with cognitive function in people recently abstinent from smoking: a (-)-[18F]flubatine PET study. Neuropsychopharmacol. 48, 683–689 (2023). https://doi.org/10.1038/s41386-023-01535-1
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DOI: https://doi.org/10.1038/s41386-023-01535-1
