Multiple sources of β2*-nicotinic acetylcholine receptor binding are differentially affected during tobacco smoking abstinence as revealed by Independent Component Analysis of [18F]Flubatine PET images

Tobacco smoking, a major cause of preventable mortality, upregulates β2 subunit-containing nicotinic acetylcholine receptors (β2*-nAChR) in most brain regions. Although the α4 subunit most frequently co-assembles with β2, other subunits likely assemble with β2 and contribute to distinct aspects of nicotine-mediated behaviors, but these factors are poorly understood in people. This work performed independent component analysis (ICA) of [18F]Flubatine positron emission tomography (PET) image data to identify maximally independent sources of specific binding to β2*-nAChRs. We then compared their magnitudes (loading coefficients) in people who recently stopped smoking cigarettes (abstinent smokers; n = 26) and people who never smoked cigarettes (non-smokers; n = 20). ICA identified 3 reproducible components: IC1 (36% of variance) in medial thalamus, lateral thalamus, and red nucleus; IC2 (18% of variance) in ventral thalamus, lateral geniculate, and midbrain; IC3 (19% of variance) in cerebellum and optic circuitry in midbrain. Nicotine challenge in an independent sample (n = 9) reduced loading coefficients of all components, confirming specific binding to nAChRs. Post-mortem autoradiography of cerebellum showed greatest [18F]Flubatine displacement by α3/α6β2*-nAChR blocker (α-Conotoxin MII) but low displacement by α6β2*-nAChR blocker (α-Conotoxin PIA), suggesting that IC3 measures α3β2*-nAChRs specific binding - a novel finding in living people. Loading coefficients of IC1 and IC2 were significantly lower in abstinent smokers compared to non-smokers. IC3 loading coefficients were significantly higher during extended smoking abstinence, and exploratory analyses suggested initial evidence for daily smoking amount correlating with nicotine dependence severity. These results could inform novel treatment development to help people quit smoking.