The Relationship of Varenicline Agonism of α4β2 Nicotinic Acetylcholine Receptors and Nicotine-Induced Dopamine Release in Nicotine-Dependent Humans

Introduction: Cigarette smoking continues to be one of the most important behavioral causes of morbidity and mortality in the world. Varenicline, an alpha 4 beta 2 nicotinic acetylcholine receptor (nAChR) partial agonist, has been shown to increase smoking quit rates compared with nicotine-based products.This human laboratory, double-blind, placebo-controlled study examined varenicline and placebo effects on alpha 4 beta 2-nAChRs occupancy, nicotine-induced change in [C-11]raclopride non-displaceable binding potential (BPND), and behavioral measures of cigarette smoking, nicotine craving, and withdrawal. Methods: Current nicotine dependent daily smokers (N = 17) were randomized to varenicline 1 mg twice daily or placebo for 13 days. Using positron emission tomography), we characterized alpha 4 beta 2-nAChRs occupancy using [F-18]AZAN and dopamine receptor binding using [C-11]raclopride as well as behavioral measures of cigarettes smoked, craving, and nicotine withdrawal. Results: Varenicline compared with placebo resulted in significant reductions in [F-18]AZAN BPND in multiple brain regions including thalamus, midbrain, putamen, and ventral striatum. Following administration of a controlled-dose nicotine cigarette, dopamine release was significantly suppressed in the ventral striatum in the varenicline-treated compared with the placebo group. There was a significant relationship between alpha 4 beta 2-nAChRs BPND measured in thalamus during the [F-18] AZAN scan and nicotine-induced change in raclopride BPND in the ventral striatum. Conclusion: This is the first human study to demonstrate a direct relationship between the extent of varenicline occupancy of alpha 4 beta 2-nAChRs and the magnitude of dopamine release following nicotine use.