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

Abstract

Introduction: Cigarette smoking continues to be one of the most important behavioral causes of morbidity and mortality in the world. Varenicline, an α4β2 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 α4β2-nAChRs occupancy, nicotine-induced change in [11C]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 α4β2-nAChRs occupancy using [18F]AZAN and dopamine receptor binding using [11C]raclopride as well as behavioral measures of cigarettes smoked, craving, and nicotine withdrawal.

Results: Varenicline compared with placebo resulted in significant reductions in [18F]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 α4β2-nAChRs BPND measured in thalamus during the [18F]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 α4β2-nAChRs and the magnitude of dopamine release following nicotine use.

Implications: It has remained unclear how nicotinic receptor blockade through partial agonist medications such as varenicline promotes smoking cessation. One hypothesized mechanism is downstream dampening of the mesolimbic reward dopamine system. For the first time in human smokers, we observed a direct relationship between the extent of varenicline blockade of α4β2-nACh nicotinic receptors and the magnitude of dopamine release following smoking. This has mechanistic and therapeutic implications for improving smoking cessation interventions.

Figure 1.

Mean and standard error of [18F]AZAN non-displaceable binding potential (BP_ND) in selected brain regions for varenicline- and placebo-treated groups. Light gray bars represented placebo-treated participants and dark gray bars represent varenicline-treated participants. Group differences in α4β2 nAChRs BP_ND were examined in midbrain (MB), thalamus (Th), caudate nucleus (CN), putamen (Pu), and ventral striatum (vS). Group differences were significant in all regions except CN.

Figure 2.

Association of [18F]AZAN non-displaceable binding potential (BP_ND) and the number of cigarettes smoked on study day 10 in thalamus (Th) and ventral striatum (vS) for all study participants. Because there was no main effect of medication on these relationships, placebo- and varenicline-treated participants were combined for these analyses. There was a positive association, with higher α4β2-nAChR BP_ND correlated with greater number of cigarettes smoked in five of six regions. Two regions are shown: Th (β = .598, p = .031) and vS (β = .652, p = .016). VOI = volume of interest.

Figure 3.

Histogram (mean boxes and standard error bars) of change in [¹¹C]raclopride non-displaceable binding potential (BP_ND) in the active cigarette smoking scan relative to the placebo cigarette smoking scan for varenicline- and placebo-treated groups in three brain regions. Light gray bars represented placebo-treated participants and dark gray bars represent varenicline-treated participants. Change in binding potential was significantly lower in the ventral striatum (vS) for the varenicline compared with placebo group (−10.9 [SD = 10.7] vs. 0.0 [SD = 5.8], p = .030). There was a trend for similar effects in caudate nucleus (CN; 5.4 [SD = 8.3] vs. 13.8 [SD = 7.7], p = .076) and putamen (Pu; 2.4 [SD = 6.2] vs. 9.6 [SD = 7.8], p = .089). VOI = volumes of interest.

Figure 4.

Relationship between α4β2-nAChR occupancy by AZAN in thalamus (Th) and nicotine-induced dopamine release in the ventral striatum (vS). There was a significant interaction between AZAN occupancy and dopamine release as a function of treatment condition (placebo-treatment [+]; varenicline-treatment [o]).