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

Overview

Journal Nicotine Tob Res

Publisher Oxford University Press

Specialty Public Health

Date 2019 May 17

PMID 31096265

Citations 5

Authors

Mary E McCaul

Gary S Wand

Hiroto Kuwabara

Robert F Dannals

Dean Wong

Xiaoqiang Xu

Affiliations

Soon will be listed here.

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.

Citing Articles

An overview of traditional smoking cessation interventions and E-cigarettes.

Alshehri F Front Pharmacol. 2024; 15:1293062.

PMID: 39104396 PMC: 11298375. DOI: 10.3389/fphar.2024.1293062.

Imaging Cholinergic Receptors in the Brain by Positron Emission Tomography.

Zhang J, Fu H, Lin R, Zhou J, Haider A, Fang W J Med Chem. 2023; 66(16):10889-10916.

PMID: 37583063 PMC: 10461233. DOI: 10.1021/acs.jmedchem.3c00573.

An inhibitory brainstem input to dopamine neurons encodes nicotine aversion.

Liu C, Tose A, Verharen J, Zhu Y, Tang L, de Jong J Neuron. 2022; 110(18):3018-3035.e7.

PMID: 35921846 PMC: 9509462. DOI: 10.1016/j.neuron.2022.07.003.

Tobacco Smoking and Liver Risk: Potential Avenues for Carcinogenesis.

Jain D, Chaudhary P, Varshney N, Razzak K, Verma D, Khan Zahra T J Oncol. 2021; 2021:5905357.

PMID: 34925509 PMC: 8683172. DOI: 10.1155/2021/5905357.

Safety of varenicline as an aid to smoking cessation in professional drivers and its impact on driving behaviors: An observational cohort study of taxi drivers in Beijing.

Chu S, Liang L, Jing H, Zhang D, Tong Z Tob Induc Dis. 2020; 18:45.

PMID: 32494237 PMC: 7263361. DOI: 10.18332/tid/120935.

References

Tiffany S, Drobes D . The development and initial validation of a questionnaire on smoking urges. Br J Addict. 1991; 86(11):1467-76. DOI: 10.1111/j.1360-0443.1991.tb01732.x. View

Hendricks P, Ditre J, Drobes D, Brandon T . The early time course of smoking withdrawal effects. Psychopharmacology (Berl). 2006; 187(3):385-96. DOI: 10.1007/s00213-006-0429-9. View

Oswald L, Wong D, McCaul M, Zhou Y, Kuwabara H, Choi L . Relationships among ventral striatal dopamine release, cortisol secretion, and subjective responses to amphetamine. Neuropsychopharmacology. 2005; 30(4):821-32. DOI: 10.1038/sj.npp.1300667. View

Ashare R, Tang K, Mesaros A, Blair I, Leone F, Strasser A . Effects of 21 days of varenicline versus placebo on smoking behaviors and urges among non-treatment seeking smokers. J Psychopharmacol. 2012; 26(10):1383-90. PMC: 3526838. DOI: 10.1177/0269881112449397. View

Mawlawi O, Martinez D, Slifstein M, Broft A, Chatterjee R, Hwang D . Imaging human mesolimbic dopamine transmission with positron emission tomography: I. Accuracy and precision of D(2) receptor parameter measurements in ventral striatum. J Cereb Blood Flow Metab. 2001; 21(9):1034-57. DOI: 10.1097/00004647-200109000-00002. View

Carson R, Breier A, de Bartolomeis A, Saunders R, Su T, Schmall B . Quantification of amphetamine-induced changes in [11C]raclopride binding with continuous infusion. J Cereb Blood Flow Metab. 1997; 17(4):437-47. DOI: 10.1097/00004647-199704000-00009. View

Patenaude B, Smith S, Kennedy D, Jenkinson M . A Bayesian model of shape and appearance for subcortical brain segmentation. Neuroimage. 2011; 56(3):907-22. PMC: 3417233. DOI: 10.1016/j.neuroimage.2011.02.046. View

Jorenby D, Hays J, Rigotti N, Azoulay S, Watsky E, Williams K . Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial. JAMA. 2006; 296(1):56-63. DOI: 10.1001/jama.296.1.56. View

Patterson F, Jepson C, Strasser A, Loughead J, Perkins K, Gur R . Varenicline improves mood and cognition during smoking abstinence. Biol Psychiatry. 2008; 65(2):144-9. PMC: 2615779. DOI: 10.1016/j.biopsych.2008.08.028. View

10.

Rollema H, Chambers L, Coe J, Glowa J, Hurst R, Lebel L . Pharmacological profile of the alpha4beta2 nicotinic acetylcholine receptor partial agonist varenicline, an effective smoking cessation aid. Neuropharmacology. 2006; 52(3):985-94. DOI: 10.1016/j.neuropharm.2006.10.016. View

11.

Kimes A, Chefer S, Matochik J, Contoreggi C, Vaupel D, Stein E . Quantification of nicotinic acetylcholine receptors in the human brain with PET: bolus plus infusion administration of 2-[18F]F-A85380. Neuroimage. 2007; 39(2):717-27. PMC: 2386978. DOI: 10.1016/j.neuroimage.2007.09.015. View

12.

Saunders J, Aasland O, Babor T, De la Fuente J, Grant M . Development of the Alcohol Use Disorders Identification Test (AUDIT): WHO Collaborative Project on Early Detection of Persons with Harmful Alcohol Consumption--II. Addiction. 1993; 88(6):791-804. DOI: 10.1111/j.1360-0443.1993.tb02093.x. View

13.

Brody A, Hubert R, Mamoun M, Enoki R, Garcia L, Abraham P . Nicotinic acetylcholine receptor availability in cigarette smokers: effect of heavy caffeine or marijuana use. Psychopharmacology (Berl). 2016; 233(17):3249-57. PMC: 4982797. DOI: 10.1007/s00213-016-4367-x. View

14.

Pidoplichko V, Debiasi M, Williams J, Dani J . Nicotine activates and desensitizes midbrain dopamine neurons. Nature. 1997; 390(6658):401-4. DOI: 10.1038/37120. View

15.

Pomerleau O, Fagerstrom K, Marks J, Tate J, Pomerleau C . Development and validation of a self-rating scale for positive- and negative-reinforcement smoking: The Michigan Nicotine Reinforcement Questionnaire. Nicotine Tob Res. 2003; 5(5):711-8. DOI: 10.1080/1462220031000158627. View

16.

Posner K, Brown G, Stanley B, Brent D, Yershova K, Oquendo M . The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. 2011; 168(12):1266-77. PMC: 3893686. DOI: 10.1176/appi.ajp.2011.10111704. View

17.

Ehrin E, Farde L, de Paulis T, Eriksson L, Greitz T, Johnstrom P . Preparation of 11C-labelled Raclopride, a new potent dopamine receptor antagonist: preliminary PET studies of cerebral dopamine receptors in the monkey. Int J Appl Radiat Isot. 1985; 36(4):269-73. DOI: 10.1016/0020-708x(85)90083-3. View

18.

Pomerleau C, Carton S, Lutzke M, Flessland K, Pomerleau O . Reliability of the Fagerstrom Tolerance Questionnaire and the Fagerstrom Test for Nicotine Dependence. Addict Behav. 1994; 19(1):33-9. DOI: 10.1016/0306-4603(94)90049-3. View

19.

Hughes J . Effects of abstinence from tobacco: valid symptoms and time course. Nicotine Tob Res. 2007; 9(3):315-27. DOI: 10.1080/14622200701188919. View

20.

Gao Y, Wang H, Mease R, Pomper M, Horti A . Improved Syntheses of Precursors for PET Radioligands [F]XTRA and [F]AZAN. Tetrahedron Lett. 2010; 51(40):5333-5335. PMC: 2936105. DOI: 10.1016/j.tetlet.2010.08.001. View