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

2019 ◽  
Vol 22 (6) ◽  
pp. 892-899 ◽  
Author(s):  
Mary E McCaul ◽  
Gary S Wand ◽  
Hiroto Kuwabara ◽  
Robert F Dannals ◽  
Dean Wong ◽  
...  
Keyword(s):  
Smoking Cessation ◽  
Cigarette Smoking ◽  
Dopamine Release ◽  
Direct Relationship ◽  
Ventral Striatum ◽  
Partial Agonist ◽  
Controlled Study ◽  
Behavioral Measures ◽  
Nicotinic Acetylcholine ◽  
Dopamine Receptor Binding

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.

scholarly journals Varenicline: For smoking cessation

1970 ◽  
Vol 7 (2) ◽  
pp. 162-164 ◽  
Author(s):  
J Rao ◽  
PK Shankar
Keyword(s):  
Clinical Trials ◽  
Smoking Cessation ◽  
Medical Journal ◽  
Sustained Release ◽  
Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptor ◽  
Partial Agonist ◽  
Efficacy And Safety ◽  
Nicotinic Acetylcholine ◽  
Superior Efficacy

Varenicline, a partial agonist of α4β2 nicotinic acetylcholine receptor (nAChR), is the most recently approved drug for smoking cessation. Despite the availability of effective treatments for smoking cessation, such as nicotine replacement therapy and Bupropion sustained-release, abstinence rates remain less than optimal. As a nAChR partial agonist, Varenicline attenuates the craving and withdrawal symptoms that occur with abstinence from nicotine and also reduces the rewarding effects of nicotine obtained from smoking in patients who lapse. Clinical trials have demonstrated superior efficacy of this drug over Bupropion-SR for achieving abstinence from smoking, and Varenicline has also been shown to significantly delay smoking relapse. As the latest agent approved for smoking cessation, the mechanism of action, efficacy, and safety of Varenicline has been reviewed in this paper. Key words: α4β2 nicotinic acetylcholine receptor; Varenicline; smoking cessation; partial agonist. DOI: 10.3126/kumj.v7i2.2714 Kathmandu University Medical Journal (2009) Vol.7, No.2 Issue 26, 162-164

scholarly journals Changes in Biomarkers of Exposure on Switching From a Conventional Cigarette to the glo Tobacco Heating Product: A Randomized, Controlled Ambulatory Study

2020 ◽  
Author(s):  
Nathan Gale ◽  
Michael McEwan ◽  
Oscar M Camacho ◽  
George Hardie ◽  
James Murphy ◽  
...  
Keyword(s):  
Smoking Cessation ◽  
Cigarette Smoking ◽  
Tobacco Product ◽  
Ambulatory Setting ◽  
Controlled Study ◽  
Control Group ◽  
Clinical Trial Registration ◽  
Randomized Controlled ◽  
Biomarkers Of Exposure ◽  
Never Smokers

Abstract Introduction Tobacco heating products (THPs) generate lower machine yields of toxicants compared to those found in conventional cigarette smoke. During use, these products are likely to expose users to lower levels of particulate matter and harmful and potentially harmful compounds compared with smoking cigarettes. Aims and Methods This randomized, controlled study is investigating whether biomarkers of exposure (BoE) to smoke toxicants are reduced when smokers switch from smoking cigarettes to using the glo THP in a naturalistic, ambulatory setting. Control groups include smokers who are abstaining from cigarette smoking and never-smokers. At a baseline study visit, 24-hour urine samples and spot blood samples were taken for BoE analysis, and exhaled carbon monoxide was also measured. N-(2-cyanoethyl) valine (CEVal) was used as a marker of compliance in subjects asked to refrain from combustible cigarette smoking. Subjects are being followed up at periodic intervals for 360 days; this article presents data following a planned interim analysis at day 90. Results In continuing smokers, BoE remained stable between baseline (day 1) and day 90. In both per-protocol and CEVal-compliant analysis populations, reductions in BoE were observed in subjects switching to using glo or undergoing smoking cessation. These reductions were statistically significant for a number of BoE when switching to glo was compared with continued smoking. Furthermore, in both populations, reductions observed in subjects switching to using glo were comparable to those seen with smoking cessation and were also to levels similar to those seen in never-smokers. Conclusion glo is a reduced-exposure tobacco product. Implications This clinical study builds on a previous 5-day confinement study and demonstrates that when smokers switched from smoking combustible cigarettes to using the glo THP in a naturalistic, ambulatory setting, their exposure to tobacco smoke toxicants was significantly decreased. For most BoE examined, this was to the same extent as that seen when a control group of smokers ceased cigarette smoking, or even to levels seen in never-smoker controls. This indicates that glo is a reduced-exposure product with the potential to be a reduced-risk tobacco product, when used by smokers whose cigarette consumption is displaced completely. Clinical trial registration ISRCTN81075760.

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