The Relationship of Varenicline Agonism of α4β2 Nicotinic Acetylcholine Receptors and Nicotine-Induced Dopamine Release in Nicotine-Dependent Humans
| Autor: | Mary E. McCaul, Hiroto Kuwabara, Dean Wong, Gary S. Wand, Xiaoqiang Xu, Robert F. Dannals |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Adult
Male Nicotine Adolescent Dopamine medicine.medical_treatment Original Investigations Receptors Nicotinic Pharmacology Young Adult 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Double-Blind Method medicine Humans Nicotinic Agonists Varenicline Raclopride Maryland business.industry Smoking Public Health Environmental and Occupational Health Brain Dopamine receptor binding Middle Aged medicine.disease Substance Withdrawal Syndrome 030227 psychiatry Nicotinic acetylcholine receptor Nicotine withdrawal Nicotinic agonist chemistry Smoking cessation Female Smoking Cessation business 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Nicotine Tob Res |
| ISSN: | 1469-994X |
| DOI: | 10.1093/ntr/ntz080 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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