Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD.
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
Nicotine Tob Res. 2020 May 26;22(6):892-899. doi: 10.1093/ntr/ntz080.
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.
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.
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.
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.
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.
吸烟仍然是世界上导致发病率和死亡率的最重要的行为因素之一。伐伦克林是一种α4β2 烟碱型乙酰胆碱受体（nAChR）部分激动剂，与基于尼古丁的产品相比，已被证明可提高戒烟率。这项人体实验室、双盲、安慰剂对照研究考察了伐伦克林和安慰剂对α4β2-nAChR 占有率、尼古丁诱导的[11C]raclopride 不可置换结合潜能（BPND）变化以及吸烟、尼古丁渴求及戒断行为测量的影响。
目前，尼古丁依赖的每日吸烟者（N=17）被随机分配接受伐伦克林 1mg，每日 2 次或安慰剂治疗 13 天。使用正电子发射断层扫描（PET），我们用[18F]AZAN 描述了α4β2-nAChR 占有率，用[11C]raclopride 描述了多巴胺受体结合，并用吸烟量、渴求及尼古丁戒断的行为测量进行了描述。
与安慰剂相比，伐伦克林在包括丘脑、中脑、壳核和腹侧纹状体在内的多个脑区显著降低了[18F]AZAN BPND。在给予受控剂量的尼古丁香烟后，与安慰剂组相比，伐伦克林治疗组腹侧纹状体中的多巴胺释放显著受到抑制。在[18F]AZAN 扫描期间测量的丘脑内的α4β2-nAChR BPND 与腹侧纹状体中 raclopride BPND 与尼古丁诱导的变化之间存在显著关系。
这是第一项证明在人类中，伐伦克林对α4β2-nAChR 的占有率与尼古丁使用后多巴胺释放量之间存在直接关系的研究。
通过像伐伦克林这样的部分激动剂药物阻断烟碱型受体如何促进戒烟一直不清楚。一种假设的机制是中脑边缘奖励多巴胺系统的下游抑制。在人类吸烟者中，我们首次观察到伐伦克林阻断α4β2-nACh 烟碱受体的程度与吸烟后多巴胺释放量之间存在直接关系。这对改善戒烟干预措施具有机制和治疗意义。
