Center for Interdisciplinary Research on Nicotine Addiction, Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA.
Drug Alcohol Depend. 2013 Dec 15;133(3):852-6. doi: 10.1016/j.drugalcdep.2013.09.003. Epub 2013 Sep 14.
Dopamine levels in the prefrontal cortex (PFC) are thought to play an important role in cognitive function and nicotine dependence. The catechol-O-methyltransferase (COMT) inhibitor tolcapone, an FDA-approved treatment for Parkinson's disease, increases prefrontal dopamine levels, with cognitive benefits that may vary by COMT genotype. We tested whether tolcapone alters working memory-related brain activity and performance in abstinent smokers.
In this double-blind crossover study, 20 smokers completed 8 days of treatment with tolcapone and placebo. In both medication periods, smokers completed blood oxygen level-dependent (BOLD) fMRI scans while performing a working memory N-back task after 24h of abstinence. Smokers were genotyped prospectively for the COMT val(158)met polymorphism for exploratory analysis.
Compared to placebo, tolcapone modestly improved accuracy (p=0.017) and enhanced suppression of activation in the ventromedial prefrontal cortex (vmPFC) (p=0.002). There were no effects of medication in other a priori regions of interest (dorsolateral PFC, dorsal cingulate/medial prefrontal cortex, or posterior cingulate cortex). Exploratory analyses suggested that tolcapone led to a decrease in BOLD signal in several regions among smokers with val/val genotypes, but increased or remained unchanged among met allele carriers. Tolcapone did not attenuate craving, mood, or withdrawal symptoms compared to placebo.
Data from this proof-of-concept study do not provide strong support for further evaluation of COMT inhibitors as smoking cessation aids.
前额皮质（PFC）中的多巴胺水平被认为在认知功能和尼古丁依赖中发挥重要作用。儿茶酚-O-甲基转移酶（COMT）抑制剂托卡朋是一种获得 FDA 批准的治疗帕金森病的药物，可增加前额叶多巴胺水平，其认知益处可能因 COMT 基因型而异。我们测试了托卡朋是否会改变戒烟者的与工作记忆相关的大脑活动和表现。
在这项双盲交叉研究中，20 名吸烟者完成了托卡朋和安慰剂的 8 天治疗。在两种药物治疗期间，吸烟者在 24 小时戒烟后完成了血氧水平依赖（BOLD）fMRI 扫描，同时执行工作记忆 N-back 任务。前瞻性地对 COMT val(158)met 多态性进行基因分型，用于探索性分析。
与安慰剂相比，托卡朋适度提高了准确性（p=0.017），并增强了腹内侧前额皮质（vmPFC）的激活抑制（p=0.002）。在其他预先设定的兴趣区域（背外侧前额叶、背侧扣带/内侧前额叶或后扣带皮质）中，药物没有影响。探索性分析表明，托卡朋导致 val/val 基因型吸烟者的几个区域的 BOLD 信号减少，但在 met 等位基因携带者中增加或保持不变。与安慰剂相比，托卡朋并没有减轻吸烟渴求、情绪或戒断症状。
这项概念验证研究的数据并未为进一步评估 COMT 抑制剂作为戒烟辅助手段提供有力支持。
