Department of Psychiatry, Denver VA Medical Center, VISN19 MIRECC, Colorado, USA.
Biol Psychiatry. 2011 Jan 1;69(1):7-11. doi: 10.1016/j.biopsych.2010.07.004. Epub 2010 Aug 21.
3-(2,4-dimethoxybenzylidene)-anabaseine (DMXB-A) is a partial agonist at α7 nicotinic acetylcholine receptors that has been evaluated clinically for treatment of schizophrenia. This study examined the effects of DMXB-A on default network activity as a biomarker for drug effects on pathologic brain function associated with schizophrenia.
Placebo and two doses of DMXB-A were administered in a random, double-blind crossover design during a Phase 2 study of DMXB-A. Functional magnetic resonance imaging was performed on 16 nonsmoking patients with schizophrenia while they performed a simple eye movement task. Independent component analysis was used to identify the default network component. Default network changes were evaluated in the context of a polymorphism in CHRNA7, the α7-nicotinic acetylcholine receptor subunit gene, which was previously found to be associated with schizophrenia.
Compared with placebo, both 150 and 75 mg twice daily DMXB-A altered default network activity, including a reduction in posterior cingulate, inferior parietal cortex, and medial frontal gyrus activity and an increase in precuneus activity. The most robust difference, posterior cingulate activity reduction, was affected by CHRNA7 genotype.
The observed DMXB-A-related changes are consistent with improved default network function in schizophrenia. Pharmacogenetic analysis indicates mediation of the effect through the α7-nicotinic receptor. These results further implicate nicotinic cholinergic dysfunction in the disease and suggest that default network activity may be a useful indicator of biological effects of novel therapeutic agents.
3-(2,4-二甲氧基苯亚甲基)烟碱（DMXB-A）是一种α7 烟碱型乙酰胆碱受体部分激动剂，已在临床上评估其用于治疗精神分裂症。本研究通过评估 DXMBA 对默认网络活动的影响，以此作为药物对与精神分裂症相关的病理性大脑功能影响的生物标志物。
在 DXMBA 的 2 期研究中，采用随机、双盲交叉设计，给予安慰剂和两种剂量的 DXMBA。16 名非吸烟精神分裂症患者在执行简单眼球运动任务时进行功能磁共振成像。采用独立成分分析识别默认网络成分。在 CHRNA7 多态性的背景下评估默认网络的变化，CHRNA7 是α7 烟碱型乙酰胆碱受体亚基基因，先前发现其与精神分裂症有关。
与安慰剂相比，150 和 75mg 每日两次 DXMBA 均可改变默认网络活动，包括后扣带回、下顶叶皮层和内侧额回活动减少，楔前叶活动增加。最明显的差异是后扣带回活动减少，受 CHRNA7 基因型的影响。
观察到的 DXMBA 相关变化与精神分裂症中默认网络功能的改善一致。药物遗传学分析表明，该效应通过α7 烟碱受体介导。这些结果进一步表明，烟碱型胆碱能功能障碍与该疾病有关，并表明默认网络活动可能是新型治疗药物生物学效应的有用指标。
