Department of Psychiatry, Denver VA Medical Center VISN19 MIRECC and University of Colorado Denver, Aurora, CO 80045, USA.
Neuropsychopharmacology. 2010 Mar;35(4):938-42. doi: 10.1038/npp.2009.196. Epub 2009 Dec 2.
3-(2,4-Dimethoxybenzylidene)-anabaseine (DMXB-A) is a partial agonist at alpha7-nicotinic acetylcholine receptors and is now in early clinical development for treatment of deficits in neurocognition and sensory gating in schizophrenia. During its initial phase 2 test, functional magnetic resonance imaging (fMRI) studies were conducted to determine whether the drug had its intended effect on hippocampal inhibitory interneurons. Increased hemodynamic activity in the hippocampus in schizophrenia is found during many tasks, including smooth pursuit eye movements, and may reflect inhibitory dysfunction. Placebo and two doses of drug were administered in a random, double-blind crossover design. After the morning drug/placebo ingestion, subjects underwent fMRI while performing a smooth pursuit eye movement task. Data were analyzed from 16 nonsmoking patients, including 7 women and 9 men. The 150-mg dose of DMXB-A, compared with placebo, diminished the activity of the hippocampus during pursuit eye movements, but the 75-mg dose was ineffective. The effect at the 150-mg dose was negatively correlated with plasma drug levels. The findings are consistent with the previously established function of alpha7-nicotinic receptors on inhibitory interneurons in the hippocampus and with genetic evidence for deficits in these receptors in schizophrenia. Imaging of drug response is useful in planning future clinical tests of this compound and other nicotinic agonists for schizophrenia.
3-(2,4-二甲氧基苯亚甲基)纳曲酮（DMXB-A）是一种α7-烟碱型乙酰胆碱受体部分激动剂，目前正处于治疗精神分裂症认知功能障碍和感觉门控缺陷的早期临床开发阶段。在其最初的 2 期测试中，进行了功能磁共振成像（fMRI）研究，以确定该药物是否对海马抑制性中间神经元产生预期的作用。在许多任务中，包括平滑追踪眼动，都发现精神分裂症患者的海马体血液动力学活动增加，这可能反映了抑制功能障碍。采用随机、双盲交叉设计，给予安慰剂和两种剂量的药物。在早晨服药/安慰剂后，受测者在执行平滑追踪眼动任务时接受 fMRI 检查。对 16 名不吸烟的患者进行了数据分析，其中包括 7 名女性和 9 名男性。与安慰剂相比，DMXB-A 的 150mg 剂量可减少平滑追踪眼动期间海马体的活动，但 75mg 剂量则无效。150mg 剂量的效果与血浆药物水平呈负相关。这些发现与先前建立的α7-烟碱型受体在海马体抑制性中间神经元中的功能以及这些受体在精神分裂症中的遗传缺陷证据一致。对药物反应的成像对规划这种化合物和其他用于治疗精神分裂症的烟碱激动剂的未来临床试验非常有用。
