1] Vanderbilt Center for Cognitive Medicine, Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN, USA [2] Clinical Neuroscience Research Unit, Department of Psychiatry, University of Vermont College of Medicine, Burlington, VT, USA.
Neuropsychopharmacology. 2013 Dec;38(13):2632-43. doi: 10.1038/npp.2013.172. Epub 2013 Jul 19.
Tamoxifen (TMX) is a selective estrogen receptor modulator that is used as an estrogen receptor antagonist for the treatment and prevention of breast cancer. Whether TMX has antagonist activities in the human brain is less clear and its effects on cognitive function have not been experimentally explored. This study examined how TMX affected cognitive performance in older women using a model of anticholinergic drug-induced cognitive dysfunction. Twenty-one postmenopausal women were administered 20 mg of oral TMX or placebo for 3 months. Participants then took part in five drug challenges using the anticholinergic antinicotinic agent mecamylamine (MECA) and antimuscarinic agent scopolamine (SCOP) and were tested on a comprehensive battery including tasks of attention and psychomotor function, verbal episodic memory, and spatial navigation. After a 3-month placebo washout, participants were then crossed over to the alternate treatment and repeated the drug challenges after 3 months. Compared with placebo treatment, TMX significantly attenuated the impairment from cholinergic blockade on tasks of verbal episodic memory and spatial navigation, but effects on attentional/psychomotor tasks were more variable. Analysis by APOE genotype showed that APO ɛ4+ women showed a greater beneficial effect of TMX on reversing the cholinergic impairment than APO ɛ4- women on most tasks. This study provides evidence that TMX may act as an estrogen-like agonist to enhance cholinergic system activity and hippocampally mediated learning.
他莫昔芬（TMX）是一种选择性雌激素受体调节剂，用作雌激素受体拮抗剂，用于治疗和预防乳腺癌。TMX 在人类大脑中是否具有拮抗剂活性尚不清楚，其对认知功能的影响也尚未通过实验进行探索。本研究使用抗胆碱能药物引起的认知功能障碍模型，研究了 TMX 如何影响老年女性的认知表现。21 名绝经后妇女接受 20mg 口服 TMX 或安慰剂治疗 3 个月。然后，参与者参加了 5 次药物挑战，使用抗胆碱能烟碱激动剂美加明（MECA）和抗毒蕈碱剂东莨菪碱（SCOP），并在包括注意力和精神运动功能、词语情节记忆和空间导航在内的综合测试中进行了测试。在 3 个月的安慰剂洗脱期后，参与者交叉到交替治疗，并在 3 个月后重复药物挑战。与安慰剂治疗相比，TMX 显着减轻了胆碱能阻断对词语情节记忆和空间导航任务的损害，但对注意力/精神运动任务的影响更为多变。通过 APOE 基因型分析表明，APO ɛ4+女性在大多数任务中，TMX 对逆转胆碱能损伤的有益作用大于 APO ɛ4-女性。本研究提供的证据表明，TMX 可能作为一种雌激素样激动剂，增强胆碱能系统的活性和海马介导的学习。
