Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Ramiro Barcelos 2350 (2 andar Centro de Pesquisas Básicas), 90035-003, Porto Alegre, Brazil.
Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, 90035-003, Porto Alegre, RS, Brazil.
J Neural Transm (Vienna). 2017 Nov;124(11):1331-1339. doi: 10.1007/s00702-017-1785-9. Epub 2017 Sep 2.
Over two-thirds of women with breast cancer have positive tumors for hormone receptors, and these patients undergo treatment with endocrine therapy, tamoxifen being the most widely used agent. Despite being very effective in breast cancer treatment, tamoxifen is associated with side effects that include cognitive impairments. However, the specific aspects and mechanisms underlying these impairments remain to be characterized. Here, we have investigated the effects of tamoxifen and interaction with estrogen receptors on formation of memory for inhibitory avoidance conditioning in female rats. In the first experiment, Wistar female rats received a single oral dose of tamoxifen (1, 3, or 10 mg/kg) or saline by gavage immediately after training and were tested for memory consolidation 24 h after training. In the second experiment, rats received a single dose of 1 mg/kg tamoxifen or saline by gavage 3 h after training and were tested 24 h after training for memory consolidation. In the third experiment, rats received a subcutaneous injection with estrogen receptor α agonist or estrogen receptor beta agonist 30 min before the training. After training, rats received a single oral dose of tamoxifen 1 mg/kg or saline and were tested 24 h after training. In the fourth experiment, rats were trained and tested 24 h later. Immediately after test, rats received a single dose of tamoxifen (1 mg/kg) or saline by gavage and were given four additional daily test trials followed by a re-instatement. Tamoxifen at 1 mg/kg impaired memory consolidation when given immediately after training and the estrogen receptor alpha agonist improved the tamoxifen-related memory impairment. Moreover, tamoxifen impairs memory consolidation of the test. These findings indicate that estrogen receptors regulate the early phase of memory consolidation and the effects of tamoxifen on memory consolidation.
超过三分之二的乳腺癌患者的肿瘤激素受体呈阳性，这些患者接受内分泌治疗，他莫昔芬是最广泛使用的药物。尽管他莫昔芬在乳腺癌治疗中非常有效，但它与包括认知障碍在内的副作用有关。然而，这些损伤的具体方面和机制仍有待描述。在这里，我们研究了他莫昔芬及其与雌激素受体相互作用对雌性大鼠抑制性回避条件反射记忆形成的影响。在第一个实验中，Wistar 雌性大鼠在训练后立即接受单次口服他莫昔芬（1、3 或 10mg/kg）或生理盐水灌胃，并在训练后 24 小时进行记忆巩固测试。在第二个实验中，大鼠在训练后 3 小时接受单次 1mg/kg 他莫昔芬或生理盐水灌胃，并在训练后 24 小时进行记忆巩固测试。在第三个实验中，大鼠在训练前 30 分钟接受皮下注射雌激素受体 α 激动剂或雌激素受体 β 激动剂。训练后，大鼠接受单次 1mg/kg 他莫昔芬或生理盐水口服，并在训练后 24 小时进行测试。在第四个实验中，大鼠进行训练和测试 24 小时后。测试后立即，大鼠接受单次 1mg/kg 他莫昔芬或生理盐水灌胃，并给予 4 次额外的每日测试试验，随后进行再呈现。他莫昔芬在 1mg/kg 时在训练后立即给药会损害记忆巩固，而雌激素受体α激动剂则改善了他莫昔芬相关的记忆损伤。此外，他莫昔芬损害了测试的记忆巩固。这些发现表明，雌激素受体调节记忆巩固的早期阶段，以及他莫昔芬对记忆巩固的影响。
