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The anticancer estrogen receptor antagonist tamoxifen impairs consolidation of inhibitory avoidance memory through estrogen receptor alpha

  • Translational Neurosciences - Original Article
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Abstract

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.

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Acknowledgements

This research was supported by the National Council for Scientific and Technological Development (CNPq; Grant Numbers 484185/2012-8, 303276/2013-4, and 400705/2014-1 to R.R); the National Science Foundation (IOS 1121886 to M.B.P.); the Children’s Cancer Institute (ICI); the Clinical Hospital institutional research fund (FIPE/HCPA); and the South American Office for Anticancer Drug Development. The funding sources had no role in the collection, analysis, and interpretation of data, in the writing of the report, and in the decision to submit the paper for publication.

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Authors and Affiliations

  1. 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

    Martina Lichtenfels, Arethuza da Silva Dornelles, Fernanda dos Santos Petry, Martina Blank, Caroline Brunetto de Farias, Rafael Roesler & Gilberto Schwartsmann

  2. Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, 90035-003, Porto Alegre, RS, Brazil

    Martina Lichtenfels, Arethuza da Silva Dornelles, Fernanda dos Santos Petry, Martina Blank & Rafael Roesler

  3. Division of Molecular Genome Analysis, German Cancer Research Centre (DKFZ), Heidelberg, Germany

    Martina Lichtenfels

  4. Center for Molecular Structural Biology, Federal University of Santa Catarina, Florianópolis, SC, 88040-900, Brazil

    Martina Blank

  5. Children’s Cancer Institute, Porto Alegre, RS, 90420-140, Brazil

    Caroline Brunetto de Farias

  6. Department of Internal Medicine, School of Medicine (INCT-TM), Porto Alegre, RS, 90035-003, Brazil

    Gilberto Schwartsmann

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  1. Martina Lichtenfels
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  2. Arethuza da Silva Dornelles
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  3. Fernanda dos Santos Petry
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Correspondence to Martina Lichtenfels.

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Lichtenfels, M., Dornelles, A.d., Petry, F.d. et al. The anticancer estrogen receptor antagonist tamoxifen impairs consolidation of inhibitory avoidance memory through estrogen receptor alpha. J Neural Transm 124, 1331–1339 (2017). https://doi.org/10.1007/s00702-017-1785-9

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  • DOI: https://doi.org/10.1007/s00702-017-1785-9

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