Long-Term Oral Tamoxifen Administration Decreases Brain Derived Neurotrophic Factor in the Hippocampus of Female Long-Evans Rats

Abstract

Tamoxifen is a selective estrogen receptor modulator (SERM) that is commonly used as an adjuvant drug therapy for estrogen receptor-positive breast cancers. While this drug is effective at reducing the rate of cancer recurrence, many patients report unwanted cognitive and affective side effects such as brain fog, confusion, memory impairment, anxiety, and depression. Despite this, the impacts of chronic tamoxifen exposure on the brain are poorly understood, and rodent models of tamoxifen exposure do not replicate the chronic oral administration seen in patients. We therefore used long-term ad lib consumption of medicated food pellets in adult female rats to model chronic tamoxifen exposure in a clinically-relevant way. Gonadally-intact adult female Long-Evans Hooded rats consumed tamoxifen medicated food pellets for approximately 12 weeks while control animals received standard chow. At the conclusion of the experiment, animals were euthanized, and blood and brain samples were collected for analyses. Blood tamoxifen levels were measured using a novel ultra-performance liquid chromatography-tandem mass spectrometry assay, which found that this administration paradigm produced serum levels of tamoxifen similar to those in human patients. In the brain, brain derived neurotrophic factor (BDNF) was visualized in the hippocampus using immunohistochemistry and quantified using background-subtracted optical densitometry. Chronic oral tamoxifen treatment resulted in a decrease in BDNF expression across several regions of the hippocampus. Together, these findings provide a novel method of modeling and measuring chronic oral tamoxifen exposure, and suggest a putative mechanism by which tamoxifen may cause cognitive and behavioral changes reported by patients.