Effects of repeated administration of chemotherapeutic agents tamoxifen, methotrexate, and 5-fluorouracil on the acquisition and retention of a learned response in mice

Abstract

A number of cancer chemotherapeutic agents have been associated with a loss of memory in breast cancer patients although little is known of the causality of this effect. To assess the potential cognitive effects of repeated exposure to chemotherapeutic agents, we administered the selective estrogen receptor modulator tamoxifen or the antimetabolite chemotherapy, methotrexate, and 5-fluorouracil, alone and in combination to mice and tested them in a learning and memory assay. Swiss-Webster male mice were injected with saline, 32 mg/kg tamoxifen, 3.2 or 32 mg/kg methotrexate, 75 mg/kg 5-fluorouracil, 3.2 or 32 mg/kg methotrexate in combination with 75 mg/kg 5-fluorouracil once per week for 3 weeks. On days 23 and 24, mice were tested for acquisition and retention of a nose-poke response in a learning procedure called autoshaping. In addition, the acute effects of tamoxifen were assessed in additional mice in a similar procedure. The chemotherapeutic agents alone and in combination reduced body weight relative to saline treatment over the course of 4 weeks. Repeated treatment with tamoxifen produced both acquisition and retention effects relative to the saline-treated group although acute tamoxifen was without effect except at a behaviorally toxic dose. Repeated treatment with methotrexate in combination with 5-fluorouracil produced effects on retention, but the magnitude of these changes depended on the methotrexate dose. These data demonstrate that repeated administration of tamoxifen or certain combination of methotrexate and 5-fluorouracil may produce deficits in the acquisition or retention of learned responses which suggest potential strategies for prevention or remediation might be considered in vulnerable patient populations.