Preserved learning and memory following 5-fluorouracil and cyclophosphamide treatment in rats

• Published in: Pharmacology, biochemistry and behavior biochemistry and behavior, 2011-11, Vol.100 (1), p.205-211
• Main Authors: Long, Jeffrey M., Lee, Garrick D., Kelley-Bell, Bennett, Spangler, Edward L., Perez, Evelyn J., Longo, Dan L., de Cabo, Rafael, Zou, Sige, Rapp, Peter R.
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Biological and medical sciences; Chemobrain; Chemofog; Cognition; Cognition Disorders - chemically induced; Cyclophosphamide - administration & dosage; Cyclophosphamide - adverse effects; Fear conditioning; Fluorouracil - administration & dosage; Fluorouracil - adverse effects; Learning - drug effects; Learning - physiology; Male; Medical sciences; Memory - drug effects; Memory - physiology; Rats; Rats, Inbred F344; Spatial memory; Treatment Outcome
• ISSN: 0091-3057; 1873-5177; 1873-5177
• DOI: 10.1016/j.pbb.2011.08.012

Some patients experience enduring cognitive impairment after cancer treatment, a condition termed “chemofog”. Animal models allow assessment of chemotherapy effects on learning and memory per se, independent of changes due to cancer itself or associated health consequences such as depression. The present study examined the long-term learning and memory effects of a chemotherapy cocktail used widely in the treatment of breast cancer, consisting of 5-fluorouracil (5FU) and cyclophosphamide (CYP). Eighty 5-month old male F344 rats received contextual and cued fear conditioning before treatment with saline, or a low or high dose drug cocktail (50mg/kg CYP and 75mg/kg 5FU, or 75mg/kg CYP and 120mg/kg 5FU, i.p., respectively) every 30days for 2months. After a 2-month, no-drug recovery, both long-term retention and new task acquisition in the water maze and 14-unit T-maze were assessed. Neither dose of the CYP/5FU cocktail impaired retrograde fear memory despite marked toxicity documented by enduring weight loss and 50% mortality at the higher dose. Acquisition in the water maze and Stone maze was also normal relative to controls in rats treated with CYP/5FU. The results contribute to a growing literature suggesting that learning and memory mediated by the hippocampus can be relatively resistant to chemotherapy. Future investigation may need to focus on assessments of processing speed, executive function and attention, and the possible interactive contribution of cancer itself and aging to the post-treatment development of cognitive impairment. ► Some patients experience “chemofog” after cancer treatment. ► Animal models allow assessment without confounds normally associated with cancer. ► Anticancer drugs did not impair fear memory retention or spatial maze acquisition. ► Some hippocampal-mediated tasks can be relatively resistant to chemotherapy.