The belief that cancer chemotherapy causes impairment of cognitive ability (termed 'chemo-fog', 'chemo- brain', or 'chemotherapy-related cognitive dysfunction') in a significant number of patients is widely accepted by patients and healthcare providers. A host of other factors are involved, such as the underlying pathology, the presence of a chronic disease, and psychological factors that are difficult to eliminate in human trials. In addition, during the course of treatment many, if not the majority, of patients receive a 'cocktail'combination of several drugs, providing abundant opportunity for drug interactions. Therefore, to accurately assess the possible cognitive effects of chemotherapeutic agents independent of the complications associated with clinical studies, we propose to directly test chemotherapeutic agents in a mouse model of learning and memory called autoshaping. The autoshaping procedure is a rapid, objective, and reliable measure of whether a drug will affect acquisition, consolidation, retrieval, extinction, spontaneous recovery, and reacquisition of a learned response. Specifically, we will treat male and female mice with multiple doses of cyclophosphamide, doxorubicin, 5-fluorouracil, methotrexate, tamoxifen, and docetaxel at various time points to measure effects on acquisition, consolidation, retrieval, extinction, spontaneous recovery, reacquisition, and state-dependent learning in the autoshaping procedure and on motivation in the progressive ratio procedure. The drugs will be tested individually and, importantly, in varying combinations using the mathematically rigorous 'joint-action analysis.'In addition, the chemotherapeutic agents and their combinations will be administered both acutely and repeatedly in male and female mice. We hypothesize that acute or repeated exposure to single or combined chemotherapeutic agents will produce greater decrements in the learning processes more heavily reliant on hippocampal functioning (consolidation, retrieval, and reacquisition) than those less reliant on hippocampal functioning (acquisition and extinction) at doses that do not alter the motivational aspects of the liquid reinforcer. Similarly, we predict that the retrieval of extinction learning (spontaneous recovery) will be affected to a greater degree by the chemotherapeutic agents than the acquisition of extinction learning. We also predict synergistic deficits with the antiestrogen tamoxifen and the other chemotherapeutic agents especially on consolidation and retrieval in female mice. Taken together, these experiments will provide the first comprehensive examination of the behavioral effects of a range of chemotherapeutic agents and their combinations in a simple, cognitive model in mice.

Public Health Relevance

The studies proposed in the present application will assess the effects of six commonly used chemotherapy agents alone and in combination for the capacity to disrupt learning and memory in a preclinical mouse model. If certain drugs/combinations produce more adverse effects than others do, clinicians can make informed choices about their patients'therapy and improve the quality of life for cancer survivors and their families.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
Program Officer
O'Mara, Ann M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Temple University
Schools of Pharmacy
United States
Zip Code
Raffa, R B (2013) Cancer 'survivor-care': II. Disruption of prefrontal brain activation top-down control of working memory capacity as possible mechanism for chemo-fog/brain (chemotherapy-associated cognitive impairment). J Clin Pharm Ther 38:265-8
Krynetskiy, Evgeny; Krynetskaia, Natalia; Rihawi, Diana et al. (2013) Establishing a model for assessing DNA damage in murine brain cells as a molecular marker of chemotherapy-associated cognitive impairment. Life Sci 93:605-10
Bisen-Hersh, Emily B; Hineline, Philip N; Walker, Ellen A (2013) Effects of early chemotherapeutic treatment on learning in adolescent mice: implications for cognitive impairment and remediation in childhood cancer survivors. Clin Cancer Res 19:3008-18
Ganti, Vaishnavi; Walker, Ellen A; Nagar, Swati (2013) Pharmacokinetic application of a bio-analytical LC-MS method developed for 5-fluorouracil and methotrexate in mouse plasma, brain and urine. Biomed Chromatogr 27:994-1002
Raffa, R B (2011) Cancer 'survivor-care': I. the ?7 nAChR as potential target for chemotherapy-related cognitive impairment. J Clin Pharm Ther 36:437-45
Bisen-Hersh, Emily B; Hineline, Philip N; Walker, Ellen A (2011) Disruption of learning processes by chemotherapeutic agents in childhood survivors of acute lymphoblastic leukemia and preclinical models. J Cancer 2:292-301
Ward, Sara Jane; Ramirez, Michael David; Neelakantan, Harshini et al. (2011) Cannabidiol prevents the development of cold and mechanical allodynia in paclitaxel-treated female C57Bl6 mice. Anesth Analg 113:947-50
Walker, Ellen A; Foley, John J; Clark-Vetri, Rachel et al. (2011) Effects of repeated administration of chemotherapeutic agents tamoxifen, methotrexate, and 5-fluorouracil on the acquisition and retention of a learned response in mice. Psychopharmacology (Berl) 217:539-48
Raffa, R B (2011) A proposed mechanism for chemotherapy-related cognitive impairment ('chemo-fog'). J Clin Pharm Ther 36:257-9
Raffa, R B (2010) Is a picture worth a thousand (forgotten) words?: neuroimaging evidence for the cognitive deficits in 'chemo-fog'/'chemo-brain'. J Clin Pharm Ther 35:1-9

Showing the most recent 10 out of 12 publications