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.
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.
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