Paclitaxel induces memory impairment and anhedonia in mice

Abstract

Inflammation may contribute to the adverse effects of chemotherapy on cognition and affect, (chemobrain). Here, we tested the hypothesis that the chemoagent paclitaxel induces sustained changes in cognitive and affective-like behavior that correspond with increased inflammation in mice. We treated BALB/c mice with paclitaxel (10 mg/kg i.p.) or vehicle every second day over two weeks. We conducted a battery of tests to examine memory, sickness and affect at 24 h and 14 days after treatment. Paclitaxel significantly reduced memory and increased depression-like behavior as measured by novel object recognition and sucrose preference at both timepoints. These effects were independent of sickness. Analysis of inflammation by ELISA showed no evidence of inflammation at 24 h, suggesting that inflammation may not be responsible. Cytotoxic effects on the brain may be responsible for these immediate behavioral changes. We confirmed that paclitaxel crosses the blood-brain barrier by HPLC, and are performing untargeted metabolomics analyses on brain tissue to examine widespread functional changes in brain metabolism and neurochemistry. Inflammation was apparent at 2 weeks, and we are confirming that inflammation is also elevated in the brain at this timepoint. These findings suggest that inflammation may be responsible for the later paclitaxel-induced cognitive and affective symptoms but cannot be responsible for the immediate effects of paclitaxel on cognition and depression-like behavior.