Doxorubicin (DOX) is a potent chemotherapeutic agent known to cause acute and long-term cognitive impairments in cancer patients. Cognitive function is presumed to be primarily mediated by neuronal circuitry in the frontal cortex (FC) and hippocampus, where glutamate is the primary excitatory neurotransmitter. Mice treated with DOX (25 mg/kg i.p.) were subjected to in vivo recordings under urethane anesthesia at 24h post-DOX injection or 5 consecutive days of cognitive testing (Morris Water Maze; MWM). Using novel glutamate-selective microelectrode arrays, amperometric recordings measured parameters of extracellular glutamate clearance and potassium-evoked release of glutamate within the medial FC and dentate gyrus (DG) of the hippocampus. By 24h post-DOX injection, glutamate uptake was 45% slower in the FC in comparison to saline-treated mice. In the DG, glutamate took 48% longer to clear than salinetreated mice. Glutamate overflow in the FC was similar between treatment groups, however, it was significantly increased in the DG of DOX treated mice. MWM data indicated that a single dose of DOX impaired swim speed without impacting total length traveled. These data indicate that systemic DOX treatment changes glutamate neurotransmission in key nuclei associated with cognitive function within 24h, without a lasting impact on spatial learning and memory. Understanding the functional effects of DOX on glutamate neurotransmission may help us understand and prevent some of the debilitating side effects of chemotherapeutic treatment in cancer survivors.
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This work was supported by a postdoctoral fellowship to Theresa Currier Thomas (T32 AG000242), the University of Kentucky Markey Cancer Center and College of Medicine, grant number UL1RR033173 from the National Center for Research Resources (NCRR), the Office of the Director, National Institutes of Health (NIH) and supported by the NIH Roadmap for Medical Research, NIH CA 139843 and CA 139844.
Thomas, Theresa Currier; Beitchman, Joshua A.; Pomerleau, Francois; Noel, Teresa; Jungsuwadee, Paiboon; Butterfield, D. Allan; St. Clair, Daret K.; Vore, Mary; and Gerhardt, Greg A., "Acute Treatment with Doxorubicin Affects Glutamate Neurotransmission in the Mouse Frontal Cortex and Hippocampus" (2017). Spinal Cord and Brain Injury Research Center Faculty Publications. 26.