Acute treatment with doxorubicin affects glutamate neurotransmission in the mouse frontal cortex and hippocampus

Brain Res. 2017 Oct 1;1672:10-17. doi: 10.1016/j.brainres.2017.07.003. Epub 2017 Jul 11.

Abstract

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 (25mg/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 saline-treated 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.

Keywords: Amperometry; Chemobrain; Dentate gyrus; Doxorubicin; Glutamate clearance; Prefrontal cortex.

MeSH terms

  • Animals
  • Cognition / drug effects
  • Dentate Gyrus / drug effects
  • Doxorubicin / metabolism
  • Doxorubicin / pharmacology*
  • Frontal Lobe / drug effects
  • Frontal Lobe / metabolism
  • Glutamic Acid / drug effects*
  • Glutamic Acid / metabolism*
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Male
  • Maze Learning / drug effects
  • Memory / drug effects
  • Memory / physiology
  • Mice
  • Spatial Learning / drug effects
  • Synaptic Transmission / drug effects
  • Temporal Lobe

Substances

  • Glutamic Acid
  • Doxorubicin