• Victoria Lutgen, Jon Resch, Krista Qualmann, Nicholas J Raddatz, Cristina Panhans, Ellen M Olander, Linghai Kong, SuJean Choi, John R Mantsch, and David A Baker.
• Department of Biomedical Sciences, Marquette University, Suite 446, 561 N. 15th St, Milwaukee, WI, 53233, USA.
• Psychopharmacology (Berl.). 2014 Dec 1;231(24):4637-47.

RationaleGaps in our understanding of glutamatergic signaling may be key obstacles in accurately modeling complex CNS diseases. System xc (-) is an example of a poorly understood component of glutamate homeostasis that has the potential to contribute to CNS diseases.ObjectivesThis study aims to determine whether system xc (-) contributes to behaviors used to model features of CNS disease states.MethodsIn situ hybridization was used to map mRNA expression of xCT throughout the brain. Microdialysis in the prefrontal cortex was used to sample extracellular glutamate levels; HPLC was used to measure extracellular glutamate and tissue glutathione concentrations. Acute administration of sulfasalazine (8-16 mg/kg, IP) was used to decrease system xc (-) activity. Behavior was measured using attentional set shifting, elevated plus maze, open-field maze, Porsolt swim test, and social interaction paradigm.ResultsThe expression of xCT mRNA was detected throughout the brain, with high expression in several structures including the basolateral amygdala and prefrontal cortex. Doses of sulfasalazine that produced a reduction in extracellular glutamate levels were identified and subsequently used in the behavioral experiments. Sulfasalazine impaired performance in attentional set shifting and reduced the amount of time spent in an open arm of an elevated plus maze and the center of an open-field maze without altering behavior in a Porsolt swim test, total distance moved in an open-field maze, or social interaction.ConclusionsThe widespread distribution of system xc (-) and involvement in a growing list of behaviors suggests that this form of nonvesicular glutamate release is a key component of excitatory signaling.

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