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Behavioral assessment of acute inhibition of system xc - in rats

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Abstract

Rationale

Gaps 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.

Objectives

This study aims to determine whether system xc - contributes to behaviors used to model features of CNS disease states.

Methods

In 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.

Results

The 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.

Conclusions

The 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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Acknowledgments

This work was supported by the National Institutes of Health grants DA017328 (DAB), DA017328 (DAB), and DK074734 (SC).

Conflict of interest

David A. Baker owns shares in Promentis Pharmaceuticals, a company developing novel antipsychotic agents. Promentis did not sponsor or otherwise support the experiments contained in this manuscript.

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Authors and Affiliations

  1. Department of Biomedical Sciences, Marquette University, Suite 446, 561 N. 15th St, Milwaukee, WI, 53233, USA

    Victoria Lutgen, Jon Resch, Krista Qualmann, Nicholas J. Raddatz, Cristina Panhans, Ellen M. Olander, Linghai Kong, SuJean Choi, John R. Mantsch & David A. Baker

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  1. Victoria Lutgen
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  2. Jon Resch
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  3. Krista Qualmann
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Correspondence to David A. Baker.

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Lutgen, V., Resch, J., Qualmann, K. et al. Behavioral assessment of acute inhibition of system xc - in rats. Psychopharmacology 231, 4637–4647 (2014). https://doi.org/10.1007/s00213-014-3612-4

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