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Behavioral assessment of acute inhibition of system xc (-) in rats. Psychopharmacology (Berl) 2014 Dec;231(24):4637-47



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Pubmed Central ID




Scopus ID

2-s2.0-84922065729   12 Citations


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.

Author List

Lutgen V, Resch J, Qualmann K, Raddatz NJ, Panhans C, Olander EM, Kong L, Choi S, Mantsch JR, Baker DA


Sujean Choi PhD in the School of Allied Health department at Marquette University
John Mantsch PhD Chair, Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Behavior, Animal
Glutamic Acid
In Situ Hybridization
Interpersonal Relations
Motor Activity
RNA, Messenger
Rats, Sprague-Dawley