In vivo and ex vivo evidence for ketamine-induced hyperglutamatergic activity in the cerebral cortex of the rat: Potential relevance to schizophrenia.

Abstract

Subanesthetic doses of ketamine, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, impair prefrontal cortex (PFC) function in the rat and produce symptoms in humans similar to those observed in patients with schizophrenia. In the present study, in vivo (1) H-MRS and ex vivo (1) H high-resolution magic angle spinning (HR-MAS) spectroscopy was used to examine the brain metabolism of rats treated with subanesthetic doses of ketamine (30 mg/kg) for 6 days. A single voxel localization sequence (PRESS, TR/TE = 4000/20 ms and NEX=512) was used to acquire the spectra in a 30-µl voxel positioned in the cerebral cortex (including mainly PFC) of the rats (ketamine group: n=12; saline group: n=12) anesthetized with isoflurane. After the in vivo (1) H-MRS acquisition, the animals were sacrificed and the cerebral cortex tissues were extracted (ketamine group: n=7; saline group: n=7) for ex vivo (1) H HR-MAS spectroscopy (CPMG sequence, 2.0-s presaturation delay, 2.0-s acquisition time, 128 transients and 4-ms inter-pulse delay) using a 500-MHz NMR spectrometer. All proton metabolites were quantified using the LCModel. For the in vivo spectra, there was a significant increase in glutamate concentration in the cerebral cortex of the ketamine group compared with the controls (p<0.05). For the ex vivo HR-MAS spectra, there was a significant increase in the glutamate/total creatine ratio, and a decrease in the glutamine/total creatine and glutamine/glutamate ratios in the cerebral cortex tissue of the ketamine group compared with the controls. The results of the present study demonstrated that administration of subanesthetic doses of ketamine in the rat may exert at least part of their effect in the cerebral cortex by activation of glutamatergic neurotransmission.

• Authors: Sang-Young Kim, Hyunseung Lee, Hyun-Ju Kim, Eunjung Bang, Sung-Ho Lee, Do-Wan Lee, Dong-Cheol Woo, Chi-Bong Choi, Kwan Soo Hong, Chulhyun Lee, Bo-Young Choe
• Journal: NMR in biomedicine (NMR Biomed) Vol. 24 Issue 10 Pg. 1235-42 (Dec 2011) ISSN: 1099-1492 [Electronic] England
• PMID: 21560175 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 John Wiley & Sons, Ltd.

Chemical References

• Glutamic Acid
• Ketamine

Topics

• Animals
• Cerebral Cortex (drug effects, metabolism)
• Glutamic Acid (metabolism)
• In Vitro Techniques
• Ketamine (pharmacology)
• Magnetic Resonance Spectroscopy
• Male
• Rats
• Rats, Sprague-Dawley
• Schizophrenia (metabolism)