title: 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.affiliation: Department of Biomedical Engineering, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Sang-Young
authors.initials: SY
authors.lastname: Kim
authors.forename: Hyunseung
authors.initials: H
authors.lastname: Lee
authors.forename: Hyun-Ju
authors.initials: HJ
authors.lastname: Kim
authors.forename: Eunjung
authors.initials: E
authors.lastname: Bang
authors.forename: Sung-Ho
authors.initials: SH
authors.lastname: Lee
authors.forename: Do-Wan
authors.initials: DW
authors.lastname: Lee
authors.forename: Dong-Cheol
authors.initials: DC
authors.lastname: Woo
authors.forename: Chi-Bong
authors.initials: CB
authors.lastname: Choi
authors.forename: Kwan Soo
authors.initials: KS
authors.lastname: Hong
authors.forename: Chulhyun
authors.initials: C
authors.lastname: Lee
authors.forename: Bo-Young
authors.initials: BY
authors.lastname: Choe
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D066298:In Vitro Techniques; D007649:Ketamine / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012559:Schizophrenia / Q000378:metabolism*
chemical_list: D018698:Glutamic Acid; D007649:Ketamine