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.

Altered neurochemical profile in the McGill‐R‐Thy1‐APP rat model of Alzheimer's disease: a longitudinal in vivo1H MRS study

“…The majority of the metabolites had average CRLBs lower than 10%, with the exception of GABA (CRLB 12-15%) and glutamine (CRLB 8-12%). The estimated concentrations in control rats were for the most part in good agreement with those reported for the same rat brain regions by others (Kim et al 2011(Kim et al , 2012.…”

“…The majority of the metabolites had average CRLBs lower than 10%, with the exception of GABA (CRLB 12-15%) and glutamine (CRLB 8-12%). The estimated concentrations in control rats were for the most part in good agreement with those reported for the same rat brain regions by others (Kim et al 2011(Kim et al , 2012.Differences in metabolite levels between McGill-R-Thy1-APP rats and controls were found in dorsal hippocampus and frontal cortex at all ages investigated. At the pre-plaque stage at age 3 months, lower concentrations of glutamate (À14%, p < 0.001), mIns (À10%, p = 0.037) and tCho (À17%, p = 0.002) were evident in dorsal hippocampus compared with controls (Fig.…”

Subanesthetic ketamine decreases the incentive-motivational value of reward-related cues

“…Ketamine (100 mg/kg) was diluted in sterile saline to make a subanesthetic dose of ketamine (32 mg/kg; 1 mL/kg; pH = 7.34–7.36). This dose was selected based upon previous studies showing that subanesthetic ketamine (30–35 mg/kg) increases brain metabolism and glutamatergic transmission in rats (Duncan et al, 1998b; Kim et al, 2011). Sterile saline was used as the vehicle control.…”

Superior effects of quetiapine compared with aripiprazole and iloperidone on MK-801-induced olfactory memory impairment in female mice

“…One of the prevailing hypotheses is that cognitive impairments are caused by the hypofunction of the N-methyl-D-aspartate (NMDA) receptor (3). The antagonists of the NMDA receptor, such as ketamine, MK-801 and phencyclidine, provoke a schizophrenia-like syndrome in normal subjects, and positive, negative and cognitive symptoms may be observed (3).…”

“…The antagonists of the NMDA receptor, such as ketamine, MK-801 and phencyclidine, provoke a schizophrenia-like syndrome in normal subjects, and positive, negative and cognitive symptoms may be observed (3). In addition, the NMDA receptor antagonists disrupt learning and cause memory impairments in animals that have similar psychosis conditions; therefore, these agents are used as a model to demonstrate cognitive dysfunctions (4,5).…”