N -methyl- d -aspartic acid receptor antagonist–induced frequency oscillations in mice recreate pattern of electrophysiological deficits in schizophrenia

• Published in: Neuroscience Vol. 158; no. 2; pp. 705 - 712
• Main Authors: Ehrlichman, R.S, Gandal, M.J, Maxwell, C.R, Lazarewicz, M.T, Finkel, L.H, Contreras, D, Turetsky, B.I, Siegel, S.J
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 23.01.2009
• Subjects: Acoustic Stimulation - methods; Amphetamine - administration & dosage; animal model; Animals; Antipsychotic Agents - pharmacology; Biological Clocks - drug effects; Central Nervous System Stimulants - administration & dosage; Disease Models, Animal; Drug Interactions; Electroencephalography; Evoked Potentials, Auditory - drug effects; Excitatory Amino Acid Antagonists - adverse effects; frequency oscillations; Haloperidol - pharmacology; Ketamine - adverse effects; Male; Mice; Mice, Inbred C57BL; Neurology; NMDA; Reaction Time - drug effects; Risperidone - pharmacology; Schizophrenia - chemically induced; Schizophrenia - drug therapy; Schizophrenia - physiopathology; electroencephalography; EEG; area under the curve; N-methyl- d-aspartic acid; electroencephalogram; AUC; ERPs; phencyclidine; NMDA; frequency oscillations; event-related potentials; animal model; PCP
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2008.10.031

Abstract Introduction: Electrophysiological responses to auditory stimuli have provided a useful means of elucidating mechanisms and evaluating treatments in psychiatric disorders. Deficits in gating during paired-click tasks and lack of mismatch negativity following deviant stimuli have been well characterized in patients with schizophrenia. Recently, analyses of basal, induced, and evoked frequency oscillations have gained support as additional measures of cognitive processing in patients and animal models. The purpose of this study is to examine frequency oscillations in mice across the theta (4–7.5 Hz) and gamma (31–61 Hz) bands in the context of N -methyl- d -aspartic acid receptor (NMDAR) hypofunction and dopaminergic hyperactivity, both of which are thought to serve as pharmacological models of schizophrenia. Experimental procedures: Electroencephalograms (EEG) were recorded from mice in five treatment groups that consisted of haloperidol, risperidone, amphetamine, ketamine, or ketamine plus haloperidol during an auditory task. Basal, induced and evoked powers in both frequencies were calculated. Results: Ketamine increased basal power in the gamma band and decreased the evoked power in the theta band. The increase in basal gamma was not blocked by treatment with a conventional antipsychotic. No other treatment group was able to fully reproduce this pattern in the mice. Conclusions: Ketamine-induced alterations in EEG power spectra are consistent with abnormalities in the theta and gamma frequency ranges reported in patients with schizophrenia. Our findings support the hypothesis that NMDAR hypofunction contributes to the deficits in schizophrenia and that the dopaminergic pathways alone may not account for these changes.