Effects of NMDA receptor antagonists and antipsychotics on high frequency oscillations recorded in the nucleus accumbens of freely moving mice

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Abstract
Rationale Abnormal oscillatory activity associated with N-methyl-D-aspartate (NMDA) receptor hypofunction is widely considered to contribute to the symptoms of schizophrenia. Objective This study aims to characterise the changes produced by NMDA receptor antagonists and antipsychotics on accumbal high-frequency oscillations (HFO; 130–180 Hz) in mice. Methods Local field potentials were recorded from the nucleus accumbens of freely moving mice. Results Systemic injection of ketamine and MK801 both dose-dependently increased the power of HFO and produced small increases in HFO frequency. The atypical antipsychotic drug, clozapine, produced a robust dose-dependent reduction in the frequency of MK801-enhanced HFO, whilst haloperidol, a typical antipsychotic drug, had little effect. Stimulation of NMDA receptors (directly or through the glycine site) as well as activation of 5-HT1A receptors, reduced the frequency of MK801-enhanced HFO, but other receptors known to be targets for clozapine, namely 5-HT2A, 5-HT7 and histamine H3 receptors had no effect. Conclusions NMDA receptor antagonists and antipsychotics produce broadly similar fundamental effects on HFO, as reported previously for rats, but we did observe several notable differences. In mice, HFO at baseline were weak or not detectable unlike rats. Post-injection of NMDA receptor antagonists HFO was also weaker but significantly faster. Additionally, we found that atypical antipsychotic drugs may reduce the frequency of HFO by interacting with NMDA and/or 5-HT1A receptors.

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