• Guofang Shen, Feng Han, and Wei-Xing Shi.
• Department of Pharmaceutical and Administrative Sciences, Loma Linda University School of Pharmacy, Loma Linda, CA 92350, USA.
• Neuroscience. 2018 Aug 1; 384: 178-187.

AbstractIndirect evidence suggests that low doses of ketamine disinhibit (excite) pyramidal neurons in the prefrontal cortex (PFC). In this study, we directly examined the effect of ketamine on PFC pyramidal neurons using simultaneous single-cell and local-field-potential (LFP) recording in chloral hydrate-anesthetized rats. In all animals studied, PFC LFPs showed oscillations (0.3-1.5 Hz) between the active UP state and the relatively quiescent DOWN state, and pyramidal neurons fired preferentially during the UP state. Ketamine (1.25-20 mg/kg, i.v.) inhibited 80% of cells tested and consistently shifted PFC LFPs toward the DOWN state. The inhibitory effect of ketamine was mimicked by MK801, but not by the NR2B-selective NMDA receptor antagonist Ro25-6981. It was not blocked by the dopamine receptor antagonist fluphenazine, the GABAA receptor antagonist picrotoxinin, or the GABAB receptor antagonist CGP46381. These results are consistent with the high density of NMDA receptors expressed on PFC pyramidal neurons and our previous studies showing that blockade of NMDA receptors by ketamine inhibits dendritic NMDA receptor-mediated bursting in PFC pyramidal neurons. Thus, in addition to the previously proposed disinhibitory effect mediated through PFC interneurons, our data suggest that ketamine has an inhibitory effect on PFC pyramidal neurons. Our evidence further suggests that the effect is mediated through non-NR2B-containing NMDA receptors, independent of ketamine's effect on dopamine and GABA transmission. Further understanding of the two opposing effects of ketamine on PFC pyramidal neurons may provide important new insights into its mechanism of action.Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

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