title: Metaplastic effects of subanesthetic ketamine on CA1 hippocampal function.
abstract: Ketamine is a non-competitive N-methyl-d-aspartate receptor (NMDAR) antagonist of interest in neuropsychiatry. In the present studies, we examined the effects of subanesthetic, low micromolar ketamine on excitatory postsynaptic potentials (EPSPs), population spikes (PSs) and synaptic plasticity in the CA1 region of rat hippocampal slices. Ketamine acutely inhibited NMDAR-mediated synaptic responses with half-maximal effects near 10 μM. When administered for 15-30 min at 1-10 μM, ketamine had no effect on baseline dendritic AMPA receptor-mediated EPSPs, but persistently enhanced somatic EPSPs in the pyramidal cell body layer and augmented PS firing. Acute low micromolar ketamine also had no effect on the induction of long-term potentiation (LTP) but blocked long-term depression (LTD). Following 30 min administration of 1-10 μM ketamine, however, a slowly developing and persistent form of LTP inhibition was observed that took two hours following ketamine washout to become manifest. This LTP inhibition did not result from prolonged or enhanced NMDAR inhibition during drug washout. Effects of low ketamine on somatic EPSPs and LTP were not mimicked by a high ketamine concentration that completely inhibited NMDARs, and both of these effects were blocked by co-administration of low ketamine with a low concentration of the competitive NMDAR antagonist, 2-amino-5-phosphonovalerate or inhibitors of nitric oxide synthase. These results indicate that concentrations of ketamine relevant to psychotropic and psychotomimetic effects have complex metaplastic effects on hippocampal function that involve activation of unblocked NMDARs during ketamine exposure.
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA; Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Yukitoshi
authors.initials: Y
authors.lastname: Izumi
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA; Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO, USA. Electronic address: zorumskc@wustl.edu.
authors.forename: Charles F
authors.initials: CF
authors.lastname: Zorumski
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000187:drug effects* / Q000502:physiology*; D003712:Dendrites / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D007649:Ketamine / Q000494:pharmacology*; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000502:physiology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000502:physiology; D046509:Tissue Culture Techniques
chemical_list: D018691:Excitatory Amino Acid Antagonists; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D009569:Nitric Oxide; D007649:Ketamine; D019001:Nitric Oxide Synthase
keywords: Memory; Modulation; NMDA receptor; Nitric oxide; Psychosis; Synaptic plasticity