Modulation of thalamo-cortical activity by the NMDA receptor antagonists ketamine and phencyclidine in the awake freely-moving rat

Research output: Contribution to journalArticle

Abstract

Non-competitive N-methyl-D-aspartate receptor antagonists mimic schizophrenia symptoms and produce immediate and persistent antidepressant effects. We investigated the effects of ketamine and phencyclidine (PCP) on thalamo-cortical network activity in awake, freely-moving male Wistar rats to gain new insight into the neuronal populations and brain circuits involved in the effects of NMDA-R antagonists. Single unit and local field potential (LFP) recordings were conducted in mediodorsal/centromedial thalamus and in medial prefrontal cortex (mPFC) using microelectrode arrays. Ketamine and PCP moderately increased the discharge rates of principal neurons in both areas while not attenuating the discharge of mPFC GABAergic interneurons. They also strongly affected LFP activity, reducing beta power and increasing that of gamma and high-frequency oscillation bands. These effects were short-lasting following the rapid pharmacokinetic profile of the drugs, and consequently were not present at 24 h after ketamine administration. The temporal profile of both drugs was remarkably different, with ketamine effects peaking earlier than PCP effects. Although this study is compatible with the glutamate hypothesis for fast-acting antidepressant action, it does not support a local disinhibition mechanism as the source for the increased pyramidal neuron activity in mPFC. The short-lasting increase in thalamo-cortical activity is likely associated with the rapid psychotomimetic action of both agents but could also be part of a cascade of events ultimately leading to the persistent antidepressant effects of ketamine. Changes in spectral contents of high-frequency bands by the drugs show potential as translational biomarkers for target engagement of NMDA-R modulators.

Details

Authors
  • Maria Amat-Foraster
  • Pau Celada
  • Ulrike Richter
  • Anders A. Jensen
  • Niels Plath
  • Francesc Artigas
  • Kjartan F. Herrik
Organisations
External organisations
  • H. Lundbeck A/S
  • University of Copenhagen
  • CSIC Institute of Biomedical Research of Barcelona (IIBB)
  • Institutd' Investigacions Biomèdiques August Pi iSunyer (IDIBAPS)
  • CIBER Salud Mental (CIBERSAM)
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Pharmaceutical Sciences

Keywords

  • Ketamine, Neuronal oscillations, NMDA receptor antagonists, Phencyclidine, Single unit recordings, Thalamo-cortical networks
Original languageEnglish
Article number107745
JournalNeuropharmacology
Volume158
Publication statusPublished - 2019
Publication categoryResearch
Peer-reviewedYes