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

Amat-Foraster, Maria ; Celada, Pau ; Richter, Ulrike LU ; Jensen, Anders A. ; Plath, Niels ; Artigas, Francesc and Herrik, Kjartan F. (2019) In Neuropharmacology 158.
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Ketamine, Neuronal oscillations, NMDA receptor antagonists, Phencyclidine, Single unit recordings, Thalamo-cortical networks
in
Neuropharmacology
volume
158
article number
107745
publisher
Elsevier
external identifiers
  • pmid:31445017
  • scopus:85071586063
ISSN
0028-3908
DOI
10.1016/j.neuropharm.2019.107745
language
English
LU publication?
yes
id
22fc55a8-37f4-4fe8-8d3a-9238bb50b0b1
date added to LUP
2019-09-16 12:49:50
date last changed
2020-01-13 02:22:14
@article{22fc55a8-37f4-4fe8-8d3a-9238bb50b0b1,
  abstract     = {<p>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.</p>},
  author       = {Amat-Foraster, Maria and Celada, Pau and Richter, Ulrike and Jensen, Anders A. and Plath, Niels and Artigas, Francesc and Herrik, Kjartan F.},
  issn         = {0028-3908},
  language     = {eng},
  publisher    = {Elsevier},
  series       = {Neuropharmacology},
  title        = {Modulation of thalamo-cortical activity by the NMDA receptor antagonists ketamine and phencyclidine in the awake freely-moving rat},
  url          = {http://dx.doi.org/10.1016/j.neuropharm.2019.107745},
  doi          = {10.1016/j.neuropharm.2019.107745},
  volume       = {158},
  year         = {2019},
}