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Neurophysiological treatment effects of mesdopetam, pimavanserin and clozapine in a rodent model of Parkinson's disease psychosis

Stan, Tiberiu Loredan LU ; Ronaghi, Abdolaziz ; Barrientos, Sebastian A LU orcid ; Halje, Pär LU ; Censoni, Luciano LU ; Garro-Martínez, Emilio ; Nasretdinov, Azat ; Malinina, Evgenya ; Hjorth, Stephan and Svensson, Peder , et al. (2024) In Neurotherapeutics 21(2). p.1-12
Abstract

Psychosis in Parkinson's disease is a common phenomenon associated with poor outcomes. To clarify the pathophysiology of this condition and the mechanisms of antipsychotic treatments, we have here characterized the neurophysiological brain states induced by clozapine, pimavanserin, and the novel prospective antipsychotic mesdopetam in a rodent model of Parkinson's disease psychosis, based on chronic dopaminergic denervation by 6-OHDA lesions, levodopa priming, and the acute administration of an NMDA antagonist. Parallel recordings of local field potentials from eleven cortical and sub-cortical regions revealed shared neurophysiological treatment effects for the three compounds, despite their different pharmacological profiles, involving... (More)

Psychosis in Parkinson's disease is a common phenomenon associated with poor outcomes. To clarify the pathophysiology of this condition and the mechanisms of antipsychotic treatments, we have here characterized the neurophysiological brain states induced by clozapine, pimavanserin, and the novel prospective antipsychotic mesdopetam in a rodent model of Parkinson's disease psychosis, based on chronic dopaminergic denervation by 6-OHDA lesions, levodopa priming, and the acute administration of an NMDA antagonist. Parallel recordings of local field potentials from eleven cortical and sub-cortical regions revealed shared neurophysiological treatment effects for the three compounds, despite their different pharmacological profiles, involving reversal of features associated with the psychotomimetic state, such as a reduction of aberrant high-frequency oscillations in prefrontal structures together with a decrease of abnormal synchronization between different brain regions. Other drug-induced neurophysiological features were more specific to each treatment, affecting network oscillation frequencies and entropy, pointing to discrete differences in mechanisms of action. These findings indicate that neurophysiological characterization of brain states is particularly informative when evaluating therapeutic mechanisms in conditions involving symptoms that are difficult to assess in rodents such as psychosis, and that mesdopetam should be further explored as a potential novel antipsychotic treatment option for Parkinson psychosis.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Animals, Clozapine/pharmacology, Parkinson Disease/complications, Antipsychotic Agents/pharmacology, Rodentia, Prospective Studies, Psychotic Disorders/etiology, Phenyl Ethers, Piperidines, Propylamines, Urea/analogs & derivatives
in
Neurotherapeutics
volume
21
issue
2
article number
e00334
pages
1 - 12
publisher
Springer
external identifiers
  • scopus:85187115561
  • pmid:38368170
ISSN
1878-7479
DOI
10.1016/j.neurot.2024.e00334
language
English
LU publication?
yes
additional info
Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.
id
0020e27d-570d-4bfe-842a-2331a5f37686
date added to LUP
2024-04-03 18:45:36
date last changed
2024-04-18 06:12:40
@article{0020e27d-570d-4bfe-842a-2331a5f37686,
  abstract     = {{<p>Psychosis in Parkinson's disease is a common phenomenon associated with poor outcomes. To clarify the pathophysiology of this condition and the mechanisms of antipsychotic treatments, we have here characterized the neurophysiological brain states induced by clozapine, pimavanserin, and the novel prospective antipsychotic mesdopetam in a rodent model of Parkinson's disease psychosis, based on chronic dopaminergic denervation by 6-OHDA lesions, levodopa priming, and the acute administration of an NMDA antagonist. Parallel recordings of local field potentials from eleven cortical and sub-cortical regions revealed shared neurophysiological treatment effects for the three compounds, despite their different pharmacological profiles, involving reversal of features associated with the psychotomimetic state, such as a reduction of aberrant high-frequency oscillations in prefrontal structures together with a decrease of abnormal synchronization between different brain regions. Other drug-induced neurophysiological features were more specific to each treatment, affecting network oscillation frequencies and entropy, pointing to discrete differences in mechanisms of action. These findings indicate that neurophysiological characterization of brain states is particularly informative when evaluating therapeutic mechanisms in conditions involving symptoms that are difficult to assess in rodents such as psychosis, and that mesdopetam should be further explored as a potential novel antipsychotic treatment option for Parkinson psychosis.</p>}},
  author       = {{Stan, Tiberiu Loredan and Ronaghi, Abdolaziz and Barrientos, Sebastian A and Halje, Pär and Censoni, Luciano and Garro-Martínez, Emilio and Nasretdinov, Azat and Malinina, Evgenya and Hjorth, Stephan and Svensson, Peder and Waters, Susanna and Sahlholm, Kristoffer and Petersson, Per}},
  issn         = {{1878-7479}},
  keywords     = {{Animals; Clozapine/pharmacology; Parkinson Disease/complications; Antipsychotic Agents/pharmacology; Rodentia; Prospective Studies; Psychotic Disorders/etiology; Phenyl Ethers; Piperidines; Propylamines; Urea/analogs & derivatives}},
  language     = {{eng}},
  number       = {{2}},
  pages        = {{1--12}},
  publisher    = {{Springer}},
  series       = {{Neurotherapeutics}},
  title        = {{Neurophysiological treatment effects of mesdopetam, pimavanserin and clozapine in a rodent model of Parkinson's disease psychosis}},
  url          = {{http://dx.doi.org/10.1016/j.neurot.2024.e00334}},
  doi          = {{10.1016/j.neurot.2024.e00334}},
  volume       = {{21}},
  year         = {{2024}},
}