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Neurophysiological Treatment Effects of Mesdopetam, Pimavanserin and Amantadine in a Rodent Model of Levodopa-Induced Dyskinesia

Ronaghi, Abdolaziz ; Stan, Tiberiu Loredan LU ; Barrientos, Sebastian A LU orcid ; Halje, Pär LU orcid ; Nasretdinov, Azat ; Censoni, Luciano LU ; Sato, Sebastian Sulis ; Malinina, Evgenya ; Tedroff, Joakim and Waters, Nicholas , et al. (2025) In European Journal of Neuroscience 61(5).
Abstract

Levodopa provides effective symptomatic treatment for Parkinson's disease. However, nonmotor symptoms are often insufficiently relieved, and its long-term use is complicated by motor fluctuations and dyskinesia. To clarify mechanisms of levodopa-induced dyskinesia and pharmacological interventions aimed at reducing dyskinetic symptoms, we have here characterized the neurophysiological activity patterns in sensorimotor and cognitive-limbic circuits in dyskinetic rats, comparing the effects of amantadine, pimavanserin, and the novel prospective antidyskinetic and antipsychotic treatment mesdopetam. Parallel recordings of local field potentials from 11 cortical and subcortical regions revealed suppression of narrowband gamma oscillations... (More)

Levodopa provides effective symptomatic treatment for Parkinson's disease. However, nonmotor symptoms are often insufficiently relieved, and its long-term use is complicated by motor fluctuations and dyskinesia. To clarify mechanisms of levodopa-induced dyskinesia and pharmacological interventions aimed at reducing dyskinetic symptoms, we have here characterized the neurophysiological activity patterns in sensorimotor and cognitive-limbic circuits in dyskinetic rats, comparing the effects of amantadine, pimavanserin, and the novel prospective antidyskinetic and antipsychotic treatment mesdopetam. Parallel recordings of local field potentials from 11 cortical and subcortical regions revealed suppression of narrowband gamma oscillations (NBGs) in sensorimotor structures by amantadine and mesdopetam in conjunction with alleviation of dyskinetic signs. Concomitant gamma oscillations in cognitive-limbic circuits were not directly linked to dyskinesia and were not affected by antidyskinetic treatments to the same extent, although treatment-induced reductions in functional coupling were observed in both sensorimotor and cognitive-limbic circuits, in parallel. In a broad frequency spectrum (1–200 Hz), mesdopetam treatment displayed greater similarities to pimavanserin than to amantadine. These findings point to the reduction of NBGs as a valuable biomarker for the characterization of antidyskinetic treatment effects and provide systems-level mechanistic insights into the antidyskinetic efficacy of mesdopetam, with potential additional benefits for the treatment of Parkinson's-related psychosis.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
LFP, multi-electrode, oscillations
in
European Journal of Neuroscience
volume
61
issue
5
article number
e70032
publisher
Wiley-Blackwell
external identifiers
  • scopus:86000040958
  • pmid:40042199
ISSN
0953-816X
DOI
10.1111/ejn.70032
language
English
LU publication?
yes
id
43d5bbcc-cd4f-4ddf-a9a0-fde1ef6fc1b5
date added to LUP
2025-06-19 09:23:48
date last changed
2025-07-03 11:37:28
@article{43d5bbcc-cd4f-4ddf-a9a0-fde1ef6fc1b5,
  abstract     = {{<p>Levodopa provides effective symptomatic treatment for Parkinson's disease. However, nonmotor symptoms are often insufficiently relieved, and its long-term use is complicated by motor fluctuations and dyskinesia. To clarify mechanisms of levodopa-induced dyskinesia and pharmacological interventions aimed at reducing dyskinetic symptoms, we have here characterized the neurophysiological activity patterns in sensorimotor and cognitive-limbic circuits in dyskinetic rats, comparing the effects of amantadine, pimavanserin, and the novel prospective antidyskinetic and antipsychotic treatment mesdopetam. Parallel recordings of local field potentials from 11 cortical and subcortical regions revealed suppression of narrowband gamma oscillations (NBGs) in sensorimotor structures by amantadine and mesdopetam in conjunction with alleviation of dyskinetic signs. Concomitant gamma oscillations in cognitive-limbic circuits were not directly linked to dyskinesia and were not affected by antidyskinetic treatments to the same extent, although treatment-induced reductions in functional coupling were observed in both sensorimotor and cognitive-limbic circuits, in parallel. In a broad frequency spectrum (1–200 Hz), mesdopetam treatment displayed greater similarities to pimavanserin than to amantadine. These findings point to the reduction of NBGs as a valuable biomarker for the characterization of antidyskinetic treatment effects and provide systems-level mechanistic insights into the antidyskinetic efficacy of mesdopetam, with potential additional benefits for the treatment of Parkinson's-related psychosis.</p>}},
  author       = {{Ronaghi, Abdolaziz and Stan, Tiberiu Loredan and Barrientos, Sebastian A and Halje, Pär and Nasretdinov, Azat and Censoni, Luciano and Sato, Sebastian Sulis and Malinina, Evgenya and Tedroff, Joakim and Waters, Nicholas and Petersson, Per}},
  issn         = {{0953-816X}},
  keywords     = {{LFP; multi-electrode; oscillations}},
  language     = {{eng}},
  number       = {{5}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{European Journal of Neuroscience}},
  title        = {{Neurophysiological Treatment Effects of Mesdopetam, Pimavanserin and Amantadine in a Rodent Model of Levodopa-Induced Dyskinesia}},
  url          = {{http://dx.doi.org/10.1111/ejn.70032}},
  doi          = {{10.1111/ejn.70032}},
  volume       = {{61}},
  year         = {{2025}},
}