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Neurophysiological treatment effects of mesdopetam, pimavanserin and amantadine in a rodent model of levodopa-induced dyskinesia
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  • Abdolaziz Ronaghi,
  • Tiberiu Loredan Stan,
  • Sebastian Barrientos,
  • Pär Halje,
  • Azat Nasretdinov,
  • Luciano Censoni,
  • Sebastian Sulis Sato,
  • Evgenya Malinina,
  • Joakim Tedroff,
  • Nicholas Waters,
  • Per Petersson
Abdolaziz Ronaghi
Umeå University
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Tiberiu Loredan Stan
Lund University
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Sebastian Barrientos
Lund University
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Pär Halje
Lund University
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Azat Nasretdinov
Umeå University
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Luciano Censoni
Umeå University
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Sebastian Sulis Sato
Umeå University
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Evgenya Malinina
Umeå University
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Joakim Tedroff
IRL AB
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Nicholas Waters
IRL AB
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Per Petersson
Lund University

Corresponding Author:per.petersson@med.lu.se

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Abstract

Levodopa provides effective symptomatic treatment for Parkinson’s disease. However, non-motor 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 eleven cortical and sub-cortical 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 was observed in both sensorimotor and cognitive-limbic circuits, in parallel. In a broad frequency spectrum (1-200Hz), mesdopetam treatment displayed greater similarities to pimavanserin than to amantadine. These findings point to reduction of NBGs as a valuable biomarker for 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.
26 Sep 2024Submitted to European Journal of Neuroscience
29 Sep 2024Submission Checks Completed
29 Sep 2024Assigned to Editor
02 Oct 2024Review(s) Completed, Editorial Evaluation Pending
02 Oct 2024Reviewer(s) Assigned
07 Nov 2024Editorial Decision: Revise Major