Neurophysiological treatment effects of mesdopetam, pimavanserin and clozapine in a rodent model of Parkinson's disease psychosisShow others and affiliations
2024 (English)In: Neurotherapeutics, ISSN 1933-7213, Vol. 21, no 2, article id e00334Article in journal (Refereed) Published
Abstract [en]
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.
Place, publisher, year, edition, pages
Elsevier, 2024. Vol. 21, no 2, article id e00334
Keywords [en]
Antipsychotics, Behavior, High-frequency oscillations, In vivo, Local field-potentials
National Category
Neurosciences Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:umu:diva-222416DOI: 10.1016/j.neurot.2024.e00334PubMedID: 38368170Scopus ID: 2-s2.0-85187115561OAI: oai:DiVA.org:umu-222416DiVA, id: diva2:1846537
Funder
Vinnova, 2019–01458Umeå UniversityThe Swedish Brain FoundationSwedish Research Council, 2018-02717Swedish Research Council, 2021–01769Olle Engkvists stiftelseParkinsonfondenÅhlén-stiftelsenPromobilia foundationStiftelsen Längmanska kulturfondenRoyal Physiographic Society in Lund2024-03-222024-03-222024-03-22Bibliographically approved