Phosphodiesterase 10A Inhibition Modulates the Corticostriatal Activity and L-DOPA-Induced Dyskinesia
The facilitation of corticostriatal transmission is modulated by the pharmacological inhibition of striatal phosphodiesterase 10A (PDE10A). Since L-DOPA-induced dyskinesia is associated with abnormal corticostriatal transmission, we hypothesized that inhibition of PDE10A would modulate L-DOPA-induce...
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MDPI AG
2022-07-01
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| author | Rayanne Poletti Guimarães Danilo Leandro Ribeiro Keila Bariotto Dos Santos Carlos Henrique Zanello Talarico Lívea Dornela Godoy Fernando E. Padovan-Neto |
| author_facet | Rayanne Poletti Guimarães Danilo Leandro Ribeiro Keila Bariotto Dos Santos Carlos Henrique Zanello Talarico Lívea Dornela Godoy Fernando E. Padovan-Neto |
| author_sort | Rayanne Poletti Guimarães |
| collection | DOAJ |
| description | The facilitation of corticostriatal transmission is modulated by the pharmacological inhibition of striatal phosphodiesterase 10A (PDE10A). Since L-DOPA-induced dyskinesia is associated with abnormal corticostriatal transmission, we hypothesized that inhibition of PDE10A would modulate L-DOPA-induced dyskinesia (LID) by regulating corticostriatal activity. 6-OHDA-lesioned rats were chronically treated with L-DOPA for one week. After that, for two additional weeks, animals were treated with the PDE10A inhibitor PDM-042 (1 and 3 mg/kg) one hour before L-DOPA. Behavioral analyses were performed to quantify abnormal involuntary movements (AIMs) and to assess the antiparkinsonian effects of L-DOPA. Single-unit extracellular electrophysiological recordings were performed in vivo to characterize the responsiveness of MSNs to cortical stimulation. The low dose of PDM-042 had an antidyskinetic effect (i.e., attenuated peak-dose dyskinesia) and did not interfere with cortically evoked spike activity. Conversely, the high dose of PDM-042 did not affect peak-dose dyskinesia, prolonged AIMs, and increased cortically evoked spike activity. These data suggest that the facilitation of corticostriatal transmission is likely to contribute to the expression of AIMs. Therefore, cyclic nucleotide manipulation is an essential target in controlling LID. |
| first_indexed | 2024-03-09T12:48:10Z |
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| id | doaj.art-9a298f92f97049a183e09f9f15afef92 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-09T12:48:10Z |
| publishDate | 2022-07-01 |
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| series | Pharmaceuticals |
| spelling | doaj.art-9a298f92f97049a183e09f9f15afef922023-11-30T22:10:04ZengMDPI AGPharmaceuticals1424-82472022-07-0115894710.3390/ph15080947Phosphodiesterase 10A Inhibition Modulates the Corticostriatal Activity and L-DOPA-Induced DyskinesiaRayanne Poletti Guimarães0Danilo Leandro Ribeiro1Keila Bariotto Dos Santos2Carlos Henrique Zanello Talarico3Lívea Dornela Godoy4Fernando E. Padovan-Neto5Department of Psychology, Faculty of Philosophy, Sciences and Letters of Ribeirão Preto, University of São Paulo, Ribeirão Preto 14040-901, SP, BrazilDepartment of Psychology, Faculty of Philosophy, Sciences and Letters of Ribeirão Preto, University of São Paulo, Ribeirão Preto 14040-901, SP, BrazilDepartment of Psychology, Faculty of Philosophy, Sciences and Letters of Ribeirão Preto, University of São Paulo, Ribeirão Preto 14040-901, SP, BrazilDepartment of Psychology, Faculty of Philosophy, Sciences and Letters of Ribeirão Preto, University of São Paulo, Ribeirão Preto 14040-901, SP, BrazilDepartment of Psychology, Faculty of Philosophy, Sciences and Letters of Ribeirão Preto, University of São Paulo, Ribeirão Preto 14040-901, SP, BrazilDepartment of Psychology, Faculty of Philosophy, Sciences and Letters of Ribeirão Preto, University of São Paulo, Ribeirão Preto 14040-901, SP, BrazilThe facilitation of corticostriatal transmission is modulated by the pharmacological inhibition of striatal phosphodiesterase 10A (PDE10A). Since L-DOPA-induced dyskinesia is associated with abnormal corticostriatal transmission, we hypothesized that inhibition of PDE10A would modulate L-DOPA-induced dyskinesia (LID) by regulating corticostriatal activity. 6-OHDA-lesioned rats were chronically treated with L-DOPA for one week. After that, for two additional weeks, animals were treated with the PDE10A inhibitor PDM-042 (1 and 3 mg/kg) one hour before L-DOPA. Behavioral analyses were performed to quantify abnormal involuntary movements (AIMs) and to assess the antiparkinsonian effects of L-DOPA. Single-unit extracellular electrophysiological recordings were performed in vivo to characterize the responsiveness of MSNs to cortical stimulation. The low dose of PDM-042 had an antidyskinetic effect (i.e., attenuated peak-dose dyskinesia) and did not interfere with cortically evoked spike activity. Conversely, the high dose of PDM-042 did not affect peak-dose dyskinesia, prolonged AIMs, and increased cortically evoked spike activity. These data suggest that the facilitation of corticostriatal transmission is likely to contribute to the expression of AIMs. Therefore, cyclic nucleotide manipulation is an essential target in controlling LID.https://www.mdpi.com/1424-8247/15/8/947L-DOPA-induced dyskinesiaParkinson’s diseasephosphodiesterase 10Amedium spiny neuronscorticostriatal pathway |
| spellingShingle | Rayanne Poletti Guimarães Danilo Leandro Ribeiro Keila Bariotto Dos Santos Carlos Henrique Zanello Talarico Lívea Dornela Godoy Fernando E. Padovan-Neto Phosphodiesterase 10A Inhibition Modulates the Corticostriatal Activity and L-DOPA-Induced Dyskinesia Pharmaceuticals L-DOPA-induced dyskinesia Parkinson’s disease phosphodiesterase 10A medium spiny neurons corticostriatal pathway |
| title | Phosphodiesterase 10A Inhibition Modulates the Corticostriatal Activity and L-DOPA-Induced Dyskinesia |
| title_full | Phosphodiesterase 10A Inhibition Modulates the Corticostriatal Activity and L-DOPA-Induced Dyskinesia |
| title_fullStr | Phosphodiesterase 10A Inhibition Modulates the Corticostriatal Activity and L-DOPA-Induced Dyskinesia |
| title_full_unstemmed | Phosphodiesterase 10A Inhibition Modulates the Corticostriatal Activity and L-DOPA-Induced Dyskinesia |
| title_short | Phosphodiesterase 10A Inhibition Modulates the Corticostriatal Activity and L-DOPA-Induced Dyskinesia |
| title_sort | phosphodiesterase 10a inhibition modulates the corticostriatal activity and l dopa induced dyskinesia |
| topic | L-DOPA-induced dyskinesia Parkinson’s disease phosphodiesterase 10A medium spiny neurons corticostriatal pathway |
| url | https://www.mdpi.com/1424-8247/15/8/947 |
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