title: Buspirone anti-dyskinetic effect is correlated with temporal normalization of dysregulated striatal DRD1 signalling in L-DOPA-treated rats.
abstract: Dopamine replacement with l-DOPA is the most effective therapy in Parkinson's disease. However, with chronic treatment, half of the patients develop an abnormal motor response including dyskinesias. The specific molecular mechanisms underlying dyskinesias are not fully understood. In this study, we used a well-characterized animal model to first establish the molecular differences between rats that did and did not develop dyskinesias. We then investigated the molecular substrates implicated in the anti-dyskinetic effect of buspirone, a 5HT1A partial agonist. Striatal protein expression profile of dyskinetic animals revealed increased levels of the dopamine receptor (DR)D3, ΔFosB and phospho (p)CREB, as well as an over-activation of the DRD1 signalling pathway, reflected by elevated ratios of phosphorylated DARPP32 and ERK2. Buspirone reduced the abnormal involuntary motor response in dyskinetic rats in a dose-dependent fashion. Buspirone (4 mg/kg) dramatically reduced the presence and severity of dyskinesias (by 83%) and normalized DARPP32 and ERK2 phosphorylation ratios, while the increases in DRD3, ΔFosB and pCREB observed in dyskinetic rats were not modified. Pharmacological experiments combining buspirone with 5HT1A and DRD3 antagonists confirmed that normalization of both pDARPP32 and pERK2 is required, but not sufficient, for blocking dyskinesias. The correlation between pDARPP32 ratio and dyskinesias was significant but not strong, pointing to the involvement of convergent factors and signalling pathways. Our results suggest that in dyskinetic rats DRD3 striatal over-expression could be instrumental in the activation of DRD1-downstream signalling and demonstrate that the anti-dyskinetic effect of buspirone in this model is correlated with DRD1 pathway normalization.
authors: Animal Model Unit, Inbiomed, Mikeletegi, 81, 20009 San Sebastian, Spain; Laboratory of Stem Cells and Neural Repair, Inbiomed, P. Mikeletegi, 81, 20009 San Sebastian, Spain. Electronic address: gazkona@ub.edu.
authors: Garikoitz
authors: G
authors: Azkona
authors: Department of Pharmacology, Faculty of Medicine and Dentistry, University of the Basque Country (UPV/EHU), B. Sarriena s/n, 48940 Leioa, Spain. Electronic address: ainhoa.sagarduy@ehu.es.
authors: Ainhoa
authors: A
authors: Sagarduy
authors: Department of Pharmacology, Faculty of Medicine and Dentistry, University of the Basque Country (UPV/EHU), B. Sarriena s/n, 48940 Leioa, Spain. Electronic address: asier.aristieta@ehu.es.
authors: Asier
authors: A
authors: Aristieta
authors: Laboratory of Stem Cells and Neural Repair, Inbiomed, P. Mikeletegi, 81, 20009 San Sebastian, Spain. Electronic address: nereavazquez@hotmail.com.
authors: Nerea
authors: N
authors: Vazquez
authors: Laboratory of Stem Cells and Neural Repair, Inbiomed, P. Mikeletegi, 81, 20009 San Sebastian, Spain. Electronic address: zubivero@hotmail.com.
authors: Verónica
authors: V
authors: Zubillaga
authors: Department of Pharmacology, Faculty of Medicine and Dentistry, University of the Basque Country (UPV/EHU), B. Sarriena s/n, 48940 Leioa, Spain. Electronic address: joseangel.ruiz@ehu.es.
authors: José Angel
authors: JA
authors: Ruíz-Ortega
authors: Department of Cell Biology, Immunology and Neurosciences, Faculty of Medicine, University of Barcelona, 08036 Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), C/ Rosselló, 149-153, 08036 Barcelona, Spain; Centro de Investigaciones Biomédicas en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Casanova, 143, Barcelona, Spain. Electronic address: estherperez@ub.edu.
authors: Esther
authors: E
authors: Pérez-Navarro
authors: Department of Pharmacology, Faculty of Medicine and Dentistry, University of the Basque Country (UPV/EHU), B. Sarriena s/n, 48940 Leioa, Spain. Electronic address: luisa.ugedo@ehu.es.
authors: Luisa
authors: L
authors: Ugedo
authors: Laboratory of Stem Cells and Neural Repair, Inbiomed, P. Mikeletegi, 81, 20009 San Sebastian, Spain. Electronic address: rpernaute@inbiomed.org.
authors: Rosario
authors: R
authors: Sánchez-Pernaute
mesh_terms: D000818:Animals; D018726:Anti-Dyskinesia Agents / Q000494:pharmacology*; D000978:Antiparkinson Agents / Q000009:adverse effects* / Q000494:pharmacology; D002065:Buspirone / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004195:Disease Models, Animal; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000378:metabolism; D007980:Levodopa / Q000009:adverse effects* / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D018726:Anti-Dyskinesia Agents; D000978:Antiparkinson Agents; D017362:Cyclic AMP Response Element-Binding Protein; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; C483820:Fosb protein, rat; C497930:Ppp1r1b protein, rat; D016760:Proto-Oncogene Proteins c-fos; D017447:Receptors, Dopamine D1; D050637:Receptors, Dopamine D3; D058825:Serotonin 5-HT1 Receptor Agonists; D007980:Levodopa; D019950:Mitogen-Activated Protein Kinase 1; D002065:Buspirone
keywords: Buspirone; DARPP32 and ERK2; DRD3; Dyskinesias; Parkinson's disease