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Buspirone anti-dyskinetic effect is correlated with temporal normalization of dysregulated striatal DRD1 signalling in L-DOPA-treated rats.
- Source :
-
Neuropharmacology [Neuropharmacology] 2014 Apr; Vol. 79, pp. 726-37. Date of Electronic Publication: 2013 Dec 10. - Publication Year :
- 2014
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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.<br /> (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Subjects :
- Animals
Antiparkinson Agents pharmacology
Corpus Striatum drug effects
Corpus Striatum metabolism
Cyclic AMP Response Element-Binding Protein metabolism
Disease Models, Animal
Dopamine and cAMP-Regulated Phosphoprotein 32 metabolism
Dose-Response Relationship, Drug
Dyskinesia, Drug-Induced metabolism
Levodopa pharmacology
Mitogen-Activated Protein Kinase 1 metabolism
Parkinsonian Disorders complications
Parkinsonian Disorders drug therapy
Parkinsonian Disorders metabolism
Proto-Oncogene Proteins c-fos metabolism
Rats
Rats, Sprague-Dawley
Receptors, Dopamine D3 antagonists & inhibitors
Receptors, Dopamine D3 metabolism
Serotonin 5-HT1 Receptor Agonists pharmacology
Severity of Illness Index
Signal Transduction drug effects
Signal Transduction physiology
Anti-Dyskinesia Agents pharmacology
Antiparkinson Agents adverse effects
Buspirone pharmacology
Dyskinesia, Drug-Induced drug therapy
Levodopa adverse effects
Receptors, Dopamine D1 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1873-7064
- Volume :
- 79
- Database :
- MEDLINE
- Journal :
- Neuropharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 24333147
- Full Text :
- https://doi.org/10.1016/j.neuropharm.2013.11.024