Document Detail


Simultaneous blockade of adenosine A2A and metabotropic glutamate mGlu5 receptors increase their efficacy in reversing Parkinsonian deficits in rats.
MedLine Citation:
PMID:  15039773     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Recent evidence suggest that antagonism of adenosine A2A receptors represent an alternative therapeutic approach to Parkinson's disease (PD). Coactivation of A2A and the glutamate subtype 5 metabotropic receptors (mGlu5) synergistically stimulates DARPP-32 phosphorylation and c-fos expression in the striatum. This study therefore tested the effects of a joint blockade of these receptors to alleviate the motor dysfunction in a rat model of PD. 6-Hydroxydopamine infusions in the striatum produced akinetic deficits in rats trained to release a lever after a stimulus in a reaction time (RT) task. At 2 weeks after the lesion, A2A and mGlu5 receptors selective antagonists 8-(3-chlorostyryl)caffeine (CSC) and 2-methyl-6-(phenylethynyl)-pyridine (MPEP) were administered daily for 3 weeks either as a single or joint treatment. Injections of CSC (1.25 mg/kg) and MPEP (1.5 mg/kg) separately or in combination reduced the increase of delayed responses and RTs induced by 6-OHDA lesions, while the same treatment had no effect in controls. Furthermore, coadministration of lower doses of 0.625 mg/kg CSC and 0.375 mg/kg MPEP noneffective as a single treatment promoted a full and immediate recovery of akinesia, which was found to be more efficient than the separate blockade of these receptors. These results demonstrate that the combined inactivation of A2A and mGlu5 receptor potentiate their beneficial effects supporting this pharmacological strategy as a promising anti-Parkinsonian therapy.
Authors:
Roberto Coccurello; Nathalie Breysse; Marianne Amalric
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology     Volume:  29     ISSN:  0893-133X     ISO Abbreviation:  Neuropsychopharmacology     Publication Date:  2004 Aug 
Date Detail:
Created Date:  2004-07-21     Completed Date:  2004-09-08     Revised Date:  2011-05-18    
Medline Journal Info:
Nlm Unique ID:  8904907     Medline TA:  Neuropsychopharmacology     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1451-61     Citation Subset:  IM    
Affiliation:
Laboratoire de Neurobiologie de la Cognition, CNRS and Université de Provence, Marseille cedex, France.
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MeSH Terms
Descriptor/Qualifier:
Adenosine A2 Receptor Antagonists*
Animals
Brain / pathology
Caffeine / pharmacology
Conditioning, Operant / drug effects
Dopamine / physiology
Dopamine and cAMP-Regulated Phosphoprotein 32
Gene Expression Regulation / drug effects
Genes, fos
Male
Nerve Tissue Proteins / metabolism
Oxidopamine
Parkinson Disease, Secondary / chemically induced,  drug therapy*,  pathology
Phosphoproteins / metabolism
Phosphorylation
Psychomotor Performance / drug effects
Pyridines / pharmacology
Rats
Reaction Time / drug effects
Receptors, Metabotropic Glutamate / antagonists & inhibitors*
Sympatholytics
Chemical
Reg. No./Substance:
0/6-methyl-2-(phenylethynyl)pyridine; 0/Adenosine A2 Receptor Antagonists; 0/Dopamine and cAMP-Regulated Phosphoprotein 32; 0/Nerve Tissue Proteins; 0/Phosphoproteins; 0/Pyridines; 0/Receptors, Metabotropic Glutamate; 0/Sympatholytics; 0/metabotropic glutamate receptor 5; 1199-18-4/Oxidopamine; 58-08-2/Caffeine

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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