Document Detail


Levodopa treatment reverses endocannabinoid system abnormalities in experimental parkinsonism.
MedLine Citation:
PMID:  12716433     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Cannabinoid receptors and their endogenous ligands are potent inhibitors of neurotransmitter release in the brain. Here, we show that in a rat model of Parkinson's disease induced by unilateral nigral lesion with 6-hydroxydopamine (6-OHDA), the striatal levels of the endocannabinoid anandamide (AEA) were increased, while the activity of its membrane transporter and hydrolase (fatty-acid amide hydrolase, FAAH) were decreased. These changes were not observed in the cerebellum of the same animals. Moreover, the frequency and amplitude of glutamate-mediated spontaneous excitatory post-synaptic currents were augmented in striatal spiny neurones recorded from parkinsonian rats. Remarkably, the anomalies in the endocannabinoid system, as well as those in glutamatergic activity, were completely reversed by chronic treatment of parkinsonian rats with levodopa, and the pharmacological inhibition of FAAH restored a normal glutamatergic activity in 6-OHDA-lesioned animals. Thus, the increased striatal levels of AEA may reflect a compensatory mechanism trying to counteract the abnormal corticostriatal glutamatergic drive in parkinsonian rats. However, this mechanism seems to be unsuccessful, since spontaneous excitatory activity is still higher in these animals. Taken together, these data show that anomalies in the endocannabinoid system induced by experimental parkinsonism are restricted to the striatum and can be reversed by chronic levodopa treatment, and suggest that inhibition of FAAH might represent a possible target to decrease the abnormal cortical glutamatergic drive in Parkinson's disease.
Authors:
Mauro Maccarrone; Paolo Gubellini; Monica Bari; Barbara Picconi; Natalia Battista; Diego Centonze; Giorgio Bernardi; Alessandro Finazzi-Agrò; Paolo Calabresi
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of neurochemistry     Volume:  85     ISSN:  0022-3042     ISO Abbreviation:  J. Neurochem.     Publication Date:  2003 May 
Date Detail:
Created Date:  2003-04-28     Completed Date:  2003-06-18     Revised Date:  2007-07-06    
Medline Journal Info:
Nlm Unique ID:  2985190R     Medline TA:  J Neurochem     Country:  England    
Other Details:
Languages:  eng     Pagination:  1018-25     Citation Subset:  IM    
Affiliation:
Dipartimento di Medicina Sperimentale e Scienze Biochimiche and Dipartimento di Neuroscienze, Università degli Studi di Roma Tor Vergata, Via Montpellier 1, 00133 Rome, Italy.
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MeSH Terms
Descriptor/Qualifier:
Amidohydrolases / metabolism
Animals
Antiparkinson Agents / therapeutic use
Arachidonic Acids / metabolism,  pharmacokinetics
Binding, Competitive / drug effects
Cerebellum / drug effects,  metabolism
Corpus Striatum / drug effects,  metabolism
Cyclohexanols / pharmacokinetics
Disease Models, Animal
Endocannabinoids
Excitatory Postsynaptic Potentials / drug effects,  physiology
Fatty Acids, Unsaturated / metabolism*
Glutamic Acid / metabolism
Glycerides / metabolism
Levodopa / therapeutic use*
Oxidopamine
Parkinsonian Disorders / chemically induced,  drug therapy*,  metabolism*
Patch-Clamp Techniques
Phospholipase D / metabolism
Polyunsaturated Alkamides
Rats
Rats, Wistar
Receptors, Cannabinoid
Receptors, Drug / agonists,  metabolism
Chemical
Reg. No./Substance:
0/Antiparkinson Agents; 0/Arachidonic Acids; 0/Cyclohexanols; 0/Endocannabinoids; 0/Fatty Acids, Unsaturated; 0/Glycerides; 0/Levodopa; 0/Polyunsaturated Alkamides; 0/Receptors, Cannabinoid; 0/Receptors, Drug; 1199-18-4/Oxidopamine; 53847-30-6/2-arachidonylglycerol; 56-86-0/Glutamic Acid; 83003-12-7/3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; 94421-68-8/anandamide; EC 3.1.4.4/Phospholipase D; EC 3.5.-/Amidohydrolases; EC 3.5.1.-/fatty-acid amide hydrolase

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


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