Abstract
Cannabinoid receptors and their endogenous ligands have been recently identified in the brain as potent inhibitors of neurotransmitter release. 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 anandamide, but not that of the other endocannabinoid 2-arachidonoylglycerol, were increased. Moreover, we observed a decreased activity of the anandamide membrane transporter (AMT) and of the anandamide hydrolase [fatty acid amide hydrolase (FAAH)], whereas the binding of anandamide to cannabinoid receptors was unaffected. Spontaneous glutamatergic activity recorded from striatal spiny neurons was higher in 6-OHDA-lesioned rats. Inhibition of AMT by N-(4-hydroxyphenyl)-arachidonoylamide (AM-404) or by VDM11, or stimulation of the cannabinoid CB1 receptor by HU-210 reduced glutamatergic spontaneous activity in both naive and 6-OHDA-lesioned animals to a similar extent. Conversely, the FAAH inhibitors phenylmethylsulfonyl fluoride and methyl-arachidonoyl fluorophosphonate were much more effective in 6-OHDA-lesioned animals. The present study shows that inhibition of anandamide hydrolysis might represent a possible target to decrease the abnormal cortical glutamatergic drive in Parkinson's disease.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amidohydrolases / antagonists & inhibitors
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Amidohydrolases / metabolism
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Animals
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Arachidonic Acids / metabolism
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Arachidonic Acids / pharmacology
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Cannabinoid Receptor Modulators
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Cannabinoids / metabolism*
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Cannabinoids / pharmacology
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Carrier Proteins / metabolism
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Corpus Striatum / chemistry
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Corpus Striatum / pathology
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Corpus Striatum / physiopathology*
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Disease Models, Animal
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Dronabinol / analogs & derivatives
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Dronabinol / pharmacology
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Endocannabinoids
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Enzyme Inhibitors / pharmacology
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Glutamic Acid / metabolism*
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Glycerides / metabolism
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Hydrolysis / drug effects
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In Vitro Techniques
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Membrane Potentials / drug effects
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Membrane Potentials / physiology
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Neurons / metabolism
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Neurons / pathology
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Oxidopamine
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Parkinsonian Disorders / chemically induced
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Parkinsonian Disorders / pathology
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Parkinsonian Disorders / physiopathology*
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Patch-Clamp Techniques
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Polyunsaturated Alkamides
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Rats
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Rats, Wistar
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Receptors, Cannabinoid
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Receptors, Drug / drug effects
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Receptors, Drug / metabolism
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Synaptic Transmission / physiology*
Substances
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Arachidonic Acids
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Cannabinoid Receptor Modulators
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Cannabinoids
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Carrier Proteins
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Endocannabinoids
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Enzyme Inhibitors
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Glycerides
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N-(2-methyl-3-hydroxyphenyl)-5,8,11,14-eicosatetraenamide
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Polyunsaturated Alkamides
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Receptors, Cannabinoid
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Receptors, Drug
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Glutamic Acid
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Dronabinol
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glyceryl 2-arachidonate
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Oxidopamine
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Amidohydrolases
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fatty-acid amide hydrolase
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HU 211
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anandamide
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N-(4-hydroxyphenyl)arachidonylamide