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The Journal of Neuroscience, August 15, 2002, 22(16):6900-6907

Experimental Parkinsonism Alters Endocannabinoid Degradation: Implications for Striatal Glutamatergic Transmission

Paolo Gubellini^{1, 3}, Barbara Picconi^{1, 4}, Monica Bari², Natalia Battista², Paolo Calabresi^{1, 4}, Diego Centonze^{1, 4}, Giorgio Bernardi^{1, 4}, Alessandro Finazzi-Agrò², and Mauro Maccarrone²

Dipartimentos di ¹ Neuroscienze and ² Medicina Sperimentale e Scienze Biochimiche, Università degli Studi di Roma "Tor Vergata", 00133 Roma, Italy, ³ Istituto di Neurobiologia e Medicina Molecolare, Consiglio Nazionale delle Ricerche, 00133 Roma, Italy, and ⁴ Istituto di Ricovero e Cura a Carattere Scientifico Fondazione "Santa Lucia", 00179 Roma, Italy

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 naïve 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.

Key words: anandamide; CB1 receptor; dopamine; excitatory amino acids; glutamate; Parkinson's disease; striatum

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22166900-08$05.00/0

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