title: Levodopa treatment reverses endocannabinoid system abnormalities in experimental parkinsonism.
abstract: 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.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.
authors.forename: Mauro
authors.initials: M
authors.lastname: Maccarrone
authors.forename: Paolo
authors.initials: P
authors.lastname: Gubellini
authors.forename: Monica
authors.initials: M
authors.lastname: Bari
authors.forename: Barbara
authors.initials: B
authors.lastname: Picconi
authors.forename: Natalia
authors.initials: N
authors.lastname: Battista
authors.forename: Diego
authors.initials: D
authors.lastname: Centonze
authors.forename: Giorgio
authors.initials: G
authors.lastname: Bernardi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Finazzi-Agrò
authors.forename: Paolo
authors.initials: P
authors.lastname: Calabresi
mesh_terms: D000581:Amidohydrolases / Q000378:metabolism; D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use; D001095:Arachidonic Acids / Q000378:metabolism / Q000493:pharmacokinetics; D001667:Binding, Competitive / Q000187:drug effects; D063385:Cannabinoid Receptor Modulators; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D003511:Cyclohexanols / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D063388:Endocannabinoids; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005231:Fatty Acids, Unsaturated / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism; D005989:Glycerides / Q000378:metabolism; D066298:In Vitro Techniques; D007980:Levodopa / Q000627:therapeutic use*; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010739:Phospholipase D / Q000378:metabolism; D053284:Polyunsaturated Alkamides; D051381:Rats; D017208:Rats, Wistar; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000819:agonists / Q000378:metabolism; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D000978:Antiparkinson Agents; D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D003511:Cyclohexanols; D063388:Endocannabinoids; D005231:Fatty Acids, Unsaturated; D018698:Glutamic Acid; D005989:Glycerides; D007980:Levodopa; D016627:Oxidopamine; D010739:Phospholipase D; D053284:Polyunsaturated Alkamides; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D000099252:Fatty Acid Amide Hydrolases; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; C094503:glyceryl 2-arachidonate; C078814:anandamide