title: Chronic cannabinoid receptor stimulation selectively prevents motor impairments in a mouse model of Huntington's disease.
abstract: Huntington's disease (HD) is a devastating neurodegenerative disease characterized by a progressive decline in motor abilities, as well as in cognitive and social behaviors. Most of these behavioral deficits are recapitulated in the R6/1 transgenic mouse, which can therefore be used as an experimental model to identify the neurobiological substrates of HD pathology and to design novel therapeutic approaches. The endocannabinoid system (ECS) is a relevant candidate to participate in the etiopathology of HD as it is a key modulator of brain function, especially in areas primarily affected by HD dysfunction such as the striatum. Thus, some studies have demonstrated an association between HD progression and alterations in the expression of several ECS elements, thereby suggesting that improving ECS function may constitute a useful strategy to eliminate or at least delay the appearance of HD symptoms. Here this hypothesis was specifically tested by evaluating whether the administration of a well-characterized cannabinoid receptor agonist (WIN 55,212), either acutely or chronically, improves the HD-like symptoms in R6/1 mice. While acute treatment did not change the behavioral phenotype of transgenic animals, chronic administration was able to prevent the appearance of motor deficits, to increase the number of striatal huntingtin inclusions and to prevent the loss of striatal medium-sized spiny neurons, without affecting the social or cognitive alterations. These findings suggest that prolonged administration of cannabinoid receptor agonists could be an appropriate strategy for selectively improving motor symptoms and stimulating neuroprotective processes in HD patients.
authors.affiliation: Institut de Neurosciences Cognitives et Intégratives d'Aquitaine, CNRS UMR 5287, Bat B2 - Avenue des Facultés, 33405 Talence Cedex, France; Université de Bordeaux, Bat B2 - Avenue des Facultés, 33405 Talence Cedex, France. Electronic address: susanna.pietropaolo@u-bordeaux.fr.
authors.forename: Susanna
authors.initials: S
authors.lastname: Pietropaolo
authors.affiliation: Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University and CIBERNED, 2 Calle José Antonio Novais, 28040 Madrid, Spain.
authors.forename: Luigi
authors.initials: L
authors.lastname: Bellocchio
authors.affiliation: Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University and CIBERNED, 2 Calle José Antonio Novais, 28040 Madrid, Spain.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ruiz-Calvo
authors.affiliation: Institut de Neurosciences Cognitives et Intégratives d'Aquitaine, CNRS UMR 5287, Bat B2 - Avenue des Facultés, 33405 Talence Cedex, France; Université de Bordeaux, Bat B2 - Avenue des Facultés, 33405 Talence Cedex, France.
authors.forename: Magali
authors.initials: M
authors.lastname: Cabanas
authors.affiliation: Institut de Neurosciences Cognitives et Intégratives d'Aquitaine, CNRS UMR 5287, Bat B2 - Avenue des Facultés, 33405 Talence Cedex, France; Université de Bordeaux, Bat B2 - Avenue des Facultés, 33405 Talence Cedex, France.
authors.forename: Zhuowei
authors.initials: Z
authors.lastname: Du
authors.affiliation: Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University and CIBERNED, 2 Calle José Antonio Novais, 28040 Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Guzmán
authors.affiliation: Institut de Neurosciences Cognitives et Intégratives d'Aquitaine, CNRS UMR 5287, Bat B2 - Avenue des Facultés, 33405 Talence Cedex, France; Université de Bordeaux, Bat B2 - Avenue des Facultés, 33405 Talence Cedex, France.
authors.forename: Maurice
authors.initials: M
authors.lastname: Garret
authors.affiliation: Institut de Neurosciences Cognitives et Intégratives d'Aquitaine, CNRS UMR 5287, Bat B2 - Avenue des Facultés, 33405 Talence Cedex, France; Université de Bordeaux, Bat B2 - Avenue des Facultés, 33405 Talence Cedex, France.
authors.forename: Yoon H
authors.initials: YH
authors.lastname: Cho
mesh_terms: D000367:Age Factors; D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000473:pathology; D002186:Cannabinoids / Q000627:therapeutic use; D004334:Drug Administration Schedule; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D006816:Huntington Disease / Q000150:complications* / Q000235:genetics; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009025:Morpholines / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009069:Movement Disorders / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control*; D009281:Naphthalenes / Q000494:pharmacology; D043882:Receptors, Cannabinoid / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics; D013028:Space Perception / Q000187:drug effects; D018911:Trinucleotide Repeats / Q000235:genetics
chemical_list: D048588:Benzoxazines; D002186:Cannabinoids; D009025:Morpholines; D009281:Naphthalenes; D043882:Receptors, Cannabinoid; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
keywords: Cannabinoid receptor; DARPP-32; Huntington's disease; RotaRod test; Social behavior