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Neuropharmacology. 2015 Feb;89:368-74. doi: 10.1016/j.neuropharm.2014.07.021. Epub 2014 Aug 11.

Chronic cannabinoid receptor stimulation selectively prevents motor impairments in a mouse model of Huntington's disease.

Author information

1
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.
2
Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University and CIBERNED, 2 Calle José Antonio Novais, 28040 Madrid, Spain.
3
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.

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.

KEYWORDS:

Cannabinoid receptor; DARPP-32; Huntington's disease; RotaRod test; Social behavior

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