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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Animals
  • Benzoxazines / pharmacology
  • Body Weight / drug effects
  • Brain / drug effects
  • Brain / pathology
  • Cannabinoids / therapeutic use
  • Drug Administration Schedule
  • Exploratory Behavior / drug effects
  • Female
  • Huntington Disease / complications*
  • Huntington Disease / genetics
  • Male
  • Maze Learning / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Morpholines / pharmacology
  • Motor Activity / drug effects
  • Motor Activity / genetics
  • Movement Disorders / etiology*
  • Movement Disorders / pathology
  • Movement Disorders / prevention & control*
  • Naphthalenes / pharmacology
  • Receptors, Cannabinoid / metabolism*
  • Serotonin Plasma Membrane Transport Proteins / genetics
  • Space Perception / drug effects
  • Trinucleotide Repeats / genetics


  • Benzoxazines
  • Cannabinoids
  • Morpholines
  • Naphthalenes
  • Receptors, Cannabinoid
  • Serotonin Plasma Membrane Transport Proteins
  • Slc6a4 protein, mouse
  • (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone