NEUROCHEMISTRY, BASIC AND CLINICALPotential involvement of cannabinoid receptors in 3-nitropropionic acid toxicity in vivoLastres-Becker, Isabel1; Bizat, Nicolas2; Boyer, Frédéric2; Hantraye, Philippe2; Fernández-Ruiz, JavierCA; Brouillet, Emmanuel2 CA Author Information Departamento de Bioquímica y Biología Molecular III, Facultad de Medicina, Universidad Complutense, 28040-Madrid, Spain 2Unité de Recherche Associée Commissariat à l'Energie Atomique – Centre Nationale de la Recherche Scientifique 2210, Service Hospitalier Frédéric Joliot, Département de Recherches Médicales, Direction des Sciences du Vivant, 4 place du Général Leclerc, 91401-Orsay Cedex, France 1Present address: Instituto de Investigaciones Biomédicas-CSIC, c/Arturo Duperier 4, 28029-Madrid, Spain CACorresponding Authors: [email protected], [email protected] Received 10 April 2004; accepted 20 July 2004 NeuroReport 15(15):p 2375-2379, October 25, 2004. Buy Abstract Several neurotransmitter systems are involved in the pathogenesis of Huntington's disease. Here, we examined the involvement of cannabinoid CB1 receptors in striatal degeneration in the rat model of this disease generated by administration of 3-nitropropionic acid (3NP). Several days before onset of striatal degeneration, G-protein activation by cannabinoid agonists was significantly decreased whereas density and mRNA levels of CB1 receptors remained essentially normal. This change was transient, CB1 receptors recovering full functionality after few days. Later, at onset of striatal degeneration, profound alterations of CB1 receptors were detected, including marked reductions of their density, mRNA levels and coupling to G proteins. In these rats, the administration of the cannabinoid agonist Δ9-tetrahydrocannabinol was neuroprotective, which indicates that the early loss of CB1 receptor signaling could be instrumental in 3NP toxicity. In conclusion, the present study supports the hypothesis that cannabinoid receptors, possibly the CB1 receptor subtype, may be involved in HD pathogenesis and could be an interesting therapeutic target to slow disease progression. © 2004 Lippincott Williams & Wilkins, Inc.