Potential involvement of cannabinoid receptors in 3-nitropropionic acid toxicity in vivo

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 Delta(9)-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.