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

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.