CANNABINOIDS REGULATE TYPE 1 CANNABINOID RECEPTOR EXPRESSION IN CELL CULTURE MODELS OF HUNTINGTON'S DISEASE

Abstract

Type 1 cannabinoid receptor (CB1) levels decline in the striatum of animal models of Huntington’s disease (HD) and in the brains of human patients suffering from HD prior to other pathogenic changes. CB1 levels can be elevated by treatment with cannabinoids in non-neuronal cells. We wanted to determine: 1) whether cannabinoid treatment could induce CB1 expression in a striatal cell line, and 2) determine the molecular mechanisms by which cannabinoids and mutant huntingtin regulate CB1 expression. Treatment of striatal cell lines with CB1-specific agonists produced a CB1 receptor-, Akt-, and NF-?B-dependent increase in CB1 promoter activity and mRNA expression that was attenuated in the presence of mutant huntingtin. Cannabinoid treatment was associated with increased expression of the trophic factor BDNF-2 and the mitochondrial regulator PGC1? in the cell types tested. In vivo, cannabinoids may initiate a positive feedback loop increasing receptor expression and restoring cannabinoid-dependent inhibition of neurotransmitter release.