Huntington’s disease (HD) is an inherited progressive neurodegenerative disease characterized
by motor, cognitive, and behavioural changes. One of the earliest changes to occur
in HD is a reduction in cannabinoid 1 receptor (CB 1 ) levels in the striatum, which
is strongly correlated with HD pathogenesis. CB 1 positive allosteric modulators
(PAM) enhance receptor affinity for, and efficacy of activation by, orthosteric ligands,
including the endocannabinoids anandamide and 2-arachidonoylglycerol. The goal of
this study was to determine whether the recently characterized CB 1 allosteric modulators
GAT211 (racemic), GAT228 ( R -enantiomer), and GAT229 ( S -enantiomer), affected the
signs and symptoms of HD. GAT211, GAT228, and GAT229 were evaluated in normal and
HD cell models, and in a transgenic mouse model of HD (7-week-old male R6/2 mice,
10 mg/kg/d, 21 d, i.p. ). GAT229 was a CB 1 PAM that improved cell viability in
HD cells and improved motor coordination, delayed symptom onset, and normalized gene
expression in R6/2 HD mice. GAT228 was an allosteric agonist that did not enhance
endocannabinoid signaling or change symptom progression in R6/2 mice. GAT211 displayed
intermediate effects between its enantiomers. The compounds used here are not drugs,
but probe compounds used to determine the potential utility of CB 1 PAMs in HD. Changes
in gene expression, and not protein, were quantified in R6/2 HD mice because HD pathogenesis
is associated with dysregulation of mRNA levels. The data presented here provide the
first proof of principle for the use of CB 1 PAMs to treat the signs and symptoms
of HD.