Reducing the signs and symptoms of Huntingtons disease by manipulating endocannabinoid tone.

The endocannabinoid system is a system of receptors and enzymes that interact with cannabinoids, molecules that are naturally produced by the body and related to the active ingredient in marijuana, THC, to cause context-specific effects. In the brain, the type 1 cannabinoid receptor (CB1) is activated by cannabinoids. Activation of CB1 inhibits excessive neuronal activity and assists in the creation of neuron-to-neuron connections. For these reasons, CB1 is considered 'neuro-protective'. In humans, expression of CB1 changes with age. For example, brain CB1 expression is higher during adolescence than during adulthood. Huntingtons disease (HD) is a neurodegenerative disorder caused by the inheritance of one copy of the mutant huntingtin gene. There is no cure for HD and no effective treatment to manage the behavioural, cognitive, and motor symptoms of the disease. During the early phases of HD, CB1 expression decreases in the regions of the brain most affected by HD. Because CB1 is neuro-protective and CB1 expression decreases early in HD, it is thought that decreased CB1 contributes to HD and increasing CB1 levels may reduce the severity of HD symptoms. Our laboratory has demonstrated that cannabinoids increase CB1 levels in cell models of HD and the viability of these cells is consequently improved. Whether this is possible in an animal or a human is not known. In HD, where CB1 receptor expression is decreased, cannabinoid-based therapies could restore expression, and provide neuro-protective benefits. I hypothesize that 1) increasing the expression of CB1 can reduce the signs and symptoms of HD, and 2)cannabinoid levels influence CB1 expression in the brain. Because brain CB1 levels are higher during adolescence than adulthood, adolescent and adult cannabinoid exposure may have differential effects on CB1 expression. In HD, where CB1 expression declines, cannabinoid-dependent induction of CB1 expression may restore normal brain function.