Abstract/Summary

The endocannabinoid system (eCBS) consists principally of (i) endogenous transmitters, including the lipid media- tor 2-arachidonoyl glycerol (2-AG) and also arachidonoyl ethanolamide (anandamide), (ii) the metabolic enzymes that control endocannabinoid (eCB) production and deg- radation, and (iii) the cannabinoid CB1 and CB2 receptors (CB1Rs and CB2Rs) upon which eCBs exert their action. Acting in concert, these elements of the eCBS coordinate the endocannabinergic tone in the cerebellum and throughout the CNS. This tone mediates short- and long- term plasticities to control cerebellar functions, including fine motor control and associative learning paradigms. Deficits in eCBS cerebellar circuitry are associated not onlywithdiseasephenotypes,mostnotablyspinocerebel- lar ataxias (SCAs), but also with increasing evidence for roles in other psychopathologies and cognitive disorders. The eCBS is also the target of exogenous cannabis, prin- cipally due to the actions of Δ9-tetrahydrocannabidol (Δ9- THC). Δ9-THC mediates the “high” associated with illicit cannabis use, but some advocate that Δ9-THC also has medicinal benefits. Less controversial is the recent use of cannabidiol (CBD) as the main cannabis constituent with reported medicinal benefits; here, CBD in isolation from the plant is the preferred option. A previous review focused on CB1R signaling in the cerebellum and its asso- ciation with cerebellar dysfunction. This updated review will consolidate the description of the eCBS bringing new findings into light and will explore potential new thera- peutic targets and consider associated strategies that tar- get the eCBS.