Cannabinoid type 1 receptor antagonism ameliorates harmaline-induced essential tremor in rat

BACKGROUND AND PURPOSE Essential tremor (ET) is a neurological disorder with unknown aetiology. Its symptoms include cerebellar motor disturbances, cognitive and personality changes, hearing and olfactory deficits. Hyperactivity of excitotoxic cerebellar climbing fibres may underlie essential tremor and has been induced in rodents by systemic harmaline administration. Cannabinoid (CB) receptor agonists can cause motor disturbances; although, there are also anecdotal reports of therapeutic benefits of cannabis in motor disorders. We set out to establish the effects of CB receptor agonism and antagonism on an established rodent model of ET using a battery of accepted behaviour assays in order to determine the risk and therapeutic potential of modulating the endocannabinoid system in ET. EXPERIMENTAL APPROACH Behavioural effects of systemic treatment with a CB receptor agonist (0.1, 0.5 and 1 mg kg(-1) WIN55, 212-2) or two CB1 receptor antagonists (1 mg kg(-1) AM251 and 10 mg kg(-1) rimonabant) on tremor induced in rats by harmaline (30 mg kg(-1); i.p.), were assessed using tremor scoring, open field, rotarod, grip and gait tests. KEY RESULTS Overall, harmaline induced robust tremor that was typically worsened across the measured behavioural domains by CB receptor agonism but ameliorated by CB1 receptor antagonism. CONCLUSIONS AND IMPLICATIONS These results provide the first evidence of the effects of modulating the endocannabinoid system on motor function in the harmalinemodel of ET. Our data suggest that CB1 receptor manipulation warrants clinical investigation as a therapeutic approach to protection against behavioural disturbances associated with ET.