The effects of cannabinoid drugs on abnormal involuntary movements in dyskinetic and non-dyskinetic 6-hydroxydopamine lesioned rats

The long term use of levodopa as a pharmacotherapy for Parkinson's disease is limited by the development of levodopa induced dyskinesias However recent studies have suggested that pharmacological targeting of the endocannabinoid system may provide a viable adjunct to suppress these motor side effects Thus this study sought to determine the effect of pharmacologically activating or blocking endocannabinoid signalling on levodopa induced dyskinesias in a rat model Male Sprague-Dawley rats with 6 hydroxydopamine lesions were made dyskinetic by 6 weeks of daily levodopa injections (10 mg/kg s c) Rats that developed stable abnormal involuntary movements (AIMs) received acute injections of the cannabinoid receptor agonist HU210 (0 0 0 5 5 0 and 500 mu g/kg i p) or the CB1 receptor antagonist/inverse agonist AM251 (0 0 and 30 mg/kg i p), whereas rats that did not develop stable AIMs received injections of the CB1 receptor antagonist/inverse agonist rimonabant (0 0 and 3 0 mg/kg i p), for 18 days In the dyskinetic rats the highest dose of HU210 significantly reduced certain subtypes of AIMs but it also impaired normal motor functioning while AM251 had no effect on AIMs In the non dyskinetic rats, rimonabant precipitated certain subtypes of AIMs Overall this study demonstrates that the ant dyskinetic effects of cannabinoid receptor agonists may not be dissociable from their motor suppressant effects thereby limiting their potential usefulness for treating established dyskinesias in parkinsonism However, it is intriguing that blockade of endocannabinoid CB1 signalling can unmask levodopa-induced AIMs and this finding suggests that endocannabinoid tone may confer protection against the development of levodopa induced dyskinesias (C) 2010 Elsevier B V All rights reserved