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

Abstract

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 (10mg/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 50.0 μg/kg i.p.), or the CB(1) receptor antagonist/inverse agonist, AM251 (0.0 and 3.0mg/kg i.p.), whereas rats that did not develop stable AIMs received injections of the CB(1) receptor antagonist/inverse agonist, rimonabant (0.0 and 3.0mg/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 anti-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-CB(1) signalling can unmask levodopa-induced AIMs, and this finding suggests that endocannabinoid tone may confer protection against the development of levodopa-induced dyskinesias.

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  • Authors+Show Affiliations

    ,

    Department of Pharmacology & Therapeutics, National University of Ireland, Galway, Ireland. s.walsh12@nuigalway.ie

    , ,

    Source

    Brain research 1363: 2010 Dec 02 pg 40-8

    MeSH

    Animals
    Antiparkinson Agents
    Disease Models, Animal
    Dronabinol
    Dyskinesia, Drug-Induced
    Levodopa
    Male
    Parkinsonian Disorders
    Piperidines
    Pyrazoles
    Rats
    Rats, Sprague-Dawley
    Receptor, Cannabinoid, CB1
    Rimonabant

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    20888328

    Citation

    Walsh, Sinéad, et al. "The Effects of Cannabinoid Drugs On Abnormal Involuntary Movements in Dyskinetic and Non-dyskinetic 6-hydroxydopamine Lesioned Rats." Brain Research, vol. 1363, 2010, pp. 40-8.
    Walsh S, Gorman AM, Finn DP, et al. The effects of cannabinoid drugs on abnormal involuntary movements in dyskinetic and non-dyskinetic 6-hydroxydopamine lesioned rats. Brain Res. 2010;1363:40-8.
    Walsh, S., Gorman, A. M., Finn, D. P., & Dowd, E. (2010). The effects of cannabinoid drugs on abnormal involuntary movements in dyskinetic and non-dyskinetic 6-hydroxydopamine lesioned rats. Brain Research, 1363, pp. 40-8. doi:10.1016/j.brainres.2010.09.086.
    Walsh S, et al. The Effects of Cannabinoid Drugs On Abnormal Involuntary Movements in Dyskinetic and Non-dyskinetic 6-hydroxydopamine Lesioned Rats. Brain Res. 2010 Dec 2;1363:40-8. PubMed PMID: 20888328.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - The effects of cannabinoid drugs on abnormal involuntary movements in dyskinetic and non-dyskinetic 6-hydroxydopamine lesioned rats. AU - Walsh,Sinéad, AU - Gorman,Adrienne M, AU - Finn,David P, AU - Dowd,Eilís, Y1 - 2010/10/01/ PY - 2010/08/06/received PY - 2010/09/22/revised PY - 2010/09/24/accepted PY - 2010/10/5/entrez PY - 2010/10/5/pubmed PY - 2011/2/25/medline SP - 40 EP - 8 JF - Brain research JO - Brain Res. VL - 1363 N2 - 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 (10mg/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 50.0 μg/kg i.p.), or the CB(1) receptor antagonist/inverse agonist, AM251 (0.0 and 3.0mg/kg i.p.), whereas rats that did not develop stable AIMs received injections of the CB(1) receptor antagonist/inverse agonist, rimonabant (0.0 and 3.0mg/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 anti-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-CB(1) signalling can unmask levodopa-induced AIMs, and this finding suggests that endocannabinoid tone may confer protection against the development of levodopa-induced dyskinesias. SN - 1872-6240 UR - https://www.unboundmedicine.com/medline/citation/20888328/abstract/The_effects_of_cannabinoid_drugs_on_abnormal_involuntary_movements_in_dyskinetic_and_non_dyskinetic_6_hydroxydopamine_lesioned_rats_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-8993(10)02152-9 DB - PRIME DP - Unbound Medicine ER -