Effects of levodopa on endocannabinoid levels in rat basal ganglia: Implications for the treatment of levodopa-induced dyskinesias

Belen Ferrer, Nick Asbrock, Satish Kathuria, Daniele Piomelli, Andrea Giuffrida

Research output: Contribution to journalArticle

124 Scopus citations

Abstract

The majority of Parkinson's disease patients undergoing levodopa therapy develop disabling motor complications (dyskinesias) within 10 years of treatment. Stimulation of cannabinoid receptors, the pharmacological target of Δ9-tetrahydrocannabinol, is emerging as a promising therapy to alleviate levodopa-associated dyskinesias. However, the mechanisms underlying this beneficial action remain elusive, as do the effects exerted by levodopa therapy on the endocannabinoid system. Although levodopa is known to cause changes in CB1 receptor expression in animal models of Parkinson's disease, we have no information on whether this drug alters the brain concentrations of the endocannabinoids anandamide and 2-arachidonylglycerol. To address this question, we used an isotope dilution assay to measure endocannabinoid levels in the caudate-putamen, globus pallidus and substantia nigra of intact and unilaterally 6-OHDA-lesioned rats undergoing acute or chronic treatment with levodopa (50 mg/kg). In intact animals, systemic administration of levodopa increased anandamide concentrations throughout the basal ganglia via activation of dopamine D1/D2 receptors. In 6-OHDA-lesioned rats, anandamide levels were significantly reduced in the caudate-putamen ipsilateral to the lesion; however, neither acute nor chronic levodopa treatment affected endocannabinoid levels in these animals. In lesioned rats, chronic levodopa produced increasingly severe oro-lingual involuntary movements which were attenuated by the cannabinoid agonist R(+)-WIN55,212-2 (1 mg/kg). This effect was reversed by the CB1 receptor antagonist rimonabant (SR141716A). These results indicate that a deficiency in endocannabinoid transmission may contribute to levodopa-induced dyskinesias and that these complications may be alleviated by activation of CB1 receptors.

Original languageEnglish (US)
Pages (from-to)1607-1614
Number of pages8
JournalEuropean Journal of Neuroscience
Volume18
Issue number6
DOIs
StatePublished - Sep 1 2003

Keywords

  • 2-arachidonylglycerol
  • 6-hydroxydopamine
  • Anandamide
  • Cannabinoid
  • Fatty acid ethanolamides

ASJC Scopus subject areas

  • Neuroscience(all)

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