Levodopa treatment reverses endocannabinoid system abnormalities in experimental parkinsonism

Mauro Maccarrone, Paolo Gubellini, Monica Bari, Barbara Picconi, Natalia Battista, Diego Centonze, Giorgio Bernardi, Alessandro Finazzi-Agrò, Paolo Calabresi

Research output: Contribution to journalArticlepeer-review

Abstract

Cannabinoid receptors and their endogenous ligands are potent inhibitors of neurotransmitter release in the brain. Here, we show that in a rat model of Parkinson's disease induced by unilateral nigral lesion with 6-hydroxydopamine (6-OHDA), the striatal levels of the endocannabinoid anandamide (AEA) were increased, while the activity of its membrane transporter and hydrolase (fatty-acid amide hydrolase, FAAH) were decreased. These changes were not observed in the cerebellum of the same animals. Moreover, the frequency and amplitude of glutamate-mediated spontaneous excitatory post-synaptic currents were augmented in striatal spiny neurones recorded from parkinsonian rats. Remarkably, the anomalies in the endocannabinoid system, as well as those in glutamatergic activity, were completely reversed by chronic treatment of parkinsonian rats with levodopa, and the pharmacological inhibition of FAAH restored a normal glutamatergic activity in 6-OHDA-lesioned animals. Thus, the increased striatal levels of AEA may reflect a compensatory mechanism trying to counteract the abnormal corticostriatal glutamatergic drive in parkinsonian rats. However, this mechanism seems to be unsuccessful, since spontaneous excitatory activity is still higher in these animals. Taken together, these data show that anomalies in the endocannabinoid system induced by experimental parkinsonism are restricted to the striatum and can be reversed by chronic levodopa treatment, and suggest that inhibition of FAAH might represent a possible target to decrease the abnormal cortical glutamatergic drive in Parkinson's disease.

Original languageEnglish
Pages (from-to)1018-1025
Number of pages8
JournalJournal of Neurochemistry
Volume85
Issue number4
Publication statusPublished - May 2003

Keywords

  • Anandamide
  • CB1 receptor
  • Dopamine
  • Glutamate
  • Levodopa
  • Striatum

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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