Experimental parkinsonism alters endocannabinoid degradation: Implications for striatal glutamatergic transmission

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

Research output: Contribution to journalArticle

Abstract

Cannabinoid receptors and their endogenous ligands have been recently identified in the brain as potent inhibitors of neurotransmitter release. 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 anandamide, but not that of the other endocannabinoid 2-arachidonoylglycerol, were increased. Moreover, we observed a decreased activity of the anandamide membrane transporter (AMT) and of the anandamide hydrolase [fatty acid amide hydrolase (FAAH)], whereas the binding of anandamide to cannabinoid receptors was unaffected. Spontaneous glutamatergic activity recorded from striatal spiny neurons was higher in 6-OHDA-lesioned rats. Inhibition of AMT by N-(4-hydroxyphenyl)-arachidonoylamide (AM-404) or by VDM11, or stimulation of the cannabinoid CB1 receptor by HU-210 reduced glutamatergic spontaneous activity in both naïve and 6-OHDA-lesioned animals to a similar extent. Conversely, the FAAH inhibitors phenylmethylsulfonyl fluoride and methylarachidonoyl fluorophosphonate were much more effective in 6-OHDA-lesioned animals. The present study shows that inhibition of anandamide hydrolysis might represent a possible target to decrease the abnormal cortical glutamatergic drive in Parkinson's disease.

Original languageEnglish
Pages (from-to)6900-6907
Number of pages8
JournalJournal of Neuroscience
Volume22
Issue number16
Publication statusPublished - Aug 15 2002

Keywords

  • Anandamide
  • CB1 receptor
  • Dopamine
  • Excitatory amino acids
  • Glutamate
  • Parkinson's disease
  • Striatum

ASJC Scopus subject areas

  • Neuroscience(all)

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