Increased L-DOPA-derived dopamine following selective MAO-A or -B inhibition in rat striatum depleted of dopaminergic and serotonergic innervation

O. Sader-Mazbar, Y. Loboda, M. J. Rabey, John P.M. Finberg

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

Background and Purpose Selective MAO type B (MAO-B) inhibitors are effective in potentiation of the clinical effect of L-DOPA in Parkinson's disease, but dopamine (DA) is deaminated mainly by MAO type A (MAO-A) in rat brain. We sought to clarify the roles of MAO-A and MAO-B in deamination of DA formed from exogenous L-DOPA in rat striatum depleted of dopaminergic, or both dopaminergic and serotonergic innervations. We also studied the effect of organic cation transporter-3 (OCT-3) inhibition by decinium-22 on extracellular DA levels following L-DOPA. Experimental Approach Striatal dopaminergic and/or serotonergic neuronal innervations were lesioned by 6-hydroxydopamine or 5,7-dihydroxytryptamine respectively. Microdialysate DA levels after systemic L-DOPA were measured after inhibition of MAO-A or MAO-B by clorgyline or rasagiline respectively. MAO subtype localization in the striatum was determined by immunofluorescence. Key Results Rasagiline increased DA extracellular levels following L-DOPA to a greater extent in double- than in single-lesioned rats (2.8- and 1.8-fold increase, respectively, relative to saline treatment); however, clorgyline elevated DA levels in both models over 10-fold. MAO-A was strongly expressed in medium spiny neurons (MSNs) in intact and lesioned striata, while MAO-B was localized in glia and to a small extent in MSNs. Inhibition of OCT-3 increased DA levels in the double- more than the single-lesion animals. Conclusions and Implications In striatum devoid of dopaminergic and serotonergic inputs, most deamination of L-DOPA-derived DA is mediated by MAO-A in MSN and a smaller amount by MAO-B in both MSN and glia. OCT-3 plays a significant role in uptake of DA from extracellular space. Inhibitors of OCT-3 are potential future targets for anti-Parkinsonian treatments.

Original languageEnglish
Pages (from-to)999-1013
Number of pages15
JournalBritish Journal of Pharmacology
Volume170
Issue number5
DOIs
StatePublished - Nov 2013
Externally publishedYes

Keywords

  • 6-hydroxydopamine
  • L-DOPA
  • OCT-3
  • Parkinson's disease
  • clorgyline
  • glial cells
  • medium spiny neurons
  • microdialysis
  • rasagiline

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