title: Increased L-DOPA-derived dopamine following selective MAO-A or -B inhibition in rat striatum depleted of dopaminergic and serotonergic innervation.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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
  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.
authors.affiliation: Department of Molecular Pharmacology, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: O
authors.initials: O
authors.lastname: Sader-Mazbar
authors.forename: Y
authors.initials: Y
authors.lastname: Loboda
authors.forename: M J
authors.initials: MJ
authors.lastname: Rabey
authors.forename: J P M
authors.initials: JP
authors.lastname: Finberg
mesh_terms: D015116:5,7-Dihydroxytryptamine / Q000633:toxicity; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology; D001479:Basal Ganglia / Q000187:drug effects* / Q000201:enzymology; D003010:Clorgyline / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology*; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007189:Indans / Q000494:pharmacology; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D017551:Microdialysis; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors / Q000378:metabolism; D016627:Oxidopamine / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D059326:Serotonergic Neurons / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000978:Antiparkinson Agents; D015259:Dopamine Agents; D005904:Glial Fibrillary Acidic Protein; D007189:Indans; D008996:Monoamine Oxidase Inhibitors; D029362:Organic Anion Transporters, Sodium-Independent; C114338:organic anion transport protein 3; C031967:rasagiline; D015116:5,7-Dihydroxytryptamine; D007980:Levodopa; D016627:Oxidopamine; D008995:Monoamine Oxidase; D003010:Clorgyline; D004298:Dopamine
keywords: 6-hydroxydopamine; L-DOPA; OCT-3; Parkinson's disease; clorgyline; glial cells; medium spiny neurons; microdialysis; rasagiline