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.
Subject(s)
Basal Ganglia/drug effects , Dopamine Agents/pharmacology , Dopamine/metabolism , Dopaminergic Neurons/drug effects , Levodopa/pharmacology , Monoamine Oxidase Inhibitors/pharmacology , Monoamine Oxidase/metabolism , Serotonergic Neurons/drug effects , 5,7-Dihydroxytryptamine/toxicity , Animals , Antiparkinson Agents/pharmacology , Basal Ganglia/enzymology , Clorgyline/pharmacology , Dopaminergic Neurons/metabolism , Fluorescent Antibody Technique , Glial Fibrillary Acidic Protein/metabolism , Indans/pharmacology , Male , Microdialysis , Organic Anion Transporters, Sodium-Independent/antagonists & inhibitors , Organic Anion Transporters, Sodium-Independent/metabolism , Oxidopamine/toxicity , Rats , Rats, Sprague-Dawley , Serotonergic Neurons/metabolismABSTRACT
Dopamine behaves mainly as a MAO-A substrate in rodent brain, but selective inhibition of MAO-B results in an increased turning activity following L-DOPA administration in hemi-Parkinsonian rodents. Unilateral substantia nigra dopaminergic denervation results in serotonergic hyper-innervation which may increase the contribution of MAO-A in the denervated striatum. Possibly as a result of this, there was no change in striatal MAO-A activity when 95% of dopaminergic innervation was reduced by 6-hydroxydopamine, as assessed by apomorphine-induced turning activity. MAO-B as well as MAO-A may contribute to deamination of dopamine produced from L-DOPA.