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Increased L ‐ DOPA ‐derived dopamine following selective MAO ‐ A or ‐ B inhibition in rat striatum depleted of dopaminergic and serotonergic innervation
Author(s) -
SaderMazbar O,
Loboda Y,
Rabey M J,
Finberg J P M
Publication year - 2013
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12349
Subject(s) - dopaminergic , serotonergic , striatum , monoamine oxidase b , dopamine , clorgyline , chemistry , pharmacology , endocrinology , monoamine oxidase , medicine , serotonin , biology , biochemistry , receptor , enzyme
Background and Purpose Selective MAO type B ( MAO ‐ B ) inhibitors are effective in potentiation of the clinical effect of L ‐ DOPA in P arkinson'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‐ P arkinsonian treatments.