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

Abstract

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 APPROACHStriatal 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 RESULTSRasagiline 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 IMPLICATIONSIn 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.Abbreviations 5,7-DHT, 5,7-dihydroxytryptamine; 5-HIAA, 5-hydroxyindoleacetic acid; 5-HT, 5-hydroxytryptamine; 6-OHDA, 6-hydroxydopamine; AAAD, L-aromatic amino acid decarboxylase; DA, dopamine; DARPP-32, dopamine and cAMPregulated phosphoprotein, Mr 32

Pb exposure prolongs the time period for postnatal transient uptake of 5-HT by murine LSO neurons

“…SC18396; Santa Cruz Biotechnology, USA). The MAOA antibody co-localizes with the TPH antibody in dorsal raphe neurons in our mouse brain sections in a similar pattern to locus coerulius neurons that are double labeled with TPH antibodies and the same MAO-A antibody as used in the present study (Sader-Mazbar et al, 2013). …”

Molecular aspects of monoamine oxidase B

“…Humans lacking MAO B have greatly elevated levels of phenylethylamine (Murphy et al, 1990). In rats, numerous microdialysis experiments have been conducted to measure amine changes in different disease models (including addiction) or to assess the effects of MAO inhibitors (for example, (Butcher et al, 1990, Lamensdorf et al, 1996, Bazzu et al, 2013, Sader-Mazbar et al, 2013, Bolea et al, 2014). After treatment with MAO inhibitor, mice showed significantly higher noradrenaline and serotonin levels and significantly lower metabolites (including DOPAC from dopamine) (Lum and Stahl, 2012).…”

The Chemistry of Neurodegeneration: Kinetic Data and Their Implications

“…However, MAO selectivity is quite poor since, for example, MAO B also decomposes serotonin only five times slower than dopamine [89]. On the other hand, experiments have demonstrated that striatal dopamine tissue levels or extracellular levels are increased by the inhibition of MAO A with clorgyline [90][91][92]. In the human brain, MAO A exists in catecholaminergic neurons, but MAO B is found in serotonergic neurons and glial cells [93].…”