Dopamine Transporter Loss in 6-OHDA Parkinson’s Model Is Unmet by Parallel Reduction in Dopamine UptakeReport as inadecuate




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The dopamine transporter DAT regulates synaptic dopamine DA in striatum and modulation of DAT can affect locomotor activity. Thus, in Parkinson’s disease PD, DAT loss could affect DA clearance and locomotor activity. The locomotor benefits of L-DOPA may be mediated by transport through monoamine transporters and conversion to DA. However, its impact upon DA reuptake is unknown and may modulate synaptic DA. Using the unilateral 6-OHDA rat PD model, we examined 3HDA uptake dynamics in relation to striatal DAT and tyrosine hydroxylase TH protein loss compared with contralateral intact striatum. Despite >70% striatal DAT loss, DA uptake decreased only ∼25% and increased as DAT loss approached 99%. As other monoamine transporters can transport DA, we determined if norepinephrine NE and serotonin 5-HT differentially modulated DA uptake in lesioned striatum. Unlabeled DA, NE, and 5-HT were used, at a concentration that differentially inhibited DA uptake in intact striatum, to compete against 3HDA uptake. In 6-OHDA lesioned striatum, DA was less effective, whereas NE was more effective, at inhibiting 3HDA uptake. Furthermore, norepinephrine transporter NET protein levels increased and desipramine was ∼two-fold more effective at inhibiting NE uptake. Serotonin inhibited 3HDA uptake, but without significant difference between lesioned and contralateral striatum. L-DOPA inhibited 3HDA uptake two-fold more in lesioned striatum and inhibited NE uptake ∼five-fold more than DA uptake in naïve striatum. Consequently, DA uptake may be mediated by NET when DAT loss is at PD levels. Increased inhibition of DA uptake by L-DOPA and its preferential inhibition of NE over DA uptake, indicates that NET-mediated DA uptake may be modulated by L-DOPA when DAT loss exceeds 70%. These results indicate a novel mechanism for DA uptake during PD progression and provide new insight into how L-DOPA affects DA uptake, revealing possible mechanisms of its therapeutic and side effect potential.



Author: Tanya Chotibut , Deana M. Apple , Rebecca Jefferis, Michael F. Salvatore

Source: http://plos.srce.hr/



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