Abstract
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 [3H]DA 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 [3H]DA uptake. In 6-OHDA lesioned striatum, DA was less effective, whereas NE was more effective, at inhibiting [3H]DA uptake. Furthermore, norepinephrine transporter (NET) protein levels increased and desipramine was ∼two-fold more effective at inhibiting NE uptake. Serotonin inhibited [3H]DA uptake, but without significant difference between lesioned and contralateral striatum. L-DOPA inhibited [3H]DA 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.
Highlights
In striatum, the dopamine transporter (DAT) is a vital component for maintaining sufficient dopamine (DA) levels for release [1,2]
We examined the extent by which 5-HT, NE, DA, and L-DOPA, affected [3H]DA uptake and determined norepinephrine transporter (NET) expression and impact of its inhibition on NE uptake to elucidate potential mechanisms by which DA is removed from the synapse with DAT loss at Parkinson’s disease (PD) symptom levels, with and without L-DOPA present
We first established that dopamine uptake in control tissue reflected the endogenous quantities of transporter, wherein there is greater DA uptake [35,36,37] and DAT protein [38] in dorsal striatum versus substantia nigra
Summary
The dopamine transporter (DAT) is a vital component for maintaining sufficient dopamine (DA) levels for release [1,2]. The degree of striatal DAT loss in Parkinson’s disease (PD) when locomotor symptoms appear (,70–80%) [3,4] would be expected to be a major factor in the deficit in DA that produces locomotor impairment. Loss of DAT is concomitant with diminished DA release, which would be expected to sustain extracellular DA concentrations [8]. Increased TH activity may maintain sufficient DA for some time during TH loss [5], [9,10]. The resulting increase in DA reuptake could diminish extracellular DA availability, thereby reducing synaptic concentrations necessary to bind post-synaptic DA receptors and drive locomotor activity. Determining DA uptake dynamics when DAT loss is at and beyond the loss associated with locomotor symptoms is critical to understand the longevity of synaptic DA and the impact of L-DOPA in this context
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