Clinical, morphological and neurochemical correlations.

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Jones SR, Gainetdinov RR, Jaber M, Giros B, Wightman RM, et al. There was no significant difference in the ability of 5-HT to inhibit DA uptake in lesioned striatal synaptosomes, as compared to the control, n = 6 paired observations. After 5 min preincubation period, 500 nM was added and uptake was determined for 2 min. Serotonin 1 µM 5-HT was added in striatal synaptosomes prepared from at least 70% lesioned striatum and from the operationally-matched contralateral control. Statistics: * p<0.05, t = 2.59, two-tailed Student’s paired t-test, n = 6 paired observations. In the lesioned striatal synaptosomes, NE was significantly more effective (38% greater inhibition than in control) to inhibit DA uptake, as compared to the control. Norepinephrine 1 µM NE was added in striatal synaptosomes prepared from at least 70% lesioned striatum and from the operationally-matched contralateral control. Statistics: * p<0.05, t = 3.47, two-tailed Student’s paired t-test, n = 6 paired observations. In the lesioned striatal synaptosomes, DA was significantly less effective (30% less inhibition than in control) effective to inhibit DA uptake, as compared to the control. 1 µM DA was added in striatal synaptosomes prepared from at least 70% lesioned striatum and from the operationally-matched contralateral control. 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.ĭopamine. 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%. Consequently, DA uptake may be mediated by NET when DAT loss is at PD levels. L-DOPA inhibited DA uptake two-fold more in lesioned striatum and inhibited NE uptake ∼five-fold more than DA uptake in naïve striatum.

Serotonin inhibited DA uptake, but without significant difference between lesioned and contralateral striatum. Furthermore, norepinephrine transporter (NET) protein levels increased and desipramine was ∼two-fold more effective at inhibiting NE uptake. In 6-OHDA lesioned striatum, DA was less effective, whereas NE was more effective, at inhibiting DA uptake. Unlabeled DA, NE, and 5-HT were used, at a concentration that differentially inhibited DA uptake in intact striatum, to compete against DA uptake. As other monoamine transporters can transport DA, we determined if norepinephrine (NE) and serotonin (5-HT) differentially modulated DA uptake in lesioned striatum. Despite >70% striatal DAT loss, DA uptake decreased only ∼25% and increased as DAT loss approached 99%. Using the unilateral 6-OHDA rat PD model, we examined DA uptake dynamics in relation to striatal DAT and tyrosine hydroxylase (TH) protein loss compared with contralateral intact striatum. However, its impact upon DA reuptake is unknown and may modulate synaptic DA. The locomotor benefits of L-DOPA may be mediated by transport through monoamine transporters and conversion to DA. Thus, in Parkinson's disease (PD), DAT loss could affect DA clearance and locomotor activity. The dopamine transporter (DAT) regulates synaptic dopamine (DA) in striatum and modulation of DAT can affect locomotor activity.

Parallels transporter