Abstract
Methylphenidate (MPD) modulates dopamine (DA) overflow in part by redistributing vesicle pools, a function shared by the presynaptic protein α-synuclein (α-syn). We suggest that α-syn modifies the effect of MPD on DA neurotransmission. The effect was studied in the dorsal striatum in wild-type mice and two mouse lines lacking α-syn by using in vivo voltammetry and microdialysis. MPD (1 mg/kg) attenuated evoked DA overflow only in mice lacking α-syn but produced a similar increase in the extracellular DA levels in all three lines. A kinetic analysis showed that MPD decreased DA release per stimulus pulse in α-syn-deficient mice but increased in wild-type mice. MPD blocked DA reuptake and produced a similar increase in the apparent affinity (Km) for DA reuptake in all three lines. Repeated-burst stimulation redistributes vesicular storage pools and facilitates DA overflow, and this form of facilitation is significantly enhanced in α-syn knockout mice. The DA reuptake inhibitor 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR12909) (10 mg/kg) completely blocked the facilitation of DA overflow in all three lines, whereas MPD (1 mg/kg) selectively decreased it only in mice lacking α-syn. MPD (5 mg/kg) and GBR12909 (10 mg/kg) produced equipotent inhibition of DA reuptake (in terms of Km), indicating that reuptake inhibition does not explain the MPD selectivity. Our data indicate that MPD decreases DA release probability in the absence of α-syn and increases it in control animals, whereas the effect of MPD on DA reuptake is independent of α-syn. We suggest that this selectivity is based on α-syn-dependent compartmentalization of presynaptic DA.
Footnotes
This work was supported by the Academy of Finland [Grants 122397, 125653]; and the Tekes European Regional Development Fund [Grant 879/31/08] (to L.Y.).
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
ABBREVIATIONS:
- α-syn
- α-synuclein
- DA
- dopamine
- DAT
- DA transporter
- MFB
- medial forebrain bundle
- MPD
- methylphenidate
- RRP
- readily releasable pool
- SNARE
- soluble N-ethylmaleimide-sensitive factor attachment protein receptor
- VMAT2
- vesicular monoamine transporter-2
- RM-ANOVA
- analysis of variance for repeated measures
- AP
- anteroposterior
- ML
- mediolateral
- GBR12909
- 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine.
- Received November 6, 2011.
- Accepted February 15, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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