title: Methylphenidate modifies overflow and presynaptic compartmentalization of dopamine via an α-synuclein-dependent mechanism.
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 (K(m)) 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 K(m)), 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.
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, P. O. Box 1627, University of Eastern Finland, Kuopio 70211, Finland. heramb.chadchankar@uef.fi
authors.forename: Heramb
authors.initials: H
authors.lastname: Chadchankar
authors.forename: Jouni
authors.initials: J
authors.lastname: Ihalainen
authors.forename: Heikki
authors.initials: H
authors.lastname: Tanila
authors.forename: Leonid
authors.initials: L
authors.lastname: Yavich
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D008774:Methylphenidate / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D018765:Dopamine Uptake Inhibitors; D051844:alpha-Synuclein; D008774:Methylphenidate; D004298:Dopamine