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 ␣-synuclein (␣-syn). We suggest that ␣-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 ␣-syn by using in vivo voltammetry and microdialysis. MPD (1 mg/kg) attenuated evoked DA overflow only in mice lacking ␣-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 ␣-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 ␣-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 ␣-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 ␣-syn and increases it in control animals, whereas the effect of MPD on DA reuptake is independent of ␣-syn. We suggest that this selectivity is based on ␣-syn-dependent compartmentalization of presynaptic DA.

α-synuclein and synapsin III cooperatively regulate synaptic function in dopamine neurons

“…6E). This evidence seems in line with previous findings that showed that repeated-burst stimulation, which redistributes vesicular storage pools and facilitates dopamine overflow, is enhanced in C57BL/6JOlaHsd mice (Chadchankar et al, 2012). The increased responsiveness of these mice to cocaine or repeated-burst stimulation might be explained by the selective increase of synapsin III in the striatum.…”

“…Cocaine abuse elevates α-syn levels in the human striatum (Qin et al, 2005), whereas overexpression of α-syn in the nucleus accumbens influences the behavior of rats in response to cocaine (Boyer and Dreyer, 2007). Furthermore, methylphenidate, which like cocaine is able to affect exocytotic dopamine release from synaptic vesicles (Volz et al, 2008), modifies overflow and presynaptic compartmentalization of dopamine through an α-syn-dependent mechanism (Chadchankar et al, 2012). All of these results suggest that drugs which mobilize dopamine vesicle pools act by regulating the function of α-syn-synapsin-III complexes.…”

Sensitized nucleus accumbens dopamine terminal responses to methylphenidate and dopamine transporter releasers after intermittent-access self-administration

“…Although this is the first study to show enhanced MPH-induced dopamine release following MPH self-administration, it is possible that dopamine transporter levels influence these effects as well. MPH has been shown to redistribute vesicles from storage pools into the readily releasable pool (Chadchankar et al, 2012; Volz et al, 2008). This could be a potential mechanism for its release effects and it is possible that these effects could be dependent on MPH binding to the dopamine transporter.…”

Illicit dopamine transients: Reconciling actions of abused drugs

“…Indeed, cocaine has been found to up-regulate vesicular dopamine release in several preparations, including brain-slice [ 53,54 ], anesthetized [ 55-57 ], and awake [ 58 ]. Up-regulation of dopamine release has more recently been extended to methylphenidate, a cocaine-like DAT-I [ 59 ], and surprisingly, even AMPH [ 42,55,56,60 ]. It should be emphasized that the evidence for up-regulated dopamine release by addictive DAT-Is is typically based on studies using a single dose administered non-contingently.…”