Methylphenidate‐Induced Alterations in Synaptic Vesicle Trafficking and Activity

Abstract

The psychostimulant, methylphenidate (MPD), is commonly prescribed to treat attention-deficit hyperactivity disorder. MPD binds to the neuronal dopamine (DA) transporter where it blocks the inward transport of DA. The present study expands upon these findings by examining the effects of in vivo MPD administration on the vesicular monoamine transporter-2 (VMAT-2) in membrane-associated vesicle and cytoplasmic vesicle subcellular fractions (i.e., those vesicles that do and do not co-fractionate with synaptosomal membranes after osmotic lysis, respectively) isolated from lysates of rat striatal synaptosomes. The results indicate that a single MPD administration redistributes VMAT-2 and associated vesicles within nerve terminals away from the synaptosomal membranes and into the cytoplasm, as assessed 1 hour after treatment. DA transport is also increased by MPD in both vesicle fractions (due to vesicle trafficking in the cytoplasmic vesicles and to kinetic upregulation of the VMAT-2 in the membrane-associated vesicles). This, in turn, leads to an increase in the DA content of both vesicle fractions as well as an increase in the velocity and magnitude of K+-stimulated DA release from striatal suspensions. Taken together, these data show that the trafficking, DA sequestration function, DA content, and exocytotic DA release function of synaptic vesicles can all be pharmacologically manipulated by in vivo MPD treatment. These findings may provide important insights useful for understanding and treating disorders involving abnormal DA transmission including drug abuse, Parkinson's disease, and attention-deficit hyperactivity disorder.

Methylphenidate Modifies Overflow and Presynaptic Compartmentalization of Dopamine via an α-Synuclein-Dependent Mechanism

“…MPD, at a therapeutically relevant dose of 1 mg/kg (Volkow et al, 2001), increased evoked DA overflow after single-burst stimulation in all three mouse lines. This effect was expected considering that MPD increases DA release (Volz et al, 2008) and inhibits reuptake (Pan et al, 1994). However, ␣-syn-deficient mice demonstrated an attenuated response to MPD, especially at the 10-Hz stimulation frequency.…”

“…Because MPD increases exocytotic DA release (Volz et al, 2008), deficits in ␣-syn-SNARE-complex interaction may play a role in the reduced DA overflow after MPD treatment, especially after high-frequency stimulation during which a small decrease in [DA] p leads to a significant overall decline in peak DA overflow (Table 1). In addition, MPD redistributes VMAT2 and the associated vesicles within the nerve terminal away from the synaptosomal membranes and into the cytoplasm (Volz et al, 2008). These data further support our finding that MPD decreased [DA] p in mice lacking ␣-syn.…”

“…MPD is known to inhibit DA reuptake (Pan et al, 1994) and redistribute synaptic vesicles within the reserve and readily releasable pools (RRPs) (Sandoval et al, 2002;Volz et al, 2008). It also up-regulates VMAT2, thereby increasing the rate of transport of cytosolic DA into the synaptic vesicles (Sandoval et al, 2002;Volz et al, 2008).…”

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

“…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.…”

Deficiency of tumor suppressor NDRG2 leads to attention deficit and hyperactive behavior

“…The dopamine deficit theory of ADHD (29,(46)(47)(48)(49)(50) (Figure 7) has been studied extensively in patients with ADHD (51,52) and is consistent with hypodopaminergic rodent models of ADHD (6). Methylphenidate, which exerts its effects by increasing synaptic dopamine levels through inhibition of dopamine transportermediated dopamine reuptake (53), has been used to treat ADHD in children and adults for many years (54).…”