Reuptake of <scp>L</scp>‐DOPA‐derived extracellular DA in the striatum of a rodent model of Parkinson's disease via norepinephrine transporter

Arai, Akira; Tomiyama, Masahiko; Kannari, Kazuya; Kimura, Takuma; Suzuki, Chieko; Watanabe, Mitsunori; Kawarabayashi, Tatsuhiko; Shen, Hongyan; Shoji, Mikio

doi:10.1002/syn.20535

Cited by 47 publications

(41 citation statements)

References 20 publications

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“…Increased extracellular DA in DAdenervated striatum is observed following DMI (Arai et al, 2008). This finding is congruent with our observations that reuptake of DA, derived from L-DOPA, may be modulated by NET.…”

Section: Norepinephrine Transporter and L-dopa Dyskinesiasupporting

confidence: 92%

Norepinephrine Transporter Inhibition with Desipramine Exacerbates L-DOPA–Induced Dyskinesia: Role for Synaptic Dopamine Regulation in Denervated Nigrostriatal Terminals

2014

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Pharmacological dopamine (DA) replacement with Levodopa [L-dihydroxyphenylalanine (L-DOPA)] is the gold standard treatment of Parkinson's disease (PD). However, long-term L-DOPA treatment is complicated by eventual debilitating abnormal involuntary movements termed L-DOPA-induced dyskinesia (LID), a clinically significant obstacle for the majority of patients who rely on L-DOPA to alleviate PD-related motor symptoms. The manifestation of LID may in part be driven by excessive extracellular DA derived from L-DOPA, but potential involvement of DA reuptake in LID severity or expression is unknown. We recently reported that in 6-hydroxydopamine (6-OHDA)-lesioned striatum, norepinephrine transporter (NET) expression increases and may play a significant role in DA transport. Furthermore, L-DOPA preferentially inhibits DA uptake in lesioned striatum. Therefore, we hypothesized that desipramine (DMI), a NET antagonist, could affect the severity of LID in an established LID model. Whereas DMI alone elicited no dyskinetic effects in lesioned rats, DMI 1 L-DOPA-treated rats gradually expressed more severe dyskinesia compared with L-DOPA alone over time. At the conclusion of the study, we observed reduced NET expression and norepinephrine-mediated inhibition of DA uptake in the DMI 1 L-DOPA group compared with L-DOPA-alone group in lesioned striatum. LID severity positively correlated with striatal extracellular signal-regulated protein kinase phosphorylation among the three treatment groups, with increased ppERK1/2 in DMI 1 L-DOPA group compared with the L-DOPA-and DMI-alone groups. Taken together, these results indicate that the combination of chronic L-DOPA and NET-mediated DA reuptake in lesioned nigrostriatal terminals may have a role in LID severity in experimental Parkinsonism.

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Section: Norepinephrine Transporter and L-dopa Dyskinesiasupporting

confidence: 92%

Norepinephrine Transporter Inhibition with Desipramine Exacerbates L-DOPA–Induced Dyskinesia: Role for Synaptic Dopamine Regulation in Denervated Nigrostriatal Terminals

2014

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“…Importantly, DA is a better substrate for NET, and NET plays a critical role in DA clearance in brain regions where DAT levels are low. In addition, NET also plays a role in striatal DA clearance in the absence of DA innervation (50,82). Cocaine up-regulation of NET is evident in both the PFC and NAc, which are important brain regions in the mesolimbic reward pathway.…”

Section: Discussionmentioning

confidence: 99%

A Role for p38 Mitogen-activated Protein Kinase-mediated Threonine 30-dependent Norepinephrine Transporter Regulation in Cocaine Sensitization and Conditioned Place Preference

Padmanabhan

Kamalakkannan

Damaj

et al. 2015

Journal of Biological Chemistry

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Background: Cocaine-activated p38 MAPK-mediated norepinephrine transporter (NET) threonine 30 phosphorylation up-regulates NET. Results: p38 MAPK inhibition and TAT-NET-Thr 30 peptide blocks cocaine-mediated NET up-regulation and cocaine-induced locomotor sensitization and conditioned place preference (CPP). Conclusion: Blockade of p38 MAPK-mediated Thr30 -dependent NET regulation attenuates cocaine-induced locomotor sensitization, CPP, and CPP reinstatement. Significance: Regulation of NET plays a mechanistic role in cocaine-mediated behaviors.

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“…In cerebral areas in which DAT levels are low, such as the frontal cortex, NET can reuptake dopamine [83–86]. A recent study suggested that L-DOPA-derived dopamine could be uptaken by NET in the striatum of 6-OHDA-lesioned rats because of an increase in dopamine levels following desipramine administration [87]. However, as displayed in Table 1, desipramine exhibits high affinity at SERT and is thus not selective for NET, raising doubt on the authors' conclusions.…”

Section: Monoamine Transportersmentioning

confidence: 99%

Monoamine Reuptake Inhibitors in Parkinson’s Disease

Huot

Fox

Brotchie

2015

Parkinson's Disease

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The motor manifestations of Parkinson's disease (PD) are secondary to a dopamine deficiency in the striatum. However, the degenerative process in PD is not limited to the dopaminergic system and also affects serotonergic and noradrenergic neurons. Because they can increase monoamine levels throughout the brain, monoamine reuptake inhibitors (MAUIs) represent potential therapeutic agents in PD. However, they are seldom used in clinical practice other than as antidepressants and wake-promoting agents. This review article summarises all of the available literature on use of 50 MAUIs in PD. The compounds are divided according to their relative potency for each of the monoamine transporters. Despite wide discrepancy in the methodology of the studies reviewed, the following conclusions can be drawn: (1) selective serotonin transporter (SERT), selective noradrenaline transporter (NET), and dual SERT/NET inhibitors are effective against PD depression; (2) selective dopamine transporter (DAT) and dual DAT/NET inhibitors exert an anti-Parkinsonian effect when administered as monotherapy but do not enhance the anti-Parkinsonian actions of L-3,4-dihydroxyphenylalanine (L-DOPA); (3) dual DAT/SERT inhibitors might enhance the anti-Parkinsonian actions of L-DOPA without worsening dyskinesia; (4) triple DAT/NET/SERT inhibitors might exert an anti-Parkinsonian action as monotherapy and might enhance the anti-Parkinsonian effects of L-DOPA, though at the expense of worsening dyskinesia.

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Reuptake of L‐DOPA‐derived extracellular DA in the striatum of a rodent model of Parkinson's disease via norepinephrine transporter

Cited by 47 publications

References 20 publications

Norepinephrine Transporter Inhibition with Desipramine Exacerbates L-DOPA–Induced Dyskinesia: Role for Synaptic Dopamine Regulation in Denervated Nigrostriatal Terminals

Norepinephrine Transporter Inhibition with Desipramine Exacerbates L-DOPA–Induced Dyskinesia: Role for Synaptic Dopamine Regulation in Denervated Nigrostriatal Terminals

A Role for p38 Mitogen-activated Protein Kinase-mediated Threonine 30-dependent Norepinephrine Transporter Regulation in Cocaine Sensitization and Conditioned Place Preference

Monoamine Reuptake Inhibitors in Parkinson’s Disease

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