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

Abstract

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.

What Mechanisms Are Responsible for the Reuptake of Levodopa-Derived Dopamine in Parkinsonian Striatum?

“…Acute systemic administration of desipramine (25 mg/kg), a selective NET inhibitor, increases the extracellular dopamine concentration after levodopa treatment in the striatum of this PD model (Arai et al, 2008). Chronic administration of desipramine (12 mg/kg) also increases the striatal dopamine concentration and enhances dyskinesia-like behaviors induced by levodopa injection to this model rat (Chotibut et al, 2014). These studies suggest that NET has a significant role in reuptake of extracellular dopamine in the PD striatum.…”

“…They discussed that the contradictory result of Arai et al (2008) is because of their high dose of desipramine (25 mg/kg), in which desipramine non-selectively binds to sites other than NET. However, Chotibut et al (2014) used a lower dose of desipramine (12 mg/kg) and demonstrated a significant increase of levodopa-derived dopamine concentration in the dopamine-denervated striatum. The inconsistencies between studies may be due to residual DAT expression and activity of SERT and other monoamine transporters in the particular experimental situation (Figure 2B).…”

Effect of serotonin transporter blockade on L-DOPA-induced dyskinesia in animal models of Parkinson’s disease

“…Indeed, blockade of the noradrenergic transporter by desipramine administration has been recently shown to produce the opposite effect on LID in rats, i.e. worsening of the dyskinesia score (Chotibut et al, 2014).…”

Modulation of l-DOPA's antiparkinsonian and dyskinetic effects by α2-noradrenergic receptors within the locus coeruleus

“…LC NE neurons terminating in the striatum may influence striatal DA levels by modifying DA uptake. Indeed, evidence shows that striatal NE transporters (NET) can take up L-DOPA-derived DA in the DA-depleted brain [72] and subsequent NET blockade exacerbated LID expression in a rodent model of LID [73]. NE from the LC could also modulate striatal DA signaling indirectly by regulating striatal DA release from the SNc [74, 75].…”