Noradrenergic Terminals Regulate <scp>l</scp>‐<scp>DOPA</scp>‐derived Dopamine Extracellular Levels in a Region‐dependent Manner in Parkinsonian Rats

Navailles, Sylvia; Milan, Léa; Khalki, Hanane; Giovanni, Giuseppe Di; Lagière, Mélanie; Deurwaerdère, Philippe De

doi:10.1111/cns.12275

Cited by 25 publications

(25 citation statements)

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“…In the striatum of a 6-OHDA-lesioned hemiparkinsonian rat, NET expression increases but norepinephrine tissue content remains the same (Chotibut et al, 2012). Navailles et al (2014) showed in a similar rat model that destruction of norepinephrine fibers using N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine does not potentiate the levodopa effect in the striatum. These results suggest that increased NET is expressed on cells other than norepinephrinergic neurons.…”

Section: The Role Of Norepinephrine Transporters In Reuptake Of Dopammentioning

confidence: 99%

“…Navailles et al (2014) showed in 6-OHDA-lesioned rats that the NET blockers desipramine (10 mg/kg) and reboxetine (3 mg/kg) potentiated the levodopa effect in the prefrontal cortex, substantia nigra pars reticulata, and hippocampus, but not in the 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.…”

Section: The Role Of Norepinephrine Transporters In Reuptake Of Dopammentioning

confidence: 99%

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

Nishijima

Tomiyama

2016

Front. Neurosci.

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Levodopa is the most effective medication for motor symptoms in Parkinson's disease. However, various motor and non-motor complications are associated with levodopa treatment, resulting from altered levodopa-dopamine metabolism with disease progression and long-term use of the drug. The present review emphasizes the role of monoamine transporters other than the dopamine transporter in uptake of extracellular dopamine in the dopamine-denervated striatum. When dopaminergic neurons are lost and dopamine transporters decreased, serotonin and norepinephrine transporters compensate by increasing uptake of excessive extracellular dopamine in the striatum. Organic cation transporter-3 and plasma membrane monoamine transporter, low affinity, and high capacity transporters, also potentially uptake dopamine when high-affinity transporters do not work normally. Selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors are often administered to patients with Parkinson's disease presenting with depression, pain or other non-motor symptoms. Thus, it is important to address the potential of these drugs to modify dopamine metabolism and uptake through blockade of the compensatory function of these transporters, which could lead to changes in motor symptoms of Parkinson's disease.

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Section: The Role Of Norepinephrine Transporters In Reuptake Of Dopammentioning

confidence: 99%

Section: The Role Of Norepinephrine Transporters In Reuptake Of Dopammentioning

confidence: 99%

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

Nishijima

Tomiyama

2016

Front. Neurosci.

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“…Our results are limited to striatal analysis because of the relative abundance of DA neuropil (although lesioned) over other DA regions like substantia nigra. DA uptake in the substantia nigra could also affect LID severity (Navailles et al, 2014), given significant noradrenergic innervation in this region. However, there is comparatively less DAT protein and DA uptake in the substantia nigra, which precluded us from examining this possibility.…”

Section: Norepinephrine Transporter and L-dopa Dyskinesiamentioning

confidence: 99%

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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“…The second consequence is that striatal DA released by L-DOPA is extremely low for at least three reasons: (i) the density of striatal 5-HT fibers is 10 to 20 times lower compared to the natural density of DA fibers; (ii) 5-HT neurons fire around 1 Hz or below and L-DOPA does not enhance the firing rate of 5-HT neurons (Miguelez et al, 2016b); DA neurons normally fire above 4 Hz (Bunney et al, 1973; Harden and Grace, 1995); (iii) the intraneuronal and neurochemical organization of striatal DA neurons (low metabolism, high rate of translocation into exocytotic vesicles) is specific to the DA terminals of the striatum and is not encountered in 5-HT terminals (De Deurwaerdère et al, 2016). The apparent higher magnitude of response to L-DOPA in the striatum compared to other brain regions simply corresponds to the stronger loss of clearance in the striatum due to the loss of DAT while the clearance of extracellular DA in extrastriatal regions is in part related to the NET (Navailles et al, 2014) (Figure 4). …”

Section: From Pathophysiology To Treatmentsmentioning

confidence: 99%

Monoaminergic and Histaminergic Strategies and Treatments in Brain Diseases

et al. 2016

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The monoaminergic systems are the target of several drugs for the treatment of mood, motor and cognitive disorders as well as neurological conditions. In most cases, advances have occurred through serendipity, except for Parkinson's disease where the pathophysiology led almost immediately to the introduction of dopamine restoring agents. Extensive neuropharmacological studies first showed that the primary target of antipsychotics, antidepressants, and anxiolytic drugs were specific components of the monoaminergic systems. Later, some dramatic side effects associated with older medicines were shown to disappear with new chemical compounds targeting the origin of the therapeutic benefit more specifically. The increased knowledge regarding the function and interaction of the monoaminergic systems in the brain resulting from in vivo neurochemical and neurophysiological studies indicated new monoaminergic targets that could achieve the efficacy of the older medicines with fewer side-effects. Yet, this accumulated knowledge regarding monoamines did not produce valuable strategies for diseases where no monoaminergic drug has been shown to be effective. Here, we emphasize the new therapeutic and monoaminergic-based strategies for the treatment of psychiatric diseases. We will consider three main groups of diseases, based on the evidence of monoamines involvement (schizophrenia, depression, obesity), the identification of monoamines in the diseases processes (Parkinson's disease, addiction) and the prospect of the involvement of monoaminergic mechanisms (epilepsy, Alzheimer's disease, stroke). In most cases, the clinically available monoaminergic drugs induce widespread modifications of amine tone or excitability through neurobiological networks and exemplify the overlap between therapeutic approaches to psychiatric and neurological conditions. More recent developments that have resulted in improved drug specificity and responses will be discussed in this review.

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Noradrenergic Terminals Regulate l‐DOPA‐derived Dopamine Extracellular Levels in a Region‐dependent Manner in Parkinsonian Rats

Abstract: Noradrenalin neurons are indirectly involved in the mechanism of action of L-DOPA in part through the heterologous reuptake of DA in extrastriatal regions.

Cited by 25 publications

References 43 publications

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

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

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

Monoaminergic and Histaminergic Strategies and Treatments in Brain Diseases

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