CNS Neuroscience & Therapeutics 2014-07-01

Noradrenergic terminals regulate L-DOPA-derived dopamine extracellular levels in a region-dependent manner in Parkinsonian rats.

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

Index: CNS Neurosci. Ther. 20(7) , 671-8, (2014)

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Abstract

Serotonin (5-HT) neurons mediate the ectopic release of dopamine (DA) induced by L-DOPA in the Parkinsonian brain. We hypothesized that the participation of noradrenalin transporters (NET) in the clearance of DA may account for the lower effect of L-DOPA in extrastriatal regions compared with the striatum.Using a multisite intracerebral microdialysis approach, we tested the influence of the pharmacological blockade of NET and/or the destruction of noradrenalin (NE) fibers on DA and 5-HT release in the striatum, hippocampus (HIPP), substantia nigra pars reticulata (SNr) and prefrontal cortex (PFC) of 6-hydroxydopamine-lesioned rats.L-DOPA (12 mg/kg, i.p.) increased DA extracellular levels to a lesser extent in the SNr, PFC and HIPP compared with the striatum. The NET blockers desipramine (10 mg/kg, i.p.) and reboxetine (3 mg/kg, i.p.) potentiated L-DOPA effect in the PFC, SNr and HIPP but not in the striatum. The NE neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (50 mg/kg, i.p. 1 week before dialysis experiment) potentiated L-DOPA effect in the SNr and HIPP. 5-HT extracellular levels were enhanced only when L-DOPA was combined to NET blockers.Noradrenalin neurons are indirectly involved in the mechanism of action of L-DOPA in part through the heterologous reuptake of DA in extrastriatal regions.© 2014 John Wiley & Sons Ltd.