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

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

CNS neuroscience & therapeutics (2014-04-30)
Sylvia Navailles, Léa Milan, Hanane Khalki, Giuseppe Di Giovanni, Mélanie Lagière, Philippe De Deurwaerdère
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.

MATERIALS
Product Number
Brand
Product Description

Supelco
Desipramine hydrochloride solution, 1.0 mg/mL in methanol (as free base), ampule of 1 mL, certified reference material, Cerilliant®
Sigma-Aldrich
Desipramine hydrochloride, ≥98% (TLC), powder
Sigma-Aldrich
6-Hydroxydopamine hydrobromide, 95%
Sigma-Aldrich
Benserazide hydrochloride, ≥98% (HPLC), solid
Sigma-Aldrich
N-(2-Chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride, ≥98%, solid
USP
Desipramine hydrochloride, United States Pharmacopeia (USP) Reference Standard
Desipramine hydrochloride, European Pharmacopoeia (EP) Reference Standard
Benserazide hydrochloride, European Pharmacopoeia (EP) Reference Standard