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

Abstract

Aims: 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. Methods: 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. Results: 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. Conclusion: Noradrenalin neurons are indirectly involved in the mechanism of action of l-DOPA in part through the heterologous reuptake of DA in extrastriatal regions.