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


CONCLUSIONS
Noradrenalin neurons are indirectly involved in the mechanism of action of L-DOPA in part through the heterologous reuptake of DA in extrastriatal regions.
Université de Bordeaux, Bordeaux Cedex, France; Unité Mixte de Recherche 5293, Centre National de la Recherche Scientifique, Bordeaux Cedex, France.
Sylvia
S
Navailles
Léa
L
Milan
Hanane
H
Khalki
Giuseppe
G
Di Giovanni
Mélanie
M
Lagière
Philippe
P
De Deurwaerdère
D059331:Adrenergic Neurons / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D045604:Extracellular Fluid / Q000378:metabolism; D007980:Levodopa / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D007980:Levodopa; D004298:Dopamine
Dopamine; Intracerebral microdialysis; Noradrenergic terminals; Serotonin; l-DOPA