Region-dependent modulation of L-DOPA-induced dopamine release by noradrenergic terminals in the hemiparkinsonian brain
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1
University of Bordeaux 2, Life Sciences, France
The therapeutic benefit of L-DOPA is commonly attributed to the restoration of dopamine (DA) extracellular levels in the striatum of Parkinsonian patients. The increase in DA release induced by L-DOPA is mediated by serotonergic neurons and therefore occurs in extrastriatal brain regions. Because noradrenalin (NA) transporters display a high affinity for DA, NA terminals may also be involved in the heterologous regulation of L-DOPA-induced DA release in the Parkinsonian brain.
In 6-hydroxydopamine-lesioned rats, we used multi-site intracerebral microdialysis coupled to high performance liquid chromatography to monitor DA extracellular levels simultaneously in the striatum, substantia nigra pars reticulata (SNr), hippocampus and prefrontal cortex (PFC). We tested the sensitivity of DA release induced by an acute intraperitoneal (ip) administration of L-DOPA (12 mg/kg 20 minutes after 15 mg/kg benserazide ip) to the NA reuptake inhibitors desipramine (10 mg/kg, ip) and reboxetine (3 mg/kg, ip) or to a lesion of NA terminals using the NA neurotoxin DSP-4 (50 mg/kg ip).
L-DOPA induced a stronger increase in DA release in the striatum compared to the SNr, PFC and hippocampus. Both the administration of desipramine and reboxetine (20 minutes before L-DOPA) potentiated L-DOPA-induced DA release in the SNr (+107% and +139% respectively), PFC (+150% and +170%), hippocampus (+139% and 565%) but not in the striatum. The lesion of NA terminals using DSP-4, that dramatically and specifically reduced the NA tissue content, potentiated the effect of L-DOPA mainly in SNr and hippocampus.
These data show that the heterologous reuptake of DA by NA fibers participate in the heterogeneity of L-DOPA-induced DA release in the Parkinsonian brain. This might be a therapeutic strategy aimed at potentiating extrastriatal DA release to improve the motor benefit of L-DOPA while dampening the emergence of side effects attributed to excessive DA tone in the striatum.
Keywords:
Dopamine,
L-Dopa,
Multi-site microdialysis,
noradrenergic transporter,
6-hydroxydopamine
Conference:
4th Conference of the Mediterrarnean Neuroscience Society, Istanbul, Türkiye, 30 Sep - 3 Oct, 2012.
Presentation Type:
Poster Presentation
Topic:
Abstracts
Citation:
De Deurwaerdère
P,
Milan
L and
NAVAILLES
S
(2013). Region-dependent modulation of L-DOPA-induced dopamine release by noradrenergic terminals in the hemiparkinsonian brain.
Conference Abstract:
4th Conference of the Mediterrarnean Neuroscience Society.
doi: 10.3389/conf.fnhum.2013.210.00019
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Received:
07 Feb 2013;
Published Online:
11 Apr 2013.
*
Correspondence:
Prof. Philippe De Deurwaerdère, University of Bordeaux 2, Life Sciences, Bordeaux, 33076, France, deurwaer@u-bordeaux.fr