Serotonergic neurons mediate ectopic release of dopamine induced by l-DOPA in a rat model of Parkinson's disease

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Abstract

Benefit and motor side effects of l-DOPA in Parkinson's disease have been related to dopamine transmission in the striatum. However, the putative involvement of serotonergic neurons in the dopaminergic effects of l-DOPA suggests that the striatum is not a preferential target of l-DOPA. By using microdialysis in a rat model of Parkinson's disease, we found that l-DOPA (3–100 mg/kg) increased dopamine extracellular levels monitored simultaneously in four brain regions receiving serotonergic innervation: striatum, substantia nigra, hippocampus, prefrontal cortex. The increase was regionally similar at the lowest dose and 2–3 times stronger in the striatum at higher doses. Citalopram, a serotonin reuptake blocker, or the destruction of serotonergic fibers by 5,7-dihydroxytryptamine impaired l-DOPA-induced dopamine release in all regions. These data demonstrate that l-DOPA induces an ectopic release of dopamine due to serotonergic neurons. The new pattern of dopamine transmission created by l-DOPA may contribute to the benefit and side effects of l-DOPA.

Introduction

l-DOPA is the treatment of choice of Parkinson's disease (PD), a motor disease characterized by the marked degeneration of nigrostriatal dopamine (DA) neurons (Hornykiewicz, 1966). l-DOPA is able to restore DA deficiency in caudate nucleus and putamen of Parkinsonian patients. Compelling evidence indicates that its efficacy and some of its side effects such as dyskinesia or psychosis are related to this increase in striatal DA transmission (de la Fuente-Fernández et al., 2004). However, the action of l-DOPA might overstep the striatal territories.

The decarboxylation of l-DOPA into DA using the endogenous amino acid decarboxylase occurs in numerous brain regions (Lloyd and Hornykiewicz, 1970). Recent data indicate that moderate to high doses of l-DOPA enhance DA extracellular levels not only in the striatum but also in the substantia nigra, the prefrontal cortex or the hippocampus (Biggs and Starr, 1997, Mizoguchi et al., 1993, Navailles et al., in press), four brain areas expressing DA receptors (Seeman, 1980). Furthermore, an increase in DA transmission in the frontal cortex or the substantia nigra has been shown to alleviate motor disabilities in neuroleptic-, tetrabenazine-or 6-hydroxydopamine-treated rats (Andersson et al., 2006, Bergquist et al., 2003, Nieoullon, 2002, Tucci et al., 1994). These data question the idea that the striatum is a preferential target of l-DOPA compared to other brain areas. In particular, behavioral data have suggested that serotonergic neurons, which broadly innervate the encephalon (Azmitia and Segal, 1978, Steinsbusch, 1984), are involved in the action of l-DOPA (Carta et al., 2007, Hollister et al., 1979, Muñoz et al., 2008).

The 5-HT system has the biochemical features to convey l-DOPA-induced DA release in the brain. 5-HT neurons possess the cellular machinery and enzymes required to decarboxylate l-DOPA (Arai et al., 1995, Hollister et al., 1979, Ng et al., 1970) and store DA into exocytosis vesicles (Miller and Abercrombie, 1999). One convincing in vivo data reports that the lesion of 5-HT system dramatically reduced l-DOPA-induced DA release in the striatum (Tanaka et al., 1999). However, only the dose of 50 mg/kg has been studied while the effects of l-DOPA are thought to be dose-dependent. At low doses of l-DOPA, the involvement of 5-HT neurons in l-DOPA-derived DA release is indirectly supported by behavioral data (Carta et al., 2007, Hollister et al., 1979) whereas it is discarded at doses reaching 100 mg/kg on the basis of DA tissue measurement, behavioral and anatomofunctional studies (Lopez et al., 2001, Melamed et al., 1980).

In this study, we have investigated the hypothesis that l-DOPA induced a widespread enhancement of DA release in the brain via 5-HT neurons in the 6-hydroxydopamine (6-OHDA) rat model of PD. The effect of a wide range of doses of l-DOPA (3–100 mg/kg) on DA extracellular levels was monitored simultaneously by intracerebral microdialysis in the ipsilateral hippocampus, striatum, prefrontal cortex and substantia nigra. The role of 5-HT neurons was further evaluated with the selective 5-HT neurotoxin 5,7-dihydroxytryptamine (De Deurwaerdère et al., 1998, De Deurwaerdère et al., 2004) and the selective 5-HT reuptake inhibitor citalopram (Mørk et al., 2003).

Section snippets

Animals

Male Sprague–Dawley rats (IFFA CREDO, Lyon, France) weighing 240–280 g were kept at constant room temperature (21 ± 2 °C) and relative humidity (60%) with a 12-light/dark cycle (dark from 8 p.m.) and had free access to water and food. All animal use procedures conformed to European Economic Community (86-6091 EEC) and the French National Committee (décret 87/848, Ministère de l'Agriculture et de la Forêt) guidelines for the care and use of laboratory animals and were approved by the Ethical

Effect of the 6-OHDA lesion on extracellular and tissue levels of DA in the STR

The unilateral injection of 6-OHDA into the medial forebrain bundle totally suppressed the extracellular and tissue levels of DA in the ipsilateral STR. Basal extracellular levels of DA were about 7.1 ± 0.8 pg/10 μl in the STR of sham-lesioned rats but were not detectable in the ipsilateral SNr, HIPP and PFC in our experimental conditions (data not shown). After the 6-OHDA lesion, basal extracellular DA levels were below the detection sensitivity in the STR (p < 0.001, Student's t test). Tissue

Discussion

In this study, the unilateral injection of 6-OHDA into the medial forebrain bundle was used as a rat model of PD. Despite the limits inherent to such a model (Wright et al., 2009), the complete DA depletion in the affected side of the brain, corresponding to advanced PD, allows investigating the neurochemical mechanisms triggered by l-DOPA (Abercrombie et al., 1990). We show in this model that l-DOPA induced a widespread enhancement of DA release due to the almost exclusive participation of

Acknowledgments

This work was supported by grants from “Centre National de la Recherche Scientifique” and Bordeaux 2 University. The authors wish to thank Dr M. Cador for providing technical equipments and Jonathan Zapata and Ouidad Hasnaoui for technical assistance.

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