What can we expect from the serotonergic side of l -DOPA?

revue neurologique 168 (2012) 927–938

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What can we expect from the serotonergic side of L-DOPA? Que pouvons-nous attendre de la composante se´rotoninergique de la L-DOPA ? P. De Deurwaerde`re *, S. Navailles UMR CNRS 5293, universite´ Victor-Segalen Bordeaux-2, institut des maladies neurode´ge´ne´ratives, 146, rue Le´o-Saignaˆt, 33076 Bordeaux cedex, France

info article

abstract

Article history:

Parkinson’s disease has long been associated with neurodegeneration of the dopaminergic

Received 21 December 2011

neurons located in the substantia nigra. The metabolic precursor L-DOPA, administered

Accepted 3 January 2012

exogenously to patients, has proven its superiority over other medications. Yet, its effecti-

Published online 2 May 2012

veness is altered after long-term use by diverse motor and non-motor symptoms. Know-

Keywords :

but do we really know where and how it works? The connexion between L-DOPA and the

L-DOPA

serotonergic system, after a sort of crusade lasting for more than 40 years, has been

ledge of its mechanism of action would be necessary to better apprehend the side effects,

Serotonin

acknowledged recently. The purpose of this review, mainly based on preclinical data, is

Dopamine

to present the pharmacological and biochemical evidence demonstrating that serotonergic

Parkinson’s disease

neurons are mainly involved in the enhancement of dopamine transmission induced by L-

Mots cle´s :

nism that are fundamental and clinical. The fundamental part will focus on the conceptual

DOPA. We are addressing thereafter the two main expectations coming from this mechaL-DOPA

framework imposed by such a mechanism, questioning notably the notion that the benefit

Se´rotonine

of L-DOPA is associated with a restoration of dopamine levels in the caudate-putamen. The

Dopamine

clinical part will discuss serotonergic strategies to ameliorate the benefit of L-DOPA treat-

Maladie de Parkinson

ment in line with past and current clinical trials. # 2012 Elsevier Masson SAS. All rights reserved.

r e´ s u m e´ La maladie de Parkinson est associe´e depuis longtemps a` la de´ge´ne´rescence des neurones dopaminergiques de la substance noire compacte. La L-DOPA, pre´curseur me´tabolique de la dopamine et administre´e de manie`re exoge`ne chez les patients, a prouve´ sa supe´riorite´ sur d’autres approches me´dicamenteuses. Pourtant, son efficacite´ est alte´re´e apre`s son administration prolonge´e par de nombreux effets moteurs et non moteurs. La connaissance de son me´canisme d’action serait ne´cessaire pour mieux appre´hender les effets inde´sirables, mais savons-nous vraiment ou` et comment agit la L-DOPA ? La connexion entre la L-DOPA et le syste`me se´rotoninergique, apparaissant aujourd’hui comme une sorte de croisade qui a dure´ plus de 40 ans, a e´te´ reconnue re´cemment. Le propos de cette revue, base´e principalement sur des donne´es pre´cliniques, est de pre´senter les donne´es pharmacologiques et

* Corresponding author. E-mail address : [email protected] (P. De Deurwaerde`re). 0035-3787/$ – see front matter # 2012 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.neurol.2012.01.585

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revue neurologique 168 (2012) 927–938

biochimiques de´montrant que les neurones se´rotoninergiques sont implique´s dans l’augmentation de la transmission dopaminergique induite par la L-DOPA. Nous avons souleve´ de`s lors deux attentes principales issues de ce me´canisme d’action et portant sur les aspects fondamentaux et cliniques. La partie fondamentale s’inte´ressera au cadre conceptuel impose´ par un tel me´canisme, questionnant notamment l’ide´e que le be´ne´fice the´rapeutique de la L-DOPA est associe´ a` une restauration des niveaux de dopamine dans le noyau caude´ et le putamen. La partie clinique discutera des strate´gies cliniques pour ame´liorer le be´ne´fice de la L-DOPA en lien avec des essais cliniques passe´s et re´cents. # 2012 Elsevier Masson SAS. Tous droits re´serve´s.

1.

Introduction

Parkinson’s disease is a neurodegenerative disorder characterized by bradykinesia, postural instability and tremor at rest. L-DOPA, the gold standard medication for treating motor symptoms in Parkinson’s disease, was introduced in the 1960s soon after the demonstration that dopamine (DA) content is dramatically decreased in the brain of patients (Cotzias, 1968; Hornykiewicz, 1966). The hallmark of the disease is indeed the loss of DA neurons in the substantia nigra pars compacta, which project to the basal ganglia (Hornykiewicz, 1973), a group of subcortical regions involved in the control of motor behaviours (Obeso et al., 2008), and mainly to the caudateputamen. L-DOPA being the metabolic precursor of DA, it has been assumed that the conversion of L-DOPA to DA via its decarboxylation inside the spared DA terminals may help to maintain adequate levels of extracellular DA in the caudateputamen (striatum in rodents). This intuitive and logical way of introducing a treatment, rewarded by a high efficacy of L-DOPA to treat the core symptoms of Parkinson’s disease, favoured durably the initial and DA-oriented believe regarding its mechanism of action. Unfortunately, L-DOPA generates some peripheral and central discomforts acutely while its efficacy after years of treatment is impaired by ‘‘on–off’’ fluctuations or loss of motor response (Ahlskog and Muenter, 2001). In addition, most patients are experiencing motor side effects including L-DOPA-induced dyskinesia that can be severe (Cotzias et al., 1969). Finally, the treatment by L-DOPA is associated in some patients with cognitive disturbances including psychosis, pathological gambling, or mood troubles including agitation, sleep disorders, anxiety or depression (Chase, 1998; Eskow Jaunarajs et al., 2011; Tan et al., 2011; Voon et al., 2009). While some of these side effects could be attributed to an excessive amount of DA produced by L-DOPA, other neuropsychiatric troubles are likely related to a combination of altered systems (Jellinger, 1991). The conceptual framework of the mechanism of action of L-DOPA needs to be improved, especially in considering that other monoaminergic systems, namely noradrenergic and serotonergic, are altered at various degrees across the course of the disease, sometimes more severely compared to DA neurons in the case of noradrenergic neurons (Braak et al., 2002; Delaville et al., 2011; Eskow Jaunarajs et al., 2011; Jenner et al., 1983). The assumption that DA neurons are involved in the enhancement of DA release induced by L-DOPA was comfortable as the increase in DA transmission would follow the original DA innervation (the concept of ‘‘restoration’’). Does anyone have reported that DA neurons are involved in

L-DOPA-stimulated DA release? The pattern of decarboxylation of L-DOPA is widespread in the brain (Lloyd and Hornykiewicz, 1970), according to the fact that other neuronal classes and cells express the l-aromatico amino acid decarboxylase (AADC) capable of converting L-DOPA to DA (Hefti et al., 1981). There are still misunderstandings regarding the neurochemical data, used to interpret preclinical and clinical data, addressing which of these systems are able to release DA. However, these neurochemical data are extremely clear. The role of 5-HT neurons has been controversial while clinical data reported that the efficacy of L-DOPA in patients correlated with the levels of metabolite of 5-HT in the plasma (Gumpert et al., 1973; Korf et al., 1974). The purpose of this review is first to make a standpoint on the role of 5-HT neurons in the mechanism of action of L-DOPA. The involvement of 5-HT neurons in the core mechanism of action of L-DOPA might change the conception of the efficacy of L-DOPA in the treatment of Parkinson’s disease and bring up opportunities to improve its efficacy through the angle of 5-HT neurons.

2. Pharmacological and biochemical analysis of the mechanism of action of L-DOPA Numerous systems other than DA neurons convert L-DOPA to DA including neurons, endothelial and glial cells (Hefti et al., 1981; Melamed et al., 1980; Tison et al., 1991). Indeed, these systems are expressing the AADC able to convert L-DOPA to DA. Although this is a fundamental point participating to the mechanism of action of L-DOPA, the presence of the AADC into a cell does not predict at all the ability of the system to release DA (Nakamura et al., 2000). In order to determine the systems involved in the raise of extracellular DA induced by L-DOPA, we have to address simple questions whose responses are in the literature (points 2.1–2.4; Fig. 1).

2.1. Is L-DOPA-induced dopamine release from a neuronal origin? A release from a neuronal origin is supposed to be exocytotic and impulse-dependent. The data accumulated in vivo in rodents indicate that the main component of L-DOPA-induced DA release comes from a neuronal system. Indeed, using tetrodotoxin (TTX), a blocker of the fast voltage-dependent sodium channel, it is possible to suppress the impulsedependent component of the output of neurotransmitters in vivo (Navailles and De Deurwaerde`re, 2011) (Fig. 1). Microdialysis studies in rodents bearing a lesion of DA neurons

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Fig. 1 – Dopaminergic transmission in physiological and Parkinsonian conditions. A.1. In physiological conditions, dopaminergic (DA) transmission relies on mesencephalic DA neurons originating from the substantia nigra pars compacta (SNc), which mainly projects to the striatum (STR). A.2. L-DOPA is the precursor of DA as it is converted into DA by aromatic amino acid decarboxylase (AADC) inside DA terminals. DA is then stored in exocytosis vesicles through the vesicular monoamine transporter 2 (VMAT2) [(1): reserpine-sensitive process] and released into the synaptic cleft in an impulsedependent manner [(2): tetrodotoxin (TTX) and calcium-sensitive]. DA release is classically regulated by auto-inhibitory feedback through DA D2 receptors at cell bodies and terminals [(3)] and cleared from the extracellular space by reuptake through DA transporter (DAT) [(4)]. B.1. In Parkinsonian conditions, DA release no longer relies on DA neurons but on serotonergic (5-HT) neurons. 5-HT neurons, which originate from raphe nuclei, send a widespread innervation throughout the brain that leads to an ectopic release of DA induced by L-DOPA. B.2. 5-HT neurons possess the same monoaminergic features as DA neurons, namely the AADC to convert 5-hydroxytryptophan (5-HTP) into 5-HT and the VMAT2 to fill exocytosis vesicles with 5-HT. Exogenous L-DOPA is therefore decarboxylated inside 5-HT neurons and the newly synthesized DA is released through a TTX- and reserpine-sensitive mechanism by 5-HT terminals. In such conditions, LDOPA-induced DA release is no longer sensitive to DA D2 autoreceptor inhibitory regulation and clearance by DAT but it is sensitive to 5-HT autoregulatory mechanisms such as 5-HT1A and 5-HT1B autoreceptors at 5-HT cell bodies and terminals respectively [(30 )] as well as 5-HT transporter (SERT) [(40 )]. Transmission dopaminergique dans des conditions physiologiques ou de maladie de Parkinson. Dans des conditions physiologiques, la transmission dopaminergique (DA) repose sur les neurones DA me´sence´phaliques originaires de la substance noire compacte (SNc), laquelle projette principalement sur le striatum (STR). A.2. La L-DOPA est le pre´curseur de la DA ; elle est convertie en DA par la de´carboxylase des acides amine´s aromatiques (AADC) dans les terminaisons DA. La DA est alors stocke´e dans les ve´sicules d’exocytose via le transporteur ve´siculaire des monoamines (VMAT2) [(1) : processus bloque´ par la re´serpine] et libe´re´e dans la fente synaptique par une libe´ration de´pendante de l’influx [(2) : processus bloque´ par la te´rodotoxine (TTX) et l’absence de calcium]. La libe´ration de DA est classiquement re´gule´e par les autore´cepteurs D2 inhibiteurs au niveau des corps cellulaires et des terminaisons, [(3)] et recapte´e de l’espace extracellulaire par les transporteurs DA (DAT) [(4)]. B.1. Dans une condition mimant la maladie de Parkinson, la libe´ration de DA ne de´pend plus des neurones DA e´pargne´s, mais repose sur les neurones 5-HT. Les neurones 5-HT, qui proviennent des noyaux du raphe´, sont responsables d’une innervation diffuse dans le cerveau, ce qui entraıˆne une libe´ration diffuse et ectopique de DA induite par la L-DOPA. B.2. Les neurones 5-HT posse`dent des caracte´ristiques communes aux neurones DA, notamment l’AADC pour convertir le 5hydroxytryptophane (5-HTP) en 5-HT et le VMAT2 pour remplir les ve´sicules d’exocytose avec la 5-HT. La L-DOPA exoge`ne est ainsi de´carboxyle´e dans les neurones 5-HT et la DA nouvellement synthe´tise´e est libe´re´e par un me´canisme TTX- et re´serpinesensible par les terminaisons 5-HT. Dans ces conditions, la libe´ration de DA induite par la L-DOPA n’est pas sensible aux autore´cepteurs D2 ou a` la clearance assure´e par le DAT, mais devient sensible aux me´canismes d’autore´gulation des neurones 5-HT tels que les re´cepteurs 5-HT1A et 5-HT1B localise´s sur les corps cellulaires et les terminaisons 5-HT respectivement [(30 )] ainsi que les transporteurs 5-HT (SERT) [(40 )].

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report that TTX reduced by 80% striatal DA release induced by 6 to 50 mg/kg L-DOPA (Lindgren et al., 2010; Miller and Abercrombie, 1999).

2.2. Are monoaminergic neurons involved in L-DOPAinduced dopamine release? Reserpine is a well-known inhibitor of the vesicular monoaminergic transporter type 2 (VMAT2). Using this compound in vivo, an 80% reduction of striatal DA release induced by 50 mg/kg L-DOPA has been reported in the unilaterally rat model of Parkinson’s disease (Kannari et al., 2000). The cells involved in the release of DA induced by L-DOPA are monoaminergic neurons.

2.3. Are dopamine neurons involved in the release of dopamine induced by L-DOPA? This topic could be the object of very long and passionate debates but based on a thorough examination of preclinical data, DA neurons cannot be involved in the release of DA induced by L-DOPA. Pragmatically, the less DA neurons are spared, the higher is the release of DA induced by L-DOPA (Abercrombie et al., 1990). Second, L-DOPA decreases DA neuron firing rate (Bunney et al., 1973; Mercuri et al., 1990), an effect that has been also reported in partially DA-depleted rats (Harden and Grace, 1995). Thus, one may wonder by which kind of mechanism L-DOPA could elicit a strong and impulsedependent release of DA via DA neurons by concomitantly inhibiting the impulse of DA neurons. Furthermore, the release of DA induced by L-DOPA in DA-depleted rats is no longer affected by a selective D2 agonist, or the non-selective D2 antagonist haloperidol (Maeda et al., 1999), or an inhibitor of the DA transporter (Miller and Abercrombie, 1999; see Fig. 1). In humans, several studies have tempted to indirectly evaluate striatal DA release induced by L-DOPA by measuring the displacement of D2 radioligand such as 11C-raclopride. The displacement of the signal induced by L-DOPA (3 mg/kg intravenously) is dependent on the stage of disease, low in early stages and higher in advanced stages. The higher displacement coincided also with fluctuations and dyskinesia. Based on preclinical data exposed above and basic neurosciences, the enhancement of DA release induced by L-DOPA could not be attributed to an enhancement of activity of spared DA terminals, against the current interpretations. In humans too, FluoroDOPA labels catecholaminergic and noncatecholaminergic cells (Brown et al., 1999). Moreover, de la Fuente-Fernandez et al. (2004) have reported that the off period does not coincide with a fall of DA release, as judged by the low displacement of 11C-raclopride. This suggests that the displacement of 11C-raclopride has a limited functional value in the striatum of Parkinsonian patients and confirms that striatal DA signals are not directly associated with effects (Spencer and Wooten, 1984). While DA neurons are not involved in L-DOPA-induced DA release, they probably play a key role in regulating DA extracellular levels that are raised by another system (see below), due to the presence of DAT on spared DA terminals (Zigmond et al., 1990). This would be a clear distinction between early and advanced stages of the disease, the latter

situation leading to the inability of the system to smooth a rise in extracellular DA levels, as shown in humans. In the former situation, DAT on spared DA terminals would maintain pseudo-physiological levels of extracellular DA in the striatum by clearing a putative excess of extracellular DA levels.

2.4. L-DOPA-induced dopamine release is almost exclusively related to serotonergic neurons Numerous data have reported that L-DOPA is entering 5-HT neurons (Arai et al., 1995; Ng et al., 1970; Tison et al., 1991). 5-HT neurons have the same AADC and vesicular transporter VMAT2 than DA neurons (Fig. 1). The available data in vivo shows that striatal DA release induced by 50 mg/kg L-DOPA is reduced by 80% in DA-depleted rats bearing a strong lesion (95%) of 5-HT neurons (Tanaka et al., 1999). The participation of 5-HT neurons in the release of DA is evident for a large range of doses of L-DOPA (Navailles et al., 2010b). This effect is also sensitive to drugs that are lowering directly or indirectly 5-HT neuron activity such as 5-HT1A agonists or selective serotonin reuptake inhibitors (SSRI) (Kannari et al., 2001; Navailles et al., 2010b; Yamato et al., 2001). Similarly, the increases in tissue DA concentrations or in the striatal expression of c-Fos, a marker of neuronal activity, induced by a 30 mg/kg of L-DOPA are reduced by the lesion of 5-HT neurons (Hollister et al., 1979; Lopez et al., 2001). More importantly for clinical perspectives, rotations or dyskinesia induced by L-DOPA in unilaterally DAdepleted rats are reduced or suppressed by the lesion of 5-HT neurons or by treatments able to lower 5-HT neuron activity (Carta et al., 2007; Hollister et al., 1979; Lopez et al., 2001).

3. Reappraisal of the mechanism of action of L-DOPA The reappraisal of the mechanisms of action of L-DOPA in its benefits or side effects in humans is conditioned by the pertinence of preclinical data related to the models used. The dose of L-DOPA is extremely important but no clear and explicit conversion has been done to make a parallel between the preclinical studies in rats (often subcutaneously or intraperitoneally) and the doses used in patients (often orally). The Fig. 2 reports a tentative of conversion to give a gross approximation, without taking into consideration all the pharmacokinetic variables, species differences, acute versus chronic treatment or changes in permeability of the blood brain barrier. Nonetheless, it offers a positioning for clinicians and neurobiologists. The take home message is to think twice before administering 100 mg/kg of L-DOPA intraperitoneally in rats or mice. It would correspond to a single take of 7 g of LDOPA in humans (more if we consider the different absorption due to the distinct route of administration), which is pointless for both clinicians and neurobiologists (Fig. 2). In fact, controversies have been raised with the high dose of 100 mg/kg and over in rats. It has been consistently reported that a lesion of 5-HT neurons does not modify rotations, c-Fos expression and tissue DA concentrations induced by 100 mg/ kg L-DOPA in DA-depleted rats (Lopez et al., 2001; Melamed et al., 1980). Nonetheless, we have brought up evidence that these controversies are related in part to both the parameters

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3.1. L-DOPA-induced dopamine release is widespread and imbalanced

Fig. 2 – Drawing reporting the doses of L-DOPA commonly used orally in parkinsonian patients and peripherally in rodents. The range of doses given to humans is about 300 mg to 1600/1800 mg/day in three doses for the lower regimen (3 T 100 mg) and several doses of 200 mg with an interval of 2 hours in higher regimens (and sometimes 400 mg/dose). In a human weighing 70 kg, this would correspond from 1.4 to 6 mg/kg at maximum (about a 4-fold range). The average dose would correspond from 3 mg/kg per intake. The range of doses used in rodent models of Parkinson’s disease is from 0.1 mg/kg (extremely rare) to 100 mg/kg (about a 1000-fold range). Most studies in rodents are in the range of 6 to 50 mg/kg. Illustration reportant les doses de L-DOPA classiquement administre´es oralement chez les patients parkinsoniens et par voie pe´riphe´rique chez les rongeurs. La gamme de doses administre´e chez l’humain s’e´chelonne de 300 a` 1600/ 1800 mg/jour en trois prises pour la posologie la plus faible (3 T 100 mg), jusqu’a` des prises re´pe´te´es de 200 mg espace´es de deux heures (voire 400 mg). Cela correspondrait chez un humain pesant 70 kg a` 1,4 mg/kg par prise jusqu’a` une gamme haute de 6 mg/kg au maximum (un facteur 4). La dose moyenne par prise correspondrait a` 3 mg/kg. La gamme de doses utilise´es dans les mode`les rongeurs de la maladie de Parkinson s’e´chelonne de 0,1 (extreˆmement rare) a` 100 mg/kg (facteur 1000). La plupart des e´tudes utilisent des doses de 6 a` 50 mg/kg.

(tissue DA versus DA release) and the extent of the 5-HT lesion (Navailles et al., 2010a). The range of L-DOPA doses in rats that could be representative of the clinical situation could be around 3 mg/kg (1 to 12 mg/kg). At these doses, L-DOPAinduced rotations and dyskinesia in rats are exclusively due to 5-HT neurons, as well as the increase in DA release (see above). We have identified several points arising from the demonstration that 5-HT neurons are involved in the mechanism of action of L-DOPA. On top of them is the uncomfortable idea that the raise in DA transmission induced by L-DOPA cannot follow the physiological pattern of central DA transmission. This situation is similar when exogenous agonists are administered.

The 5-HT neurons whose cell bodies are located in the median and raphe nuclei innervate virtually the entire encephalon (Molliver, 1987; Steinbusch, 1984). The 5-HT innervation is homogeneous compared to the central DA innervation, the substantia nigra receiving the densest 5-HT innervation. Similar to widespread pattern of decarboxylation, it has been reported that L-DOPA increases DA release in various brain areas of DA-denervated rats including the striatum, the substantia nigra, the internal globus pallidus, the prefrontal cortex or the hippocampus (Biggs and Starr, 1997; Navailles et al., 2010b; Sarre et al., 1992, 1997). The corollary of the homogeneous release of DA coming from 5-HT neurons is that the magnitude of the effect could be low in the striatum compared to physiological values, and extremely high in the other brain regions. The Fig. 3 reports the magnitude of the effect elicited by L-DOPA on DA extracellular levels in various brain regions compared to the physiological situation. It is noticeable that, at the dose of 3 mg/kg L-DOPA known to be efficient and even to induce contraversive rotations and dyskinesia in DA-depleted rodents (Berthet and Bezard, 2009; Hollister et al., 1979), LDOPA-induced DA release reaches only 1/3 of the physiological values in the striatum (speculatively lower than the intact side) while it reaches two to five times the values obtained in other brain regions. The role of striatal DA release stimulated by L-DOPA is further questionable as some functional recovery in preclinical studies in rodents have been reported at doses as low as 0.1 to 1 mg/kg (Marti et al., 2007). At these doses, the enhancement of DA extracellular levels in the striatum of fully-depleted rats barely reaches 1/ 10 of physiological values or is even undetectable (unpublished results).

3.2. L-DOPA-stimulated dopamine transmission is imbalanced The dramatic increase in extracellular DA in multiple brain regions raises the question of the presence of DA receptors in those regions. Even if the physiological tone of DA release is low in the hippocampus and cortex, it is well known that DA receptors are expressed in substantial quantities in rats, monkeys and humans (Bordet, 2004; Seeman, 1980). Consequently, the excessive enhancement of DA release may dramatically increase DA transmission in those regions. Behaviourally, the administration of DA agonists in the substantia nigra of DA-depleted rats mimics the effect of peripheral L-DOPA suggesting that the raise in DA transmission in the substantia nigra participate in the effects of anti-Parkinsonian medication (Orosz and Bennett, 1992; Robertson and Robertson, 1989). The situation for other brain regions is speculative. Nevertheless, a huge increase in DA transmission in the cortex, thought to inhibit cortico-striatal glutamatergic pathways (Carlsson and Carlsson, 1990; Tucci et al., 1994), would palliate the low DA tone in the caudate. Similarly, an increase in DA release induced by L-DOPA might occur in the STN, participating to L-DOPA-induced dyskinesia (Soghomonian, 2006).

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Extracellular levels of DA (pg/10 µl averaged for 3hr monitoring)

16

STR SNr CPF HIPP

14 12 10 8 6

striatum

Physiological levels

4 2 0

others

6 12 3 Dose L-DOPA (mg/kg) Fig. 3 – Dose response effect of peripheral L-DOPA on extracellular levels of dopamine (DA) in various rat brain regions of 6-hydroxydopamine rats. DA extracellular levels have been measured using intracerebral microdialysis simultaneously in the ipsilateral striatum (STR), substantia nigra pars reticulata (SNr), hippocampus (HIPP) and prefrontal cortex (PFC). Dot lines represent the extracellular levels of DA monitored in those regions in intact rats. The graphic shows that the average increase in DA release triggered by L-DOPA in the striatum of fully DAdepleted rats, is reached for doses of l-DOPA over 6 mg/kg. On the other hand, extracellular levels of DA triggered by L-DOPA overwhelm physiological values in the other rat brain regions already at low doses. Effet dose de la L-DOPA pe´riphe´rique sur les niveaux extracellulaires de dopamine (DA) dans plusieurs re´gions ce´re´brales du rat le´se´ a` la 6-hydroxydopamine. Les niveaux extracellulaires de DA ont e´te´ mesure´s par microdialyse intrace´re´brale simultane´ment dans le striatum ipsilate´ral (STR), la substance noire re´ticule´e (SNr), l’hippocampe (HIPP) et le cortex pre´frontal (PFC). Les lignes en pointille´s repre´sentent les niveaux de base mesure´s chez des rats naı¨fs dans ces re´gions. Le graphique montre que l’augmentation moyenne des niveaux extracellulaires de DA induite par la LDOPA dans le striatum, chez des rats pleinement le´se´s en DA, est atteinte pour des doses de 6 mg/kg et plus. D’un autre coˆte´, les niveaux extracellulaires de DA induits par la L-DOPA surpassent les valeurs physiologiques dans les autres re´gions ce´re´brales de´ja` a` faibles doses. Adapted from Navailles et al., 2010a.

In this schema, the striatum could no longer be the main locus of the therapeutic benefit of L-DOPA which would be also associated with an increase in DA transmission in other brain regions. Similarly, the efficacy of the high-frequency stimulation of the subthalamic nucleus occurs independently of an increase in DA release in the striatum. This latter fact comes in support to the idea that an action located elsewhere than the striatum may be valuable. The striatum could be one important target of the dyskinesia induced by L-DOPA after chronic L-DOPA

treatment. L-DOPA-induced dyskinesia is a choreic form of abnormal movements. Their behavioural assessment in rats has been elegantly set up by Angela Cenci (2009). The dyskinesia in rats occurs already at low doses (1–12 mg/kg) after a subchronic treatment. Their appearance is progressive and does not require an increase in dose regimen (Carta et al., 2007). This could support the hypothesis that L-DOPA-induced dyskinesia results from an aberrant learning and could correspond to a sensitization of an abnormal behavioural response (Calabresi et al., 2000; Picconi et al., 2005). The dyskinesias are suppressed by the lesion of 5-HT neurons or by drugs known to reduce the activity of 5-HT neurons such as 5HT1A or/and 5-HT1B agonists (see below) (Carta et al., 2007). These effects are also reported in primate models of Parkinson’s disease (Bibbiani et al., 2001; Iravani et al., 2003; Munoz et al., 2008). While some biochemical data have suggested that the increase in DA release induced by L-DOPA is magnified after chronic treatment (Meissner et al., 2006), others did not find modification or even reported a decrease in striatal DA release induced by L-DOPA in chronically L-DOPA treated rats (Navailles et al., 2011). On the other hand, we have found after a chronic treatment that L-DOPA-induced DA release was dramatically reduced in the brain areas other than the striatum (Navailles et al., 2011). The reason why the striatum maintains a higher DA response to L-DOPA compared to other structures is not known. It has been reported however a higher incidence and morphological changes of 5-HT synapses in rats and monkeys that had developed dyskinesia (Rylander et al., 2010; Zeng et al., 2010). Our hypothesis is that the initial and efficient imbalance created by L-DOPA is affected by chronic treatment. The striatal response could be less affected compared to other brain regions, possibly leading to abnormal DA release and altered movements (Navailles and De Deurwaerde`re, 2012). In addition, the modifications of DA release induced by L-DOPA occur in a context of multiple molecular changes (Berthet and Bezard, 2010; Cenci, 2002).

3.3. L-DOPA-induced dopamine release at the speed of serotonergic neurons It has been demonstrated at several occasions that L-DOPA reached the cytosol of 5-HT neurons and is converted into DA inside 5-HT neurons (Tison et al., 1991). The demonstration in animals that 5-HT neurons are solely involved in L-DOPAstimulated DA release is therefore puzzling as the release of DA is conditioned by the activity of 5-HT neurons. 5-HT neurons do not follow the same pattern of activity compared to DA neurons and do not respond to the same stimuli (Bromberg-Martin et al., 2010a,b; Nakamura et al., 2008). The pattern of activity of 5-HT neurons might be altered also by the presence of DA because the exocytosis activity is less controlled due to the fact that DA does not exert a feedback control on the activity of 5-HT neurons. Such a release of a ‘‘false neurotransmitter’’ would be uncontrolled (Carta et al., 2007). In early stages of the disease, that can be associated with 50 to 70% loss of DA neurons, the contribution of striatal DA released by 5-HT terminals could be minimal compared to the endogenous DA tone produced by remaining DA fibres. First, it

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is estimated that 5-HT fibres represent 1/10 to 1/20 of DA fibres in the striatum (Fahn et al., 1971). In case of minimal lesion of DA neurons, DA fibres are still in excess compared to 5-HT fibres in the striatum. Second, as speculated above, the presence of DAT would permit to smooth extracellular levels of DA (Fig. 1). Third, remaining DA neurons would fire at a higher frequency compared to most 5-HT neurons, though the firing and the number of DA cells firing in burst is lowered by LDOPA (Harden and Grace, 1995). However, DA released by 5-HT terminals will also occur in other brain areas in which DA fibres are physiologically less represented compared to 5-HT fibres (cortex, hippocampus, subthalamic nucleus, pallidum, etc.). Thus, in our opinion, the DA signal triggered by L-DOPA from 5-HT neurons would largely overwhelm the physiological DA signal in areas poorly innervated by DA neurons whereas it would be considered as a noise in the striatum in early stages. The progressive loss of DA neurons would lead to enhance the contribution of 5-HT terminals in the DA signal triggered by L-DOPA and could participate to aberrant learning in the striatum (Calabresi et al., 2000).

3.4.

Alteration of serotonergic function

One may wonder how the system ensures a proper 5-HT transmission when the 5-HT terminals are filled up with DA and release DA. The results are not that clear as the available data report that L-DOPA may enhance, inhibit or barely affect 5-HT release (Biggs and Starr, 1997; Lindgren et al., 2010; Navailles et al., 2010b, 2011; Ng et al., 1970). It appears however that the effects are region-dependent (Navailles et al., 2011), according to the heterogeneity of 5-HT neurons and terminals recently described (Amilhon et al., 2010; Kiyasova et al., 2011). 5-HT transmission will be affected by L-DOPA, and chronically, it can be associated with a dramatic decrease in basal 5-HT release in numerous brain regions, depending on the regimen of L-DOPA (Lindgren et al., 2010; Navailles et al., 2011; Navailles and De Deurwaerde`re, 2012). In addition to the profound alteration related to the loss of DA neurons, one may expect modifications of 5-HT receptor expression and sensitivity in various regions consequent to alteration of 5-HT neuron activity (De Deurwaerde`re, 2011; Di Matteo et al., 2008; Fox et al., 2009; Navailles et al., 2011).

3.5.

Alteration of serotonergic neurons

Another consequence is related to the possible life threatening of L-DOPA inside 5-HT neurons. The entry of L-DOPA is associated with the synthesis of DA that can be metabolized by monoamine oxydase B (MAOB), which is far more efficient toward DA than 5-HT. Consequently, a high concentration of newly synthesized DA inside 5-HT cells could generate a high concentration of free radicals that could alter the functional integrity of the cell. It has been reported that chronic administration of L-DOPA reduced tissue concentrations and basal extracellular levels of 5-HT and its metabolite 5-HIAA in various brain regions of DA-depleted rats (Navailles et al., 2011). Importantly, no clear evidence exists from clinical studies to support such a possibility (Kish et al., 2008; Politis et al., 2010; Scholtissen et al., 2006), though the clinical

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situation is often, if not always, associated with early loss of 5HT neurons (Braak et al., 2002; Kish et al., 2008; Politis et al., 2010).

3.6.

Conceptual consequences for preclinical studies

We feel that these neurobiological elements are sufficiently important to be taken into account or thoroughly examined for developing future strategies. One preclinical strategy developed over years was to enhance the efficacy of LDOPA-induced DA release in the striatum mainly by acting on heterologous systems to limit the dose of L-DOPA administered and inherent side effects. This strategy remains interesting notably to counteract the decrease in DA neuron excitability elicited by L-DOPA itself in the early stage of the disease. Nevertheless, this strategy may also affect the release of DA coming from 5-HT terminals not only in the striatum, but also in other brain regions (Lindgren et al., 2010), dampening the physiological meaning of DA extracellular levels. In the advanced stages of the disease, the strategies should be developed toward the control of 5-HT neuron activity. Moreover, the prevention of dyskinesia in rats by the lesion of 5-HT neurons or the administration of a 5-HT1A agonist occurs without aggravating some motor responses (Carta et al., 2007; Lindgren et al., 2010). As weird as it could be, these data stress again the point that the efficacy of L-DOPA occurs with barely detectable extracellular DA levels in the striatum. Thus, striatal grafts of cells able to synthesize and release DA would be a counterproductive strategy in increasing the risk of dyskinesia appearance. Their benefit would not be clear as this surgical approach is associated with L-DOPA administration for which the clinical efficacy would result from an enhancement of DA transmission in multiple brain regions (see above).

4. Serotonergic neurons and strategies in clinics Numerous clinical reports have been published on the effects of 5-HT drugs combined with classical DA therapies. The rationale for using these drugs was not presumably taking into consideration the 5-HT side of L-DOPA and often corresponded to the need to treat associated disorders, notably constipation, anxiety, depression or psychosis.

4.1.

5-HT1A/5-HT1B agonists and dyskinesia

Numerous studies have reported the anti-dyskinetic properties of 5-HT1A agonists and 5-HT1B agonists in animal models (Bishop et al., 2006; Carta et al., 2007; Munoz et al., 2008) and Parkinsonian patients (Bara-Jimenez et al., 2005; Bibbiani et al., 2001; Bonifati et al., 1994; Goetz et al., 2007; Olanow et al., 2004). Furthermore, partial 5-HT1A agonists reduce dyskinesia without worsening of Parkinsonian symptoms, sometimes improving L-DOPA-induced motor benefits. However, the antidyskinetic actions of 5-HT1A agonists may be either limited (Merck KGaA, NCT00105521) or accompanied by a dosedependent worsening of motor disabilities in rats (Dupre et al., 2007), monkeys (Iravani et al., 2006) and humans (Goetz

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et al., 2007; Olanow et al., 2004). Such inconsistency could be related to the stimulation of pre- versus postsynaptic 5-HT1A receptors (Eskow et al., 2009) and/or the dose of agonists used. On the one hand, it is assumed that the efficacy of 5-HT1A and/or 5-HT1B agonists to dose-dependently decrease L-DOPAinduced dyskinesias depends on their ability to diminish L-DOPA-derived DA that is released as a ‘‘false transmitter’’ by 5-HT neurons (Kannari et al., 2001; Navailles et al., 2010a,b). These effects constitute the rationale for the presynaptic model of L-DOPA-induced dyskinesia (Carta et al., 2007; Ulusoy et al., 2010). The anti-dyskinetic action of systemically administered 5-HT1A agonists would be related to the stimulation of 5-HT1A autoreceptors in the raphe nuclei (Eskow et al., 2009). On the other hand, the postsynaptic 5HT1A receptors are likely involved in the benefit of 5-HT1A agonists. Indeed, intracerebral administrations of 5-HT1A agonists into the subthalamic nucleus, the striatum or the cortex have been shown to decrease L-DOPA-induced dyskinesia in rodents (Bishop et al., 2009; Marin et al., 2009; Ostock et al., 2011). These results not only dampen the participation of 5-HT1A receptors in the raphe in the anti-dyskinetic effects of 5-HT1A agonists, but also recall that brain regions other than the striatum are involved in L-DOPA-induced dyskinesia including the substantia nigra, subthalamic nucleus, and cortex. The combination of sub-threshold doses of 5-HT1A and 5HT1B agonists has been shown to have a better potency in blocking L-DOPA-induced dyskinesias in monkeys and rats (Carta et al., 2007; Munoz et al., 2008). This synergistic action favours the idea that their efficacy could be primarily due to a concomitant inhibition of DA release from 5-HT neurons (Carta et al., 2010). The use of low doses of 5-HT1A agonists would optimize their efficacy in limiting the appearance of 5HT1A-dependent side effects known as the 5-HT syndrome.

4.2.

Selective Serotonin Reuptake Inhibitor (SSRI)

Some studies have reported the benefit of SSRI in L-DOPAinduced dyskinesia and also in DA agonists-induced dyskinesia. Their prescription is not systematic as their primary use is to treat depression and anxiety. Depression is a common symptom in Parkinson’s disease, affecting between 30% and 40% of patients (Tandberg et al., 1996) and may precede the development of motor symptoms (Schuurman et al., 2002; Shiba et al., 2000). However, the depressive symptoms in Parkinsonian patients are different from classical depression, with less anhedonia and guilt feelings (Ehrt et al., 2006) and antidepressant therapy is less effective (Weintraub et al., 2005). In addition, L-DOPA may aggravate the syndrome (Eskow Jaunarajs et al., 2011) and we have indeed reported in animals that a chronic treatment with L-DOPA lowers tissue and extracellular 5-HT content (Navailles et al., 2011). It is interesting to note that a higher rate of depression in patients could occur with the use of L-DOPA compared to DA agonists (Ne`gre-Page`s et al., 2010). The 5-HT side of L-DOPA has to be taken into account because one may wonder whether the neurobiological hypothesis regarding the mechanism of action of SSRI in depression are the same when 5-HT neurons release also DA. The SSRI sertraline has been reported to be at least as efficient

as the D2/D3 agonist pramipexol to limit depressive symptoms in parkinsonian patients (Barone et al., 2006). The anxiolytic profile of some SSRI has been proposed to participate in their ability to reduce dyskinesia (Durif et al., 1995; Kuan et al., 2008). The situation could be similar in the case of HFS-STN because this strategy lowers also 5-HT release in the cortex or hippocampus of rodents (Navailles et al., 2010a). The use of SSRI has been suggested in depressed patients that have been operated for HFS-STN (Tan et al., 2011; Temel et al., 2007). Regarding the putative excess of DA transmission elicited by L-DOPA, SSRI could reduce stimulated DA release by indirectly inhibiting the activity of 5-HT neurons (Yamato et al., 2001) and, putatively, by directly blocking the output of DA from 5-HT terminals occurring via the 5-HT transporter (Navailles et al., 2010b). On the other hand, the efficacy of some agonists such as pramipexol against the core symptoms of the disease has been related to their ability to reduce non-motor symptoms (Barone et al., 2010). Thus, the overall picture regarding non-motor symptoms in Parkinson’s disease is complicated as it refers to multiple pathophysiological alterations that are distinct from those described for depression or anxiety. In rats, depressive-like symptoms are obtained in animals bearing major depletion of the noradrenergic (NA), DA and 5-HT systems while anxious-like states are marked in case of depletion of two monoaminergic systems, provided that DA system is depleted (Delaville et al., 2012). Based on such clinical and preclinical data, it is possible to envision strategies directed toward DA transmission, like pramipexol, instead of 5-HT transmission to limit specifically non-motor symptoms in Parkinson’s disease.

4.3.

Rasagiline

Rasagiline has been reported to prolong the efficacy of L-DOPA (Rascol et al., 2005; Weinreb et al., 2010). Rasagiline is a nonselective inhibitor of MAOB, which are present in the 5-HT, but not DA, cells and which are more efficient to convert DA compared to 5-HT. In a biochemical point of view, it is easy to imagine that blockade of MAOB would avoid the degradation of DA inside 5-HT neurons. This would permit to maintain substantial concentrations of intracellular DA levels inside 5HT cells with lower doses of L-DOPA, and would prevent a putative destruction of 5-HT neurons through an enhancement of oxidative metabolism (see above). The efficacy of rasagiline is also associated with sites other than MAOB (Mandel et al., 2007).

4.4.

Other clinical perspectives

As DA is released in several brain regions after L-DOPA administration, one may wonder the relative contribution of this mechanism to the therapeutic benefit of L-DOPA. In particular, in identifying brain areas involved in the benefit (for instance, cortex, substantia nigra), one could imagine to potentiate DA transmission in these brain regions with respect to the striatum. For instance, NA neurons, known to reuptake extracellular DA via the norepinephine transporter (NET), are poorly represented in the striatum. If NA neurons are spared in some patients, the blockade of NET

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might enhance L-DOPA-induced increase in extracellular DA in various brain regions other than the striatum.

5.

Conclusions

The correlation between functional recovery induced by and striatal DA release is not clear and the therapeutic benefit of L-DOPA does not correspond in preclinical studies to a restoration of the extracellular levels of DA in the striatum. The relative homogeneity of the increase in DA release induced by LDOPA in the brain results from the unique involvement of 5-HT neurons. Conceptually, the 5-HT side of L-DOPA brings up the idea that there is a hypodopaminergy in the striatum and a hyperdopaminergy in other brain regions. It also stresses the point that 5-HT neurons are dramatically affected by the presence of DA in 5-HT neurons. Clinically, the 5-HT side of LDOPA could permit to target the activity of 5-HT system in order to limit L-DOPA-induced DA release at least in the striatum or enhance L-DOPA-induced DA release in brain regions other than the striatum to counteract the detrimental effects of L-DOPA thought to be triggered by abnormal striatal DA released. In fine, 5-HT neurons participate in the mechanism of action L-DOPA, since the first administration of L-DOPA. It would be necessary to make a diagnosis on the status of 5-HT neurons in patients in order to adapt the safer strategy of treatment. In conclusion, one can expect from the 5-HT side of L-DOPA in Parkinson’s disease to: L-DOPA

 change the old textbooks and teach the valid mechanism of L-DOPA;  better apprehend the benefit and side effects of L-DOPA in light of its mechanism of action;  hopefully improve the treatment of Parkinson’s disease.

Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.

Acknowledgments This work was supported by grants from ‘‘Centre national de la recherche scientifique’’, the University of Bordeaux, the ‘‘Fondation de France’’ and the ‘‘Socie´te´ franc¸aise de physiologie’’. The authors report no biomedical financial interest or potential conflict of interest. The authors thank Dr Martin Guthrie for linguistic assistance.

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