Parkinson’s Disease

Parkinson’s Disease / 2012 / Article
Special Issue

Dyskinesia in Parkinson’s Disease Therapy

View this Special Issue

Review Article | Open Access

Volume 2012 |Article ID 323686 | https://doi.org/10.1155/2012/323686

Sylvia Navailles, Philippe De Deurwaerdère, "Imbalanced Dopaminergic Transmission Mediated by Serotonergic Neurons in L-DOPA-Induced Dyskinesia", Parkinson’s Disease, vol. 2012, Article ID 323686, 16 pages, 2012. https://doi.org/10.1155/2012/323686

Imbalanced Dopaminergic Transmission Mediated by Serotonergic Neurons in L-DOPA-Induced Dyskinesia

Academic Editor: Anna Rosa Carta
Received01 Jul 2011
Accepted02 Aug 2011
Published11 Oct 2011

Abstract

L-DOPA-induced dyskinesias (LIDs) are one of the main motor side effects of L-DOPA therapy in Parkinson's disease. The review will consider the biochemical evidence indicating that the serotonergic neurons are involved in the dopaminergic effects of L-DOPA in the brain. The consequences are an ectopic and aberrant release of dopamine that follows the serotonergic innervation of the brain. After mid- to long-term treatment with L-DOPA, the pattern of L-DOPA-induced dopamine release is modified. In several brain regions, its effect is dramatically reduced while, in the striatum, its effect is quite preserved. LIDs could appear when the dopaminergic effects of L-DOPA fall in brain areas such as the cortex, enhancing the subcortical impact of dopamine and promoting aberrant motor responses. The consideration of the serotonergic system in the core mechanism of action of L-DOPA opens an important reserve of possible strategies to limit LIDs.

1. Introduction

Parkinson’s disease is the second most devastating neurodegenerative disease affecting more than 6 million people worldwide and whose prevalence is expected to double within the next twenty years [1]. This neurological disorder is characterized by the progressive loss of mesencephalic dopaminergic (DA) neurons from the substantia nigra pars compacta and associated with numerous motor symptoms (bradykinesia, rigidity, and tremor) [2, 3]. L-DOPA, the precursor of DA, has been introduced in the mid 60’s as a miracle pill to prevent the motor symptoms [4, 5]. However, upon chronic use of this medication, its efficacy slowly decreases leading to increase the doses of L-DOPA, which generate numerous side effects. After 5 to 10 years of L-DOPA treatment, Parkinsonian patients develop dyskinesias [6], which consist of stereotypical choreic or ballistic movements involving mostly the head, trunk, and limbs [7]. These abnormal involuntary movements are often more debilitating than the motor symptoms themselves.

Preclinical research has permitted validating animal models to study the mechanisms of L-DOPA-induced dyskinesias (LIDs). The most commonly used rat model that shows best face and predictive validity, has been developed by Cenci and collaborators [8, 9] by producing severe lesion of the nigrostriatal DA pathway in adult rats with the unilateral injection of 6-hydroxydopamine (6-OHDA) in the medial forebrain bundle [10, 11]. A chronic treatment with L-DOPA for 3 weeks at low therapeutic doses (6–10 mg/kg) induced axial, limb, and orolingual abnormal involuntary movements (ALO AIMs) of variable occurrence and severity in rats [9, 12]. Despite extensive research done to understand how these motor complications develop in the Parkinsonian brain, all hypotheses could not be fully validated and new insights in this field need to be pushed forward to further gain in understanding of LIDs. In the present review, we will focus on the literature showing a prominent role of serotonergic neurons (5-HT) in the mechanisms of action of L-DOPA and how these neurons may contribute to the development of LIDs. Specifically, we will try to develop a new hypothesis that LIDs appear when the effect of L-DOPA falls in brain areas such as the cortex, then enhancing the subcortical impact of DA at the risk to elicit LIDs.

2. Mechanism of Action of L-DOPA in 5-HT Neurons and Collateral Consequences

It has long been thought that the therapeutic benefit of L-DOPA may depend on its ability to restore DA extracellular levels in the striatum through spared DA neurons [1315]. However, contradictory data have shown that the fewer DA neurons that are spared, the more pronounced is the release of DA induced by L-DOPA [1621]. Furthermore, L-DOPA-induced DA release is not sensitive to DA autoregulatory processes (DA-D2 autoreceptor stimulation and DAT blockade) [19]. Other monoaminergic cells [22, 23], namely serotonergic (5-HT) neurons, that are able to convert L-DOPA into DA, store and induce an exocytotic release of DA, rather participate in the mechanism of action of L-DOPA [24].

2.1. L-DOPA and 5-HT Neurons

5-HT neurons express the amino acid decarboxylase (AADC) that converts L-DOPA into DA and the vesicular membrane transporter VMAT2 that packages DA into exocytosis vesicles [2528]. In line with these molecular features, 5-HT neurons have been shown for several years to release the newly synthesized DA from their cell bodies and terminals [25, 29, 30]. Indeed, 5-HT neurons are responsible for the TTX-sensitive, reserpine-sensitive, and DA drugs-insensitive release of DA induced by L-DOPA. The lesion of 5-HT neurons by the selective neurotoxin 5,7-DHT drastically reduces the increase in DA extracellular levels induced by a wide range of L-DOPA doses (3–100 mg/kg) [31, 32]. This effect is dependent on the extent of 5-HT denervation [31], which excludes the involvement of any other cellular system in the release of DA induced by L-DOPA. Furthermore, L-DOPA-induced DA release is sensitive to 5-HT autoregulatory mechanisms. Both the stimulation of 5-HT1A autoreceptors by the 5-HT1A agonist 8-OHDPAT [33] and the blockade of 5-HT transporters (SERT) by the selective serotonergic reuptake inhibitors (SSRI) fluoxetine [34] or citalopram [31] reduce the increase in L-DOPA-derived DA extracellular levels. These effects are thought to occur via the inhibition of 5-HT neuron activity [3542]. Accordingly, it has been recently shown that high-frequency stimulation of the subthalamic nucleus, a surgical approach in Parkinson’s disease able to inhibit 5-HT neuronal firing [43], also reduces L-DOPA-induced DA release [44].

5-HT neurons send a widespread innervation from the raphe nuclei to the entire forebrain including the striatum [46, 47]. Beyond the increase in striatal DA extracellular levels, L-DOPA also induces a massive rise in DA levels in the prefrontal cortex (PFC), the substantia nigra pars reticulata (SNr), and the hippocampus (HIPP) [31]. In all brain regions, L-DOPA-induced DA release is sensitive to 5-HT pharmacological manipulation and the lesion of 5-HT neurons [31, 44, 48]. This ectopic release of DA induced by L-DOPA via 5-HT neurons creates a new balance in DA chemistry throughout the Parkinsonian brain (Figure 1) [24, 31]. In physiological conditions, basal DA concentrations are more than 30 times higher in the striatum compared to other brain regions, in line with the restricted innervation of mesencephalic DA neurons to striatal territories [5, 49]. While DA extracellular levels are from 4.6 to 7.8 fmol/uL, they are barely detectable depending on experimental conditions (below 0.2 fmol/uL) in the PFC, SNr, and HIPP although DA receptors are expressed [50]. In Parkinsonian conditions, the dose of L-DOPA required to “restore” similar DA concentrations in the DA-denervated striatum is about 12 mg/kg while it increases about 10 to 25 times DA concentrations in other brain regions (see Figure 1). Interestingly, L-DOPA at 3 mg/kg enhances DA levels to similar amounts (0.7 to 1.3 fmol) in the PFC, SNr, HIPP, and striatum. Therefore, huge amounts of DA can be released beyond the striatum [51] and may impact on DA receptors throughout the Parkinsonian brain. In keeping with the increased sensitivity of DA receptors that develops after DA denervation [5254], such an imbalanced DA transmission between the striatum and other brain regions may participate in the emergence in both short-term benefits and long-term side effects of L-DOPA treatment (see Section 4).

2.2. Chronic Impact of L-DOPA on DA Release Pattern in the Entire Forebrain

The therapeutic efficacy of L-DOPA treatment decreases over time with the development of numerous side effects including L-DOPA-induced dyskinesias (LIDs). LIDs are thought to emerge as a consequence of the dysregulated release of DA as a “false neurotransmitter” from 5-HT neurons [12, 31, 33, 44, 48, 5763]. Indeed, the inhibition of L-DOPA-induced DA release by 5-HT1 autoreceptors stimulation [33, 48] and/or 5,7-DHT lesion [31, 32] is associated with a marked reduction in LIDs [48, 61]. However, these mechanisms have been described mostly in the striatum while other brain regions could be involved in the development of LIDs [60, 6469]. Furthermore, the dose of L-DOPA used, even within the therapeutic range (3–12 mg/kg), represents a critical parameter to consider in the understanding of LIDs [70].

The occurrence and severity of LIDs in animals treated chronically with L-DOPA depend on numerous parameters, that is, the dose of L-DOPA, the site of 6-OHDA injection, the extent of DA lesion, and rat strain. About half of animals treated chronically with 3 mg/kg of L-DOPA develop LIDs. At 6 mg/kg, about 2/3 of the animals treated with L-DOPA display severe LIDs. At 12 mg/kg and above, almost all animals develop LIDs [9]. One consistent result observed after chronic L-DOPA treatment is that, whatever the dose, basal DA extracellular levels remain barely detectable in all brain regions. In our experimental conditions (12 mg/kg for 10 days), basal DA levels were below the detection limit in the striatum, SNr, PFC, and HIPP (Figure 1) [45]. In another study using a 14-day treatment with 6 mg/kg L-DOPA, baseline DA concentrations were reduced by 99% to 0.04 fmol/μL in the striatum compared to intact animals (4 fmol/μL) without changes in the SNr (0.1-0.2 fmol/μL) [48]. One study showed a slight increase in basal DA levels in the striatum (reaching about 0.6 fmol/μL) by using a higher dose (25 mg/kg) of L-DOPA administered twice a day [81].

Dynamics in the increase in DA release after each L-DOPA administration may, however, differ regarding the dose of L-DOPA used. Some authors have proposed that LIDs may emerge as a consequence of abnormal fluctuations in synaptic DA levels induced by L-DOPA treatment in dyskinetic animals [48, 58, 59, 61, 73]. Larger increases in synaptic DA levels induced by L-DOPA have been proposed to be responsible for the emergence of peak-dose dyskinesia in PD patients [59]. Data obtained with a chronic L-DOPA treatment at 6 mg/kg have shown that the kinetics of DA release are different in animals developing LIDs or not [73]. Although a higher magnitude of DA release was observed in the striatum and SNr of dyskinetic animals compared to nondyskinetic animals [48], this has not been consistently observed [73]. In a recent report, our data have provided new evidence for reconsidering the mechanisms of L-DOPA within the Parkinsonian brain and the putative consequences in many side effects including LIDs [45]. We showed that after a chronic L-DOPA treatment at 12 mg/kg for 10 days, the reactivity of 5-HT neurons to an acute challenge at 3 or 12 mg/kg of L-DOPA was modified and resulted in a potent loss of efficacy of L-DOPA to increase DA release (Figure 1). Most importantly, our data could depict a new imbalance created by chronic L-DOPA treatment within the striatum and other brain regions. The capacity of 5-HT neurons to increase DA release in the SNr, HIPP, and PFC was drastically reduced (about 70 to 90%) while it was less affected in the striatum. Indeed, the increase in striatal DA release induced by 3 mg/kg of L-DOPA after a 12 mg/kg treatment for 10 days was similar to that induced by an acute administration of 3 mg/kg. At 12 mg/kg, the effect of L-DOPA was reduced by only 50% after chronic compared to acute treatment. It appears that different mechanisms may be processed in the striatum compared to other brain structures that may account for the relatively preserved striatal DA effect of L-DOPA. Some of these mechanisms may be directly related to the specific features and heterogeneity of 5-HT terminals within brain regions. The resulted imbalance between cortical versus subcortical brain regions in DA transmission may potentially participate in development of LIDs.

The following paragraph corresponds to the description of the Figure 1, (a) in physiological conditions, dopaminergic neurons originating from the substantia nigra pars compacta (SNc) densely innervate the striatum (STR) where basal dopamine (DA) concentrations range between 4.6 and 7.8 nM. In the prefrontal cortex (PFC), the hippocampus (HIPP), and the substantia nigra pars reticulata (SNr), basal DA concentrations are much lower (<0.2 nM). All these brain regions express DA receptors and are innervated by serotonergic neurons that originate from the dorsal and medial raphe nuclei (DR/MR). (b) In Parkinsonian conditions (i.e., unilateral 6-hydroxydopamine lesion in rats, 6-OHDA rats), the neurodegeneration of DA neurons leads to undetectable levels of DA in any brain region examined. (c) In the absence of DA neurons, L-DOPA is decarboxylated into DA, stored into exocytosis vesicles, and released in the extracellular space by serotonergic neurons. In such physiopathological condition, an acute administration of L-DOPA at the low therapeutic dose of 3 mg/kg induces a homogeneous increase in DA concentrations in all brain regions (see values in the square box). These concentrations are 2, 2.5, and 5 times higher than in physiological conditions in the SNr, PFC, and HIPP, respectively, while they are 5 times lower in the STR. (d) An acute administration of L-DOPA at the moderate therapeutic dose of 12 mg/kg increases DA concentrations in the STR within the range of physiological values. Similar concentrations of DA are observed in the SNr and corresponded to >25 times the physiological concentrations. In the PFC and HIPP, DA concentrations are >10 times higher than in physiological conditions. (e) After a chronic L-DOPA treatment at a dose known to induce dyskinesias in all 6-OHDA rats (12 mg/kg/day for 10 days), basal DA concentrations remain below the detection limit in all brain regions. All biochemical 5-HT indexes (extracellular and tissue levels of 5-HT and its metabolite 5-HIAA) are decreased after chronic L-DOPA treatment, suggesting that 5-HT neurons suffer from chronic exposure to L-DOPA. Numerous data provide evidence for a 5-HT sprouting occurring specifically in the striatum [55, 56]. (f) After a chronic L-DOPA treatment (12 mg/kg/day for 10 days), a subsequent administration of 3 mg/kg L-DOPA is less efficient to increase DA release in the SNr, PFC, and HIPP compared to an acute administration of the same dose in L-DOPA-naïve 6-OHDA rats (see (c)). The ability of L-DOPA to increase DA levels is reduced by 43%, 68%, and 45% in the SNr, PFC, and HIPP, respectively. However, the efficacy of L-DOPA is not altered in the STR as DA levels reached similar concentrations in both L-DOPA-treated and L-DOPA-naïve 6-OHDA rats. (g) The ability of L-DOPA at 12 mg/kg to increase DA release is diminished in all brain regions after chronic L-DOPA treatment (12 mg/kg/day for 10 days). The highest loss of efficacy is observed in the SNr (−92%), then in the HIPP (−79%) and the PFC (62%). By comparison, the efficacy of L-DOPA remained mostly preserved in the STR (−50%), an effect that may be related to the striatal 5-HT hyperinnervation [55].

3. Changes in 5-HT Transmission Associated with L-DOPA Treatment

L-DOPA, by entering 5-HT neurons, mediates numerous changes in 5-HT neuron homeostasis [45]. The production of massive amounts of DA has tremendous impact on 5-HT function at the level of the metabolism, the activity, and the morphology of 5-HT neurons (Table 1). Changes in 5-HT indexes have been associated with the emergence of LIDs (Table 2). Such changes may represent critical indicators of the physiopathological state of the Parkinsonian brain that should be taken into consideration to better control 5-HT transmission and L-DOPA’s side effects [24, 82, 83].


Animal modelL-DOPA treatmentBiochemical 5-HT indexes% of changeReference

[3H]-5-HT preloaded rat10 μM[3H]-5-HT release+60%[25, 29, 30]
midbrain slices
naive ratsintra-SNr 5 μMext 5-HT: STR and SNr+55% in STR [71]
+102% in SNr
6-OHDA rats3, 6, 12, 100 mg/kg/d ipext 5-HT: STR, SNr, HIPP, PFC3:
6: STR/PFC , SNr −22%, [31] + unpublished observations
HIPP −27%
12: STR/HIPP , SNr −17%,
PFC −27%
100: STR/SNr/HIPP , PFC −28%
tiss 5-HT: STR3–12: [31]
100:−73%
6-OHDA rats12 mg/kg/d ip 14 dext 5-HT and 5-HIAA: STR, SNr, HIPP,5-HT: STR −39%, SNr −45%,[45]
PFCHIPP −29%, PFC –47%
5-HIAA: STR −32%, SNr −58%,
HIPP −44%, PFC −51%
tiss 5-HT and 5-HIAA: STR and CX5-HT: STR −48%, CX −63%,
5-HIAA: STR −67%,
CX −73%
6-OHDA rats6 mg/kg/d ip 14 dext 5-HT and 5-HIAA: STR and SNr5-HT: STR-LID +125%,
STR-LND +75%; SNr-LID +104%,
SNr-LND +108%
5-HIAA: STR-LID −30%,
STR-LND −73%; SNr-LID −28%, SNr-LND −37%
[48]
tiss 5-HT and 5-HIAA: STR and SNr5-HT: STR-LID −32%,
STR-LND −78%
5-HIAA: STR-LND −76%
6-OHDA rats6 mg/kg/d ip 14 dtiss 5-HT: STR−48% [61]
6-OHDA rats6 mg/kg/d ip 21 dtiss 5-HT: STR+150% [72]

Animal modelL-DOPA treatmentMorphological 5-HT indexes% of changeReference

6-OHDA rats5 mg/kg/d ip 14 dSERT immunoreactivity: STR+266% [73]
6-OHDA rats6 mg/kg/d ip 21 d5-HT immunoreactivity: STR+70% in STR-LID
in STR-LND [74]
6-OHDA rats6 and 50 mg/kg/d ip 14–21 dSERT-binding density: STR and CX6: STR +37.5%, CX +75%
50: STR +87.5%, CX +125%
5-HT immunoreactivity: number of6: +125%
varicosities, STR50: +200%[55]
5-HT immunoreactivity: synapse6: +155%
incidence in STR
MPTP monkeysModopar (4 : 1) 15–20 mg/kg poSERT-binding density: PUT and GPPUT-LID +72%, GP-LID +400%, LND
6–8 m [55]
MPTP monkeys12.5 mg/kg/d po 1 mTPH immunoreactivity: STR and GPSTR: increased number and size of varicosities and
enlargement
GP: enlargement in GPi/e + increased number of varicosities and length of fibres in GPe [56]

Animal modelL-DOPA treatmentMolecular 5-HT indexes% of changeReference

6-OHDA mice and rats(1) mice: 50 mg/kg/d ip 28 d5-HT1BR binding: STR, GP and SNr(1) STR +20%, GP , SNr +30%
(2) rat: 100 mg/kg 2×d ip 5 d
(3) rat: 10 mg/kg/d ip 28 d
(2) STR +17%, GP +38%, SNr + 61%
(3) STR +25%, GP , SNr +55%
[75]
6-OHDA rats100 mg/kg 2×d ip 5 d5-HT1BR protein: STR+33% [75]
6-OHDA rats100 mg/kg 2×d ip 5 d5-HT2AR mRNA: STR−57%
5-HT2CR mRNA: STR and STN[76]
MPTP monkeysModopar5-HT1AR-binding: STR, premotor-motoracute:
acute: 14.6 mg/kg poCX, HIPPchronic: +140% in Caud matrix [77]
chronic: 14.6 mg/kg 2×d po 120 d
MPTP monkeysProlopa 100/25 mg/kg po 1 m5-HT2AR binding: STR and PFC+58% in DM Caud[78]
PD patients (LIDs)5-HT2CR binding: SNr+108% [79, 80]

6-OHDA: 6-hydroxydopamine; MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; ip: intraperitoneal; sc: subcutaneous; po: oral; d: day; m: month; 2×d: twice a day; tiss: tissue; ext: extracellular; 5-HT: serotonin; 5-HIAA: 5-hydroxyindolacetic acid; AADC: amino acid decarboxylase; SERT: serotonergic transporter; 5-HT1AR: serotonin 1A receptor; 5-HT1BR: serotonin 1B receptor; 5-HT2AR: serotonin 2A receptor; 5-HT2CR: serotonin 2C receptor; STR: striatum; CX: cortex; PFC: prefrontal cortex; HIPP: hippocampus; SNr: substantia nigra pars reticulata; PUT: putamen; PFC: prefrontal cortex; STN: subthalamic nucleus; GPi/e: globus pallidus, internal/external part; DM Caud: dorsomedial caudate nucleus; LID: L-DOPA-treated dyskinetic animals; LND: L-DOPA-treated nondyskinetic animals; LIDs: L-DOPA-induced dyskinesias.

Animal modelL-DOPA treatmentBiochemical 5-HT indexesLID versus LND (R)Reference

6-OHDA rats6 mg/kg/d ip 14 dtiss 5-HT: STR and CXLID > LND
R = 0.73 in CX
[84]
6-OHDA rats12 mg/kg/d sc 5 dtiss 5-HT (5,7-DHT): STRR = 0.713 [85]
6-OHDA rats6 mg/kg/d sc 14 dext and tiss 5-HT and 5-HIAA: STR and SNrLID > LND in STR [48]
6-OHDA rats6 mg/kg/d ip 21 dtiss 5-HT: STRLID > LND
R = −0.655
[72]

Animal modelL-DOPA treatmentMorphological 5-HT indexesLID versus LND (R)Reference

6-OHDA rats5 mg/kg/d ip 14 dSERT immunoreactivity: STRLID > LND [73]
6-OHDA rats6 mg/kg/d ip 21 d5-HT immunoreactivity and AADC levels: STRLID > LND [74]
6-OHDA rats6 and 50 mg/kg/d ip 14–21 dSERT-binding density: STR and CXLID > LND, R = 0.796 in STR [55]
MPTP monkeysModopar (4 : 1) 15–20 mg/kg po 6–8 mSERT-binding density: PUT and GPLID > LND in PUT [55]

Animal modelL-DOPA treatmentMolecular 5-HT indexesLID versus LND (R)Reference

MPTP monkeysProlopa 100/25 mg/kg po 1 m5-HT2AR-binding: STR and PFCLID > LND in DM Caud and anterior cingulate gyrus [78]

6-OHDA: 6-hydroxydopamine; MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; ip: intraperitoneal; sc: subcutaneous; po: oral; d: day; m: month; tiss: tissue; ext: extracellular; 5-HT: serotonin; 5-HIAA: 5-hydroxyindolacetic acid; 5,7-DHT: 5,7-dihydroxytryptamine; AADC: amino acid decarboxylase; SERT: serotonergic transporter; 5-HT2AR: serotonin 2A receptor; STR: striatum; CX: cortex; SNr: substantia nigra pars reticulata; PUT: putamen; PFC: prefrontal cortex; GP: globus pallidus; DM Caud: dorsomedial caudate nucleus; LID: L-DOPA-treated dyskinetic animals; LND: L-DOPA-treated nondyskinetic animals; R: correlation.
3.1. Impact of L-DOPA on 5-HT Transmission

Since the beginning of the 70’s, numerous evidences started accumulating for an alteration of 5-HT neuron activity in response to L-DOPA (Table 1) [8688]. The first report in 1970 by Ng et al. [25] showed that L-DOPA-enhanced [3H]-5-HT release from [3H]-5-HT preloaded midbrain slices. This increase in 5-HT release has been later confirmed in vivo by local administration of L-DOPA in the substantia nigra [71, 89]. The potent increase in 5-HT levels observed in these studies has been suggested to account for a nonexocytotic efflux of 5-HT via 5-HT transporters due to the strong displacement of 5-HT from exocytosis vesicles by the newly synthesized DA [24]. However, recent data using systemic administration of L-DOPA at moderate doses (3–12 mg/kg) have reported distinct effects on 5-HT release depending on the dose and the brain region dialysated. While an acute injection of 12 mg/kg L-DOPA decreases 5-HT extracellular levels in the PFC and SNr, a biphasic effect was observed in the HIPP and no effect in the striatum [44, 45]. A transient increase in 5-HT levels has been observed only after the very high dose of 100 mg/kg in all brain regions (Navailles et al., unpublished observation; see Table 1). Different mechanisms could be triggered regarding the dose of L-DOPA used (exocytotic versus nonexocytotic) while the region-dependent effects of L-DOPA on 5-HT release may reflect the anatomo-functional heterogeneity of 5-HT terminals [24].

After a chronic L-DOPA treatment (12 mg/kg/day for 10 days), the reactivity of 5-HT terminals to a subsequent challenge of L-DOPA (3–12 mg/gk) was further modified in a region-dependent manner [45]. The inhibitory effect of L-DOPA at 3 and 12 mg/kg on 5-HT release was potentiated in the SNr and HIPP of L-DOPA-treated rats but not in the PFC. In the striatum of L-DOPA-treated rats, 5-HT release remained unaltered by L-DOPA whatever the dose used. Interestingly, this region-dependent reactivity of 5-HT terminals appears to correlate with the ability of L-DOPA to increase DA release after a chronic treatment (see Section 2). Of particular interest, the lack of sensitivity of striatal 5-HT terminals to L-DOPA on 5-HT release is associated with a preserved increase in L-DOPA-induced DA release while the highest sensitivity of 5-HT terminals observed in the SNr leads to the most profound loss of efficacy of L-DOPA to increase DA release [45]. This imbalance between the striatum and the SNr could not be unmasked after a chronic treatment with L-DOPA at 6 mg/kg, which did not change the effect of L-DOPA on 5-HT release [48]. Nevertheless, it appears that, for a moderate though therapeutic dose of L-DOPA (12 mg/kg), its effects on DA transmission occur in detriment of 5-HT transmission [45]. The distinct molecular (variable expression and sensitivity to 5-HT1A/1B receptors, SERT, VGLUT3, cation channels) [9097], anatomical (originating from the medial or dorsal raphe nuclei) [46, 98], ontogenesis (pet1-dependent versus pet1-resistant 5-HT neurons) [99, 100] characteristics of 5-HT neurons projecting to these different brain regions may participate in this region-dependent changes in 5-HT and DA releases [24]. In addition, chronic L-DOPA treatment by itself also alters the morphology of these 5-HT neurons and the synaptic plasticity in various brain regions (Table 1) [55, 56, 101104], an effect that may participate in the imbalanced 5-HT and DA transmissions within structures in the Parkinsonian brain and favor the onset of LIDs (see below).

Beyond the changes of 5-HT release (Table 1), chronic L-DOPA also alters 5-HT transmission by modifying the expression and function of numerous 5-HT receptors. Studies that aimed at improving L-DOPA’s effects have focused on 5-HT1A/1B receptors. Although a decrease in 5-HT1A receptor expression in the dorsal raphe (and hippocampus) [105, 106] may be directly linked to the loss of 5-HT neurons in Parkinsonian patients [107111], an increase has been described in the neocortex of Parkinson’s disease patients [112], the putamen [105], caudate nucleus, and middle layers of premotor-motor cortices of MPTP-treated monkeys [77]. Although it remains difficult to attribute these effects to the progression of the disease or to L-DOPA therapy in Parkinsonian patients [107, 113], a massive increase in 5-HT1A receptor binding could be observed in the caudate nucleus of L-DOPA-treated MPTP-lesioned monkeys [77]. No alteration in 5-HT1B binding has been observed in the striatum and substantia nigra of Parkinsonian patients [114] and 6-OHDA rats [115] while an increase in 5-HT1B receptor expression in these brain regions has been reported after chronic L-DOPA treatment in 6-OHDA-lesioned rats [75]. Other 5-HT receptors such as 5-HT2A and 5-HT2C receptors have been proposed to improve L-DOPA therapy in Parkinson’s disease [69, 79, 116119]. These receptors are known to be sensitive to chronic alteration of DA transmission [119122]. However, the few data available have reported conflicting results. 5-HT2A receptor expression has been shown to increase in the striatum of 6-OHDA rats [76] and the neocortex of Parkinsonian patients [112] while it did not change in the putamen and PFC of MPTP-treated monkeys [78]. Although L-DOPA reversed the increase in the striatum of 6-OHDA rats [76], it increased 5-HT2A receptor binding in the dorsomedial caudate nucleus of MPTP-treated monkeys [78]. 5-HT2C receptor expression was decreased in the striatum but not in the subthalamic nucleus of 6-OHDA rats without any change after L-DOPA treatment [76]. However, the increased expression of 5-HT2C receptors in the substantia nigra pars reticulata in Parkinsonian patients [80] appears to participate in the overactivity of this brain region by dampening the antiparkinsonian action of DA drugs in 6-OHDA rats primed with L-DOPA [120, 121]. Altogether, these data indicate that chronic L-DOPA treatment alters 5-HT function and the resulted changes in 5-HT markers have been mostly associated with the genesis and expression of LIDs.

3.2. Biochemical, Morphological, and Molecular Changes in 5-HT Indexes Associated with LIDs

Changes in 5-HT indexes have recently gained growing importance as they may reflect fluctuations in L-DOPA-induced DA release from 5-HT neurons that have been associated with the emergence of LIDs (Table 2) [61, 62]. In this attempt, most studies have focused on modifications of tissue and extracellular levels of 5-HT together with changes in 5-HT terminals density and morphology in 6-OHDA rats developing or not dyskinesias after a chronic treatment with 6 mg/kg of L-DOPA. Conflicting results, however, have emerged regarding 5-HT tissue and extracellular levels. Independently of the emergence of LIDs, chronic L-DOPA treatment either reduced [45, 48, 61], did not affect [72, 78], or tended to increase [84] 5-HT tissue and extracellular levels in the striatum. In most studies, however, tissue and extracellular 5-HT levels in the striatum and the cortex, but not the SNr, of rats developing LIDs were significantly higher than in nondyskinetic rats [48, 72, 84] suggesting a positive correlation to LIDs. Accordingly, Eskow et al. [85], by using selective 5,7-DHT lesions that are known to abolish both LIDs [61] and L-DOPA-induced DA release [31], could establish a positive correlation between striatal 5-HT levels and LIDs. These results are in contrast with the study by Gil et al. [72] in which 5-HT tissue levels were negatively correlated to axial, limb, and orolingual abnormal involuntary movements (AIMs). Interestingly, Carta et al. [84] could not establish a link between striatal 5-HT levels but did observe a positive correlation between 5-HT levels in the PFC and AIMs providing further evidence for a role of 5-HT function beyond the striatum in the emergence of LIDs.

In support of an increased 5-HT function in the genesis of LIDs, chronic L-DOPA treatment has been shown to increase AADC protein expression without increasing tyrosine hydroxylase expression in the lesioned-side striatum of dyskinetic rats [74]. This effect was associated with a higher 5-HT immunoreactivity compared to nondyskinetic animals, highlighting an increased 5-HT fiber density mediated by L-DOPA [74]. In line with this, Rylander et al. [55] have shown that chronic L-DOPA induced a dose-dependent increase in SERT-binding densities on the lesioned striatum (and motor-premotor cortices) that was associated with an increased number of striatal 5-HT varicosities but not with an increase in the number of 5-HT cell bodies or expression of SERT mRNA in raphe cells. Both striatal SERT binding and number of 5-HT varicosities correlated positively with the AIMs scores, showing that L-DOPA induced a sprouting of striatal 5-HT terminals in dyskinetic animals [55]. Furthermore, SERT-immunoreactive varicosities displayed larger synaptic incidence with striatal neurons and resulted in larger amount of stimulated (KCl evoked) [3H]-DA release in striatal slices from L-DOPA-treated dyskinetic rats [55]. However, Lundblad et al. [73] failed to correlate the higher 5-HT nerve density in the lesioned striatum of dyskinetic rats with the magnitude of KCl-evoked DA release measured in vivo by chronoamperometry after chronic L-DOPA treatment. Although SERT binding was decreased in the putamen and globus pallidus (GP) of MPTP-treated monkeys [55], a marked hyperinnervation of TPH-positive fibers (increase in number and diameter of TPH-positive axon varicosities) was observed in the dorsal caudate and putamen, but not the GP of MPTP-intoxicated monkeys [56]. Nevertheless, using both 5-HT markers, these studies have consistently shown an elevated SERT binding and a further increase in the number and enlargement of TPH positive axonal varicosities in caudate nucleus and putamen of MPTP-treated monkeys that develop LIDs [55, 56]. In Parkinsonian patients, SERT-binding levels were also significantly increased in both the putamen and GP of dyskinetic patients [55]. Regarding the lifetime L-DOPA medication, results indicate that patients with highest levels of SERT binding were those developing LIDs earliest during their PD treatment [55]. However, by using another marker of serotonin transporter (11C-DASP) in PET, Politis et al. [123] could not establish a correlation between 11C-DASP binding and exposure to dopaminergic therapy. Altogether, these data suggest that L-DOPA pharmacotherapy induced a maladaptive plasticity of 5-HT axon terminals that may predispose to LIDs. Indeed, the 5-HT hyperinnervation together with marked hypertrophy of 5-HT axon varicosities may worsen the fluctuations of L-DOPA-induced DA release [48, 55, 56, 59].

The combination of 5-HT1A and 5-HT1B agonists provides useful pharmacological manipulation to reduce the large increases in DA efflux and the occurrence of LIDs [48, 61, 124]. Their efficacy is reached when combining subthreshold doses of 5-HT1A and 5-HT1B agonists that are thought to activate presynaptic 5-HT1 receptors and dampen the release of L-DOPA-derived DA from 5-HT neurons [64]. The stimulation of postsynaptic 5-HT1 receptors on non-5-HT neurons may also contribute to their antidyskinetic effect by modulating GABA and glutamate release [64]. However, adverse effects involving the stimulation of postsynaptic 5-HT1A receptors could worsen their therapeutic efficacy [125, 126]. Some studies have identified specific changes induced by chronic L-DOPA treatment on 5-HT1B postsynaptic receptors that may be directly involved in the development of LIDs. Chronic L-DOPA treatment increased the expression of 5-HT1B receptors and its adaptor protein p11 at striatonigral neurons [75]. The ability of 5-HT1B agonist to reduce LIDs was p11 dependent [75]. Moreover, in L-DOPA-treated 6-OHDA rats that recovered from AIMs after a chronic treatment with citalopram (a selective serotonergic reuptake inhibitor, SSRI), the expression of 5-HT1B receptors in the striatum was almost fully abolished [127]. The authors could reveal a positive correlation between the decreased anxiety induced by citalopram and its ability to reduce AIMs that involves a marked reduction in 5-HT1B receptor expression (Table 2). However, in keeping with data obtained in the study by Zhang et al. [75], the reduction of LIDs by citalopram may not solely account for its effect on 5-HT1B receptor expression but may also involve the ability of citalopram to abolish L-DOPA-induced DA release [31]. Nevertheless, these data allow identifying a new association between 5-HT1B receptors and LIDs. A recent work could also highlight a relationship between 5-HT2A receptors and LIDs in MPTP-treated monkeys [78]. [3H]Ketanserin-specific binding to 5-HT2A receptors was increased in the dorsomedial caudate nucleus and anterior cingulated gyrus of dyskinetic L-DOPA-treated MPTP-intoxicated monkeys, an effect reversed by drugs inhibiting the expression of LIDs. The authors could reveal a positive correlation between the maximal dyskinesia scores at the end of L-DOPA treatment and 5-HT2A receptor-specific binding in the anterior and posterior caudate nucleus as well as the nucleus accumbens [78].

Despite the high degree of variability observed in the changes of 5-HT markers across studies performed in different animal models and Parkinsonian patients, the available data to date allow establishing a clear role of the 5-HT system in the induction and maintenance of LIDs. The numerous 5-HT indexes used could provide interesting insights into the mechanisms of action of L-DOPA in mediating LIDs. However, the failure to fully correlate one change in 5-HT markers with a complex behavior such as LIDs may encourage future studies to reconsider the heterogeneity and the widespread influence of the 5-HT system as a whole fundamental index in the genesis of LIDs. Indeed, the numerous changes in 5-HT function induced by L-DOPA in multiple brain regions may concur in synergy to an imbalanced DA transmission that may participate in the emergence of LIDs.

4. Functional Outcomes of 5-HT Neuron-Mediated DA Transmission in LIDs

Because the 5-HT terminals are responsible for the gross increase in DA, leading to a homogeneous and ectopic release of DA in the brain, one may wonder the extent to which the striatum is involved in the therapeutic benefit of L-DOPA. It is far from our purpose to rule out many years of research centred on striatal DA transmission, but it is important to conceive that other brain regions play an important role in motor responses induced by L-DOPA. The main argument to look beyond the striatum is the success of the deep brain stimulation of the subthalamic nucleus in Parkinson patients, a surgical approach of the disease that does not rely on striatal DA release.

4.1. Role of Imbalanced Cortical-Subcortical DA Transmission in Motor Output

It is a common sense to reaffirm that DA transmission is altered in PD and that the relationships between DA transmission, symptoms severity, and medication coevolve with the deleterious progression of the disease. Nonetheless, adding the evidence that 5-HT neurons participate in the raise of extracellular DA offers a larger picture of the putative scenarios. In early stages of the disease, the presence of spared DA terminals and DAT in the striatum limits the excessive increase in DA extracellular levels induced by L-DOPA from 5-HT neurons. However, the increase in DA from 5-HT terminals in the striatum likely introduces a noise in the “coherent” DA transmission. Indeed, this aberrant release is not regulated while the “coherent” release from spared DA neurons is impaired due to the inhibitory effect of electrical activity of L-DOPA on DA neurons activity [19]. The more the disease progresses, the higher should be the contribution of 5-HT neurons in L-DOPA-induced DA release. Thus, even in the early stages of the disease, it is noticeable that L-DOPA is efficient to treat the core symptoms of the disease (tremor, bradykinesia, rigidity, posture) but has limited effects on precise coordinated movements or some impaired cognitive functions [128]. In the advanced stages of the disease, spared DA neurons are no longer able to buffer excessive swings of DA released from 5-HT neurons, a condition favoring motor fluctuations and LIDs [61].

Whatever the stage of the disease, the small release of DA from 5-HT neurons has potentially a larger impact beyond the striatum where DAT are poorly expressed. The impact may also be magnified due to altered pattern of activities found in extrastriatal territories such as the cortex or the HIPP. Indeed, numerous studies in humans using functional imaging have reported changes in activities in several cortical territories and the HIPP [129]. These brain areas expressing substantial amount of DA receptors [50], the excessive increase in DA release induced by L-DOPA in these territories could have a higher impact on the functions exerted by these brain regions. Of note, it has been described for many years that an increase in cortical DA may counteract aberrant DA signaling in subcortical areas. For instance, the catalepsy induced by the DA antagonist haloperidol, a rat model of Parkinsonism, is reversed by the direct infusion of DA into the PFC. Moreover, the increase in DA release induced by L-DOPA is very high in the SN, one of the brain regions receiving the strongest 5-HT innervation [46], and it has been shown for several years that the SN directly participates in the motor effects of L-DOPA in the 6-OHDA rat model of Parkinson’s disease [68, 130].

The minimal release of striatal DA after therapeutic doses of L-DOPA could be compensated by an increase in D2 receptor efficiency. An increase in striatal D2 receptors has been reported in early stages of the disease, but some data have reported that DA “replacement” therapy reduced the excessive expression of striatal D2 receptors to levels comparable to matched controls [131, 132]. Based on the neurochemical data in the 6-OHDA rat model of Parkinson’s disease, the benefit of L-DOPA could be an uneven release of DA or a hypodopaminergy in the striatum combined with an extrastriatal hyperdopaminergy.

4.2. Role of Imbalanced Cortical-Subcortical DA Transmission in LIDs

The increase in DA release induced by L-DOPA has been directly incriminated in LIDs [133]. Our data showing that chronic treatment with L-DOPA is associated with a dramatic loss of DA release in various rat brain areas compared to the striatum [45] points to an inverse schema. First, the inhibitory tone provided by cortical DA upon subcortical DA function would be lowered after chronic treatment, and subcortical DA release by 5-HT fibers would be preserved due to some sprouting of striatal 5-HT fibers [55, 56]. The situation is not known for several brain regions though it has been reported that LIDs in rodents is associated with an increase in c-Fos expression in the STN [134]. Besides, chronic L-DOPA treatment has been shown to increase c-Fos expression also in the cortex and globus pallidus [135, 136]. In addition, excessive DA tone in some brain regions other than the striatum may promote abnormal involuntary movement of the face, one clinical manifestation reported in LIDs in primates and rodents [79]. Second, the aberrant release of DA via 5-HT neurons would favor abnormal learning, at least in the striatum. Indeed, DA is critically involved in procedural learning, and LIDs is thought to result in part from aberrant molecular events at the level of medium spiny neurons of the striatum that involve DA receptors [104, 137, 138]. The postulated pathological form of synaptic plasticity may occur in the different territories of the striatum. It has been reported in MPTP-treated monkeys that LID involved not only the sensorimotor part of the striatum, but also its associative and limbic territories [139]. Third, as noted above, 5-HT processes could be involved as well [122, 140], particularly in considering that the “coherent” 5-HT transmission is altered by L-DOPA [24]. As for DA transmission, alteration in 5-HT transmission occurring elsewhere than the sensorimotor part of the striatum may promote abnormal movements in rodents [122, 141].

In a therapeutic point of view, one possibility is to limit the excessive DA transmission by administering a neuroleptic at risk of generating Parkinsonism. Nevertheless, the atypical neuroleptic clozapine has been shown to limit dyskinesia without aggravating the motor score [117]. It is difficult to interpret the origin of its efficacy as clozapine or other atypical antipsychotic drugs may slightly block subcortical DA transmission and enhance cortical DA transmission [142, 143]. Similar effects could account for the proposed efficacy of the antipsychotic and partial DA agonist drug aripiprazole [144]. According to the hypothesis above, treatment that is enhancing DA transmission in the cortex, that would limit the impact of cortico-subcortical glutamate transmission [145], could be a focus of future strategy against LIDs. It is noticeable that blockers of the N-methyl-d-aspartate receptor such as amantadine can also limit LIDs in patients [146].

The direct control of striatal DA transmission via 5-HT drugs is difficult to manage because the biochemical and behavioral relationships between 5-HT receptors and DA transmission are not well understood [147]. The use of 5-HT drugs able to control 5-HT nerve activity, to control the output of DA from 5-HT neurons, is a great opportunity, and clinical trials are currently underwent to alleviate LIDs using this strategy. The limit of this approach is that 5-HT drugs used may also act directly on cells other than 5-HT neurons due to the widespread distribution of 5-HT receptors in the brain. Also, a general decrease in DA release from 5-HT neurons may counteract dyskinesia and aggravate Parkinsonism [148153]. Again, 5-HT drugs could be used to reinforce the initial imbalance created by L-DOPA, namely, the quite homogeneous pattern of DA release induced by L-DOPA, through cortical mechanisms.

5. Conclusion

The consideration of the 5-HT system in the core mechanism of action of L-DOPA opens many opportunities to better apprehend LIDs and to propose diverse therapeutic strategies in the treatment of LIDs. The excess of striatal DA released by L-DOPA remains an important preoccupation, but the possibility to facilitate DA transmission in the cortex could be also an interesting strategy. Additional studies are warranted to further study the imbalance of DA transmission promoted by the intervention of 5-HT neurons in the mechanism of action of L-DOPA to propose additional brain targets.

Acknowledgments

This work was supported by grants from “Centre National de la Recherche Scientifique” and the University of Bordeaux. The authors wish to thank the “Fondation de France” for the financial support and the “Société Française de Physiologie” for the award attributed to Sylvia Navailles in 2010.

References

  1. E. R. Dorsey, R. Constantinescu, J. P. Thompson et al., “Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030,” Neurology, vol. 68, no. 5, pp. 384–386, 2007. View at: Publisher Site | Google Scholar
  2. O. Hornykiewicz, “Dopamine (3-hydroxytyramine) and brain function,” Pharmacological Reviews, vol. 18, no. 2, pp. 925–964, 1966. View at: Google Scholar
  3. H. Bernheimer, W. Birkmayer, O. Hornykiewicz, K. Jellinger, and F. Seitelberger, “Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations,” Journal of the Neurological Sciences, vol. 20, no. 4, pp. 415–455, 1973. View at: Publisher Site | Google Scholar
  4. G. C. Cotzias, “L-Dopa for Parkinsonism,” New England Journal of Medicine, vol. 278, no. 11, p. 630, 1968. View at: Google Scholar
  5. O. Hornykiewicz, “Dopamine in the basal ganglia. Its role and therapeutic implications (including the clinical use of L-DOPA),” British Medical Bulletin, vol. 29, no. 2, pp. 172–178, 1973. View at: Google Scholar
  6. J. E. Ahlskog and M. D. Muenter, “Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature,” Movement Disorders, vol. 16, no. 3, pp. 448–458, 2001. View at: Publisher Site | Google Scholar
  7. J. Jankovic, “Motor fluctuations and dyskinesias in Parkinson's disease: clinical manifestations,” Movement Disorders, vol. 20, no. 11, pp. S11–S16, 2005. View at: Publisher Site | Google Scholar
  8. M. Lundblad, M. Andersson, C. Winkler, D. Kirik, N. Wierup, and M. A. Cenci Nilsson, “Pharmacological validation of behavioural measures of akinesia and dyskinesia in a rat model of Parkinson's disease,” European Journal of Neuroscience, vol. 15, no. 1, pp. 120–132, 2002. View at: Publisher Site | Google Scholar
  9. M. A. Cenci and K. E. Ohlin, “Rodent models of treatment-induced motor complications in Parkinson's disease,” Parkinsonism and Related Disorders, vol. 15, supplement 4, pp. S13–S17, 2009. View at: Publisher Site | Google Scholar
  10. U. Ungerstedt, “6-hydroxy-dopamine induced degeneration of central monoamine neurons,” European Journal of Pharmacology, vol. 5, no. 1, pp. 107–110, 1968. View at: Google Scholar
  11. M. Olsson, G. Nikkhah, C. Bentlage, and A. Bjorklund, “Forelimb akinesia in the rat Parkinson model: differential effects of dopamine agonists and nigral transplants as assessed by a new stepping test,” Journal of Neuroscience, vol. 15, no. 5, pp. 3863–3875, 1995. View at: Google Scholar
  12. M. A. Cenci, “L-DOPA-induced dyskinesia: cellular mechanisms and approaches to treatment,” Parkinsonism and Related Disorders, vol. 13, no. 3, pp. S263–S267, 2007. View at: Publisher Site | Google Scholar
  13. U. Ungerstedt, “Postsynaptic supersensitivity after 6-hydroxy-dopamine induced degeneration of the nigro-striatal dopamine system,” Acta Physiologica Scandinavica, vol. 367, supplement, pp. 69–93, 1971. View at: Google Scholar
  14. U. Ungerstedt, “Striatal dopamine release after amphetamine or nerve degeneration revealed by rotational behaviour,” Acta Physiologica Scandinavica, vol. 367, supplement, pp. 49–68, 1971. View at: Google Scholar
  15. T. Zetterstrom, M. Herrera-Marschitz, and U. Ungerstedt, “Simultaneous measurement of dopamine release and rotational behaviour in 6-hydroxydopamine denervated rats using intracerebral dialysis,” Brain Research, vol. 376, no. 1, pp. 1–7, 1986. View at: Google Scholar
  16. B. S. Bunney, G. K. Aghajanian, and R. H. Roth, “Comparison of effects of L dopa amphetamine and apomorphine on firing rate of rat dopaminergic neurones,” Nature New Biology, vol. 245, no. 143, pp. 123–125, 1973. View at: Google Scholar
  17. N. B. Mercuri, P. Calabresi, and G. Bernardi, “Responses of rat substantia nigra compacta neurones to L-DOPA,” British Journal of Pharmacology, vol. 100, no. 2, pp. 257–260, 1990. View at: Google Scholar
  18. D. G. Harden and A. A. Grace, “Activation of dopamine cell firing by repeated L-DOPA administration to dopamine-depleted rats: its potential role in mediating the therapeutic response to L-DOPA treatment,” Journal of Neuroscience, vol. 15, no. 9, pp. 6157–6166, 1995. View at: Google Scholar
  19. T. Maeda, K. Kannari, T. Suda, and M. Matsunaga, “Loss of regulation by presynaptic dopamine D2 receptors of exogenous L- DOPA-derived dopamine release in the dopaminergic denervated striatum,” Brain Research, vol. 817, no. 1-2, pp. 185–191, 1999. View at: Publisher Site | Google Scholar
  20. D. W. Miller and E. D. Abercrombie, “Role of high-affinity dopamine uptake and impulse activity in the appearance of extracellular dopamine in striatum after administration of exogenous L-DOPA: studies in intact and 6-hydroxydopamine-treated rats,” Journal of Neurochemistry, vol. 72, no. 4, pp. 1516–1522, 1999. View at: Publisher Site | Google Scholar
  21. S. Sarre, N. De Klippel, P. Herregodts, G. Ebinger, and Y. Michotte, “Biotransformation of locally applied L-dopa in the corpus striatum of the hemi-Parkinsonian rat studied with microdialysis,” Naunyn-Schmiedeberg's Archives of Pharmacology, vol. 350, no. 1, pp. 15–21, 1994. View at: Google Scholar
  22. K. Kannari, H. Tanaka, T. Maeda, M. Tomiyama, T. Suda, and M. Matsunaga, “Reserpine pretreatment prevents increases in extracellular striatal dopamine following L-DOPA administration in rats with nigrostriatal denervation,” Journal of Neurochemistry, vol. 74, no. 1, pp. 263–269, 2000. View at: Publisher Site | Google Scholar
  23. W. Y. Lee, J. W. Chang, N. L. Nemeth, and U. J. Kang, “Vesicular monoamine transporter-2 and aromatic l-amino acid decarboxylase enhance dopamine delivery after L-3,4-dihydroxyphenylalanine administration in parkinsonian rats,” Journal of Neuroscience, vol. 19, no. 8, pp. 3266–3274, 1999. View at: Google Scholar
  24. S. Navailles, M. Carta, M. Guthrie, and P. De Deurwaerdere, “L-DOPA and serotonergic neurons: functional implication and therapeutic perspectives in Parkinson’s disease,” Central Nervous System Agents in Medicinal Chemistry. In press. View at: Google Scholar
  25. L. K. Ng, T. N. Chase, R. W. Colburn, and I. J. Kopin, “l-dopa-induced release of cerebral monoamines,” Science, vol. 170, no. 953, pp. 76–77, 1970. View at: Google Scholar
  26. F. Tison, N. Mons, M. Geffard, and P. Henry, “The metabolism of exogenous L-Dopa in the brain: an immunohistochemical study of its conversion to dopamine in non-catecholaminergic cells of the rat brain,” Journal of Neural Transmission, vol. 3, no. 1, pp. 27–39, 1991. View at: Google Scholar
  27. R. Arai, N. Karasawa, M. Geffard, and I. Nagatsu, “L-DOPA is converted to dopamine in serotonergic fibers of the striatum of the rat: a double-labeling immunofluorescence study,” Neuroscience Letters, vol. 195, no. 3, pp. 195–198, 1995. View at: Publisher Site | Google Scholar
  28. H. Yamada, Y. Aimi, I. Nagatsu, K. Taki, M. Kudo, and R. Arai, “Immunohistochemical detection of l-DOPA-derived dopamine within serotonergic fibers in the striatum and the substantia nigra pars reticulata in Parkinsonian model rats,” Neuroscience Research, vol. 59, no. 1, pp. 1–7, 2007. View at: Publisher Site | Google Scholar
  29. L. K. Ng, R. W. Colburn, and I. J. Kopin, “Effects of L-dopa on accumulation and efflux of monoamines in particles of rat brain homogenates,” Journal of Pharmacology and Experimental Therapeutics, vol. 183, no. 2, pp. 316–325, 1972. View at: Google Scholar
  30. L. K. Ng, T. N. Chase, R. W. Colburn, and I. J. Kopin, “L-dopa in Parkinsonism. A possible mechanism of action,” Neurology, vol. 22, no. 7, pp. 688–696, 1972. View at: Google Scholar
  31. S. Navailles, B. Bioulac, C. Gross, and P. De Deurwaerdère, “Serotonergic neurons mediate ectopic release of dopamine induced by l-DOPA in a rat model of Parkinson's disease,” Neurobiology of Disease, vol. 38, no. 1, pp. 136–143, 2010. View at: Publisher Site | Google Scholar
  32. H. Tanaka, K. Kannari, T. Maeda, M. Tomiyama, T. Suda, and M. Matsunaga, “Role of serotonergic neuron in L-DOPA-derived extracellular dopamine in the striatum of 6-OHDA-lesioned rats,” NeuroReport, vol. 10, no. 3, pp. 631–634, 1999. View at: Google Scholar
  33. K. Kannari, H. Yamato, H. Shen, M. Tomiyama, T. Suda, and M. Matsunaga, “Activation of 5-HT1A but not 5-HT1B receptors attenuates an increase in extracellular dopamine derived from exogenously administered L-DOPA in the striatum with nigrostriatal denervation,” Journal of Neurochemistry, vol. 76, no. 5, pp. 1346–1353, 2001. View at: Publisher Site | Google Scholar
  34. H. Yamato, K. Kannari, H. Shen, T. Suda, and M. Matsunaga, “Fluoxetine reduces L-DOPA-derived extracellular DA in the 6-OHDA-lesioned rat striatum,” NeuroReport, vol. 12, no. 6, pp. 1123–1126, 2001. View at: Google Scholar
  35. J. S. Sprouse and G. K. Aghajanian, “Electrophysiological responses of serotonergic dorsal raphe enurons to 5-HT1A and 5-HT1B agonists,” Synapse, vol. 1, no. 1, pp. 3–9, 1987. View at: Google Scholar
  36. F. J. Bosker, T. Y. C. E. De Winter, A. A. Klompmakers, and H. G. M. Westenberg, “Flesinoxan dose-dependently reduces extracellular 5-hydroxytryptamine (5-HT) in rat median raphe and dorsal hippocampus through activation of 5-HT1A receptors,” Journal of Neurochemistry, vol. 66, no. 6, pp. 2546–2555, 1996. View at: Google Scholar
  37. D. A. Knobelman, H. F. Kung, and I. Lucki, “Regulation of extracellular concentrations of 5-hydroxytryptamine (5- HT)in mouse striatum by 5-HT(1A) and 5-HT(1B) receptors,” Journal of Pharmacology and Experimental Therapeutics, vol. 292, no. 3, pp. 1111–1117, 2000. View at: Google Scholar
  38. M. Riad, S. Garcia, K. C. Watkins et al., “Somatodendritic localization of 5-HT1A and preterminal axonal localization of 5-HT1B serotonin receptors in adult rat brain,” Journal of Comparative Neurology, vol. 417, no. 2, pp. 181–194, 2000. View at: Publisher Site | Google Scholar
  39. T. Sharp, S. R. Bramwell, S. Hjorth, and D. G. Grahame-Smith, “Pharmacological characterization of 8-OH-DPAT-induced inhibition of rat hippocampal 5-HT release in vivo as measured by microdialysis,” British Journal of Pharmacology, vol. 98, no. 3, pp. 989–997, 1989. View at: Google Scholar
  40. A. Adell, A. Carceller, and F. Artigas, “In vivo brain dialysis study of the somatodendritic release of serotonin in the raphe nuclei of the rat: effects of 8-hydroxy-2-(di-n- propylamino)tetralin,” Journal of Neurochemistry, vol. 60, no. 5, pp. 1673–1681, 1993. View at: Google Scholar
  41. J. M. Casanovas and F. Artigas, “Differential effects of ipsapirone on 5-hydroxytryptamine release in the dorsal and median raphe neuronal pathways,” Journal of Neurochemistry, vol. 67, no. 5, pp. 1945–1952, 1996. View at: Google Scholar
  42. L. Arborelius, G. G. Nomikos, P. Grillner et al., “5-HT(1A) receptor antagonists increase the activity of serotonergic cells in the dorsal raphe nucleus in rats treated acutely or chronically with citalopram,” Naunyn-Schmiedeberg's Archives of Pharmacology, vol. 352, no. 2, pp. 157–165, 1995. View at: Google Scholar
  43. Y. Temel, L. J. Boothman, A. Blokland et al., “Inhibition of 5-HT neuron activity and induction of depressive-like behavior by high-frequency stimulation of the subthalamic nucleus,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 43, pp. 17087–17092, 2007. View at: Publisher Site | Google Scholar
  44. S. Navailles, A. Benazzouz, B. Bioulac, C. Gross, and P. De Deurwaerdère, “High-frequency stimulation of the subthalamic nucleus and L-3,4-dihydroxyphenylalanine inhibit in vivo serotonin release in the prefrontal cortex and hippocampus in a rat model of Parkinson's disease,” Journal of Neuroscience, vol. 30, no. 6, pp. 2356–2364, 2010. View at: Publisher Site | Google Scholar
  45. S. Navailles, B. Bioulac, C. Gross, and P. De Deurwaerdère, “Chronic L-DOPA therapy alters central serotonergic function and L-DOPA-induced dopamine release in a region-dependent manner in a rat model of Parkinson's disease,” Neurobiology of Disease, vol. 41, no. 2, pp. 585–590, 2011. View at: Publisher Site | Google Scholar
  46. E. C. Azmitia and M. Segal, “An autoradiographic analysis of the different ascending projections of the dorsal and median raphe nuclei in the rat,” Journal of Comparative Neurology, vol. 179, no. 3, pp. 641–667, 1978. View at: Google Scholar
  47. H. W. Steinbusch, “Serotonin-immunoreactive neurons and their projections in the CNS,” in Handbook of Chemical Neuroanatomy—Classical Transmitters and Transmitters Receptors in the CNS Part II, A. Björklund, T. Hökfelt, and M. J. Kuhar, Eds., pp. 68–125, Amsterdam,The Netherlands, 1984. View at: Google Scholar
  48. H. S. Lindgren, D. R. Andersson, S. Lagerkvist, H. Nissbrandt, and M. A. Cenci, “L-DOPA-induced dopamine efflux in the striatum and the substantia nigra in a rat model of Parkinson's disease: temporal and quantitative relationship to the expression of dyskinesia,” Journal of Neurochemistry, vol. 112, no. 6, pp. 1465–1476, 2010. View at: Publisher Site | Google Scholar
  49. J. A. Obeso, C. Marin, C. Rodriguez-Oroz et al., “The basal ganglia in Parkinson's disease: current concepts and unexplained observations,” Annals of Neurology, vol. 64, no. 2, pp. S30–S46, 2008. View at: Publisher Site | Google Scholar
  50. P. Seeman, “Brain dopamine receptors,” Pharmacological Reviews, vol. 32, no. 3, pp. 229–313, 1980. View at: Google Scholar
  51. W. D. Brown, M. D. Taylor, A. D. Roberts et al., “FluoroDOPA PET shows the nondopaminergic as well as dopaminergic destinations of levodopa,” Neurology, vol. 53, no. 6, pp. 1212–1218, 1999. View at: Google Scholar
  52. R. M. Kostrzewa, “Dopamine receptor supersensitivity,” Neuroscience and Biobehavioral Reviews, vol. 19, no. 1, pp. 1–17, 1995. View at: Publisher Site | Google Scholar
  53. J. Tong, P. S. Fitzmaurice, L. C. Ang, Y. Furukawa, M. Guttman, and S. J. Kish, “Brain dopamine-stimulated adenylyl cyclase activity in Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy,” Annals of Neurology, vol. 55, no. 1, pp. 125–129, 2004. View at: Publisher Site | Google Scholar
  54. M. R. Ahmed, A. Berthet, E. Bychkov et al., “Lentiviral overexpression of GRK6 alleviates L-Dopa-induced dyskinesia in experimental parkinson's disease,” Science Translational Medicine, vol. 2, no. 28, pp. 28–ra28, 2010. View at: Publisher Site | Google Scholar
  55. D. Rylander, M. Parent, S. S. O-Sullivan et al., “Maladaptive plasticity of serotonin axon terminals in levodopa-induced dyskinesia,” Annals of Neurology, vol. 68, no. 5, pp. 619–628, 2010. View at: Publisher Site | Google Scholar
  56. B. Y. Zeng, M. M. Iravani, M. J. Jackson, S. Rose, A. Parent, and P. Jenner, “Morphological changes in serotoninergic neurites in the striatum and globus pallidus in levodopa primed MPTP treated common marmosets with dyskinesia,” Neurobiology of Disease, vol. 40, no. 3, pp. 599–607, 2010. View at: Publisher Site | Google Scholar
  57. T. N. Chase, “Levodopa therapy: consequences of the nonphysiologic replacement of dopamine,” Neurology, vol. 50, supplement 5, pp. S17–S25, 1998. View at: Google Scholar
  58. C. W. Olanow and J. A. Obeso, “Pulsatile stimulation of dopamine receptors and levodopa-induced motor complications in Parkinson's disease: implications for the early use of COMT inhibitors,” Neurology, vol. 55, supplement 4, no. 11, pp. S72–SS77, 2000. View at: Google Scholar
  59. R. De La Fuente-Fernández, V. Sossi, Z. Huang et al., “Levodopa-induced changes in synaptic dopamine levels increase with progression of Parkinson's disease: implications for dyskinesias,” Brain, vol. 127, no. 12, pp. 2747–2754, 2004. View at: Publisher Site | Google Scholar
  60. M. A. Cenci and M. Lundblad, “Post- versus presynaptic plasticity in L-DOPA-induced dyskinesia,” Journal of Neurochemistry, vol. 99, no. 2, pp. 381–392, 2006. View at: Publisher Site | Google Scholar
  61. M. Carta, T. Carlsson, D. Kirik, and A. Björklund, “Dopamine released from 5-HT terminals is the cause of L-DOPA-induced dyskinesia in parkinsonian rats,” Brain, vol. 130, no. 7, pp. 1819–1833, 2007. View at: Publisher Site | Google Scholar
  62. M. Carta, T. Carlsson, A. Muñoz, D. Kirik, and A. Björklund, “Serotonin-dopamine interaction in the induction and maintenance of L-DOPA-induced dyskinesias,” Progress in Brain Research, vol. 172, pp. 465–478, 2008. View at: Publisher Site | Google Scholar
  63. A. Ulusoy, G. Sahin, and D. Kirik, “Presynaptic dopaminergic compartment determines the susceptibility to L-DOPA-induced dyskinesia in rats,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 29, pp. 13159–13164, 2010. View at: Publisher Site | Google Scholar
  64. A. Muñoz, T. Carlsson, E. Tronci, D. Kirik, A. Björklund, and M. Carta, “Serotonin neuron-dependent and -independent reduction of dyskinesia by 5-HT1A and 5-HT1B receptor agonists in the rat Parkinson model,” Experimental Neurology, vol. 219, no. 1, pp. 298–307, 2009. View at: Publisher Site | Google Scholar
  65. C. Marin, E. Aguilar, M. C. Rodríguez-Oroz, G. D. Bartoszyk, and J. A. Obeso, “Local administration of sarizotan into the subthalamic nucleus attenuates levodopa-induced dyskinesias in 6-OHDA-lesioned rats,” Psychopharmacology, vol. 204, no. 2, pp. 241–250, 2009. View at: Publisher Site | Google Scholar
  66. S. Sarre, P. Herregodts, D. Deleu et al., “Biotransformation of L-DOPA in striatum and substantia nigra of rats with a unilateral, nigrostriatal lesion: a microdialysis study,” Naunyn-Schmiedeberg's Archives of Pharmacology, vol. 346, no. 3, pp. 277–285, 1992. View at: Google Scholar
  67. S. Sarre, I. Smolders, K. Thorré, G. Ebinger, and Y. Michotte, “Biotransformation of locally applied precursors of dopamine, serotonin and noradrenaline in striatum and hippocampus: a microdialysis study,” Journal of Neural Transmission, vol. 104, no. 11-12, pp. 1215–1228, 1997. View at: Publisher Site | Google Scholar
  68. D. Orosz and J. P. Bennett, “Simultaneous microdialysis in striatum and substantia nigra suggests that the nigra is a major site of action of L-dihydroxyphenylalanine in the “hemiparkinsonian” rat,” Experimental Neurology, vol. 115, no. 3, pp. 388–393, 1992. View at: Publisher Site | Google Scholar
  69. V. Di Matteo, M. Pierucci, E. Esposito, G. Crescimanno, A. Benigno, and G. Di Giovanni, “Serotonin modulation of the basal ganglia circuitry: therapeutic implication for Parkinson's disease and other motor disorders,” Progress in Brain Research, vol. 172, pp. 423–463, 2008. View at: Publisher Site | Google Scholar
  70. D. B. Putterman, A. C. Munhall, L. B. Kozell, J. K. Belknap, and S. W. Johnson, “Evaluation of levodopa dose and magnitude of dopamine depletion as risk factors for levodopa-induced dyskinesia in a rat model of Parkinson's disease,” Journal of Pharmacology and Experimental Therapeutics, vol. 323, no. 1, pp. 277–284, 2007. View at: Publisher Site | Google Scholar
  71. K. Thorré, S. Sarre, I. Smolders, G. Ebinger, and Y. Michotte, “Dopaminergic regulation of serotonin release in the substantia nigra of the freely moving rat using microdialysis,” Brain Research, vol. 796, no. 1-2, pp. 107–116, 1998. View at: Publisher Site | Google Scholar
  72. S. J. Gil, C. H. Park, J. E. Lee, Y. K. Minn, and H. C. Koh, “Positive association between striatal serotonin level and abnormal involuntary movements in chronic l-DOPA-treated hemiparkinsonian rats,” Brain Research Bulletin, vol. 96, no. 6, pp. 1718–1727, 2011. View at: Publisher Site | Google Scholar
  73. M. Lundblad, S. Af Bjerkén, M. A. Cenci, F. Pomerleau, G. A. Gerhardt, and I. Strömberg, “Chronic intermittent L-DOPA treatment induces changes in dopamine release,” Journal of Neurochemistry, vol. 108, no. 4, pp. 998–1008, 2009. View at: Publisher Site | Google Scholar
  74. S. Gil, C. Park, J. Lee, and H. Koh, “The roles of striatal serotonin and l-amino-acid decarboxylase on l-DOPA-induced dyskinesia in a hemiparkinsonian rat model,” Cellular and Molecular Neurobiology, vol. 30, no. 6, pp. 817–825, 2010. View at: Publisher Site | Google Scholar
  75. X. Zhang, P. E. Andren, P. Greengard, and P. Svenningsson, “Evidence for a role of the 5-HT1B receptor and its adaptor protein, p11, in L-DOPA treatment of an animal model of Parkinsonism,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 6, pp. 2163–2168, 2008. View at: Publisher Site | Google Scholar
  76. X. Zhang, P. E. Andren, and P. Svenningsson, “Changes on 5-HT2 receptor mRNAs in striatum and subthalamic nucleus in Parkinson's disease model,” Physiology and Behavior, vol. 92, no. 1-2, pp. 29–33, 2007. View at: Publisher Site | Google Scholar
  77. P. Huot, T. H. Johnston, J. B. Koprich, L. Winkelmolen, S. H. Fox, and J. M. Brotchie, “Regulation of cortical and striatal 5-HT(1A) receptors in the MPTP-lesioned macaque,” Neurobiology of Aging. In press. View at: Publisher Site | Google Scholar
  78. G. Riahi, M. Morissette, M. Parent, and T. Di Paolo, “Brain 5-HT2A receptors in MPTP monkeys and levodopa-induced dyskinesias,” European Journal of Neuroscience, vol. 33, no. 10, pp. 1823–1831, 2011. View at: Publisher Site | Google Scholar
  79. S. L. Nicholson and J. M. Brotchie, “5-Hydroxytryptamine (5-HT, serotonin) and Parkinson's disease—opportunities for novel therapeutics to reduce the problems of levodopa therapy,” European Journal of Neurology, vol. 9, supplement 3, pp. 1–6, 2002. View at: Publisher Site | Google Scholar
  80. S. H. Fox and J. M. Brotchie, “5-HT(2C) receptor binding is increased in the substantia Nigra pars reticulata in Parkinson's disease,” Movement Disorders, vol. 15, no. 6, pp. 1064–1069, 2000. View at: Publisher Site | Google Scholar
  81. W. Meissner, P. Ravenscroft, R. Reese et al., “Increased slow oscillatory activity in substantia nigra pars reticulata triggers abnormal involuntary movements in the 6-OHDA-lesioned rat in the presence of excessive extracelullar striatal dopamine,” Neurobiology of Disease, vol. 22, no. 3, pp. 586–598, 2006. View at: Publisher Site | Google Scholar
  82. S. H. Fox, R. Chuang, and J. M. Brotchie, “Serotonin and Parkinson's disease: on movement, mood, and madness,” Movement Disorders, vol. 24, no. 9, pp. 1255–1266, 2009. View at: Publisher Site | Google Scholar
  83. B. Scholtissen, F. R. J. Verhey, J. J. Adam, W. Weber, and A. F. G. Leentjens, “Challenging the serotonergic system in Parkinson disease patients: effects on cognition, mood, and motor performance,” Clinical Neuropharmacology, vol. 29, no. 5, pp. 276–285, 2006. View at: Publisher Site | Google Scholar
  84. M. Carta, H. S. Lindgren, M. Lundblad, R. Stancampiano, F. Fadda, and M. A. Cenci, “Role of striatal L-DOPA in the production of dyskinesia in 6-hydroxydopamine lesioned rats,” Journal of Neurochemistry, vol. 96, no. 6, pp. 1718–1727, 2006. View at: Publisher Site | Google Scholar
  85. K. L. Eskow, K. B. Dupre, C. J. Barnum, S. O. Dickinson, J. Y. Park, and C. Bishop, “The role of the dorsal raphe nucleus in the development, expression, and treatment of L-dopa-induced dyskinesia in hemiparkinsonian rats,” Synapse, vol. 63, no. 7, pp. 610–620, 2009. View at: Publisher Site | Google Scholar
  86. G. Bartholini, M. Da Prada, and A. Pletscher, “Decrease of cerebral 5-hydroxytryptamine by 3,4-dihydroxyphenylalanine after inhibition of extracerebral decarboxylase,” Journal of Pharmacy and Pharmacology, vol. 20, no. 3, pp. 228–229, 1968. View at: Google Scholar
  87. G. M. Everett and J. W. Borcherding, “L-dopa: effect on concentrations of dopamine, norepinephrine, and serotonin in brains of mice,” Science, vol. 168, no. 3933, pp. 849–850, 1970. View at: Google Scholar
  88. H. Tohgi, T. Abe, S. Takahashi, J. Takahashi, and H. Hamato, “Alterations in the concentration of serotonergic and dopaminergic substances in the cerebrospinal fluid of patients with Parkinson's disease, and their changes after L-dopa administration,” Neuroscience Letters, vol. 159, no. 1-2, pp. 135–138, 1993. View at: Google Scholar
  89. F. Hery, G. Simonnet, S. Bourgoin et al., “Effect of nerve activity on the in vivo release of [3H]serotonin continuously formed from L-[3H]tryptophan in the caudate nucleus of the cat,” Brain Research, vol. 169, no. 2, pp. 317–334, 1979. View at: Publisher Site | Google Scholar
  90. P. Blier, A. Serrano, and B. Scatton, “Differential responsiveness of the rat dorsal and median raphe 5-HT systems to 5-HT1 receptor agonists and p-chloroamphetamine,” Synapse, vol. 5, no. 2, pp. 120–133, 1990. View at: Google Scholar
  91. D. S. Kreiss and I. Lucki, “Differential regulation of serotonin (5-HT) release in the striatum and hippocampus by 5-HT(1A) autoreceptors of the dorsal and median raphe nuclei,” Journal of Pharmacology and Experimental Therapeutics, vol. 269, no. 3, pp. 1268–1279, 1994. View at: Google Scholar
  92. I. Hervás, N. Bel, A. G. Fernández, J. M. Palacios, and F. Artigas, “In vivo control of 5-hydroxytryptamine release by terminal autoreceptors in rat brain areas differentially innervated by the dorsal and median raphe nuclei,” Naunyn-Schmiedeberg's Archives of Pharmacology, vol. 358, no. 3, pp. 315–322, 1998. View at: Publisher Site | Google Scholar
  93. R. Invernizzi, M. Carli, A. Di Clemente, and R. Samanin, “Administration of 8-hydroxy-2-(di-n-propylamino)tetralin in raphe nuclei dorsalis and medianus reduces serotonin synthesis in the rat brain: differences in potency and regional sensitivity,” Journal of Neurochemistry, vol. 56, no. 1, pp. 243–247, 1991. View at: Publisher Site | Google Scholar
  94. R. Invernizzi, C. Velasco, M. Bramante, A. Longo, and R. Samanin, “Effect of 5-HT(1A) receptor antagonists on citalopram-induced increase in extracellular serotonin in the frontal cortex, striatum and dorsal hippocampus,” Neuropharmacology, vol. 36, no. 4-5, pp. 467–473, 1997. View at: Publisher Site | Google Scholar
  95. J. M. Casanovas, M. Lésourd, and F. Artigas, “The effect of the selective 5-HT(1A) agonists alnespirone (S-20499) and 8-OH-DPAT on extracellular 5-hydroxytryptamine in different regions of rat brain,” British Journal of Pharmacology, vol. 122, no. 4, pp. 733–741, 1997. View at: Publisher Site | Google Scholar
  96. L. Romero and F. Artigas, “Preferential potentiation of the effects of serotonin uptake inhibitors by 5-HT(1A) receptor antagonists in the dorsal raphe pathway: role of somatodendritic autoreceptors,” Journal of Neurochemistry, vol. 68, no. 6, pp. 2593–2603, 1997. View at: Google Scholar
  97. B. Amilhon, E. Lepicard, T. Renoir et al., “VGLUT3 (vesicular glutamate transporter type 3) contribution to the regulation of serotonergic transmission and anxiety,” Journal of Neuroscience, vol. 30, no. 6, pp. 2198–2210, 2010. View at: Publisher Site | Google Scholar
  98. R. McQuade and T. Sharp, “Functional mapping of dorsal and median raphe 5-hydroxytryptamine pathways in forebrain of the rat using microdialysis,” Journal of Neurochemistry, vol. 69, no. 2, pp. 791–796, 1997. View at: Google Scholar
  99. P. Gaspar, O. Cases, and L. Maroteaux, “The developmental role of serotonin: news from mouse molecular genetics,” Nature Reviews Neuroscience, vol. 4, no. 12, pp. 1002–1012, 2003. View at: Google Scholar
  100. V. Kiyasova, S. P. Fernandez, J. Laine et al., “A genetically defined morphologically and functionally unique subset of 5-HT neurons in the mouse raphe nuclei,” Journal of Neuroscience, vol. 31, no. 8, pp. 2756–2768, 2011. View at: Publisher Site | Google Scholar
  101. B. Picconi, A. Pisani, I. Barone et al., “Pathological synaptic plasticity in the striatum: implications for parkinson's disease,” NeuroToxicology, vol. 26, no. 5, pp. 779–783, 2005. View at: Publisher Site | Google Scholar
  102. B. Picconi, V. Ghiglieri, and P. Calabresi, “L-3,4-dihydroxyphenylalanine-induced sprouting of serotonin axon terminals: a useful biomarker for dyskinesias?” Annals of Neurology, vol. 68, no. 5, pp. 578–580, 2010. View at: Publisher Site | Google Scholar
  103. I. A. Prescott, J. O. Dostrovsky, E. Moro, M. Hodaie, A. M. Lozano, and W. D. Hutchison, “Levodopa enhances synaptic plasticity in the substantia nigra pars reticulata of Parkinson's disease patients,” Brain, vol. 132, no. 2, pp. 309–318, 2009. View at: Publisher Site | Google Scholar
  104. A. Berthet, G. Porras, E. Doudnikoff et al., “Pharmacological analysis demonstrates dramatic alteration of D1 dopamine receptor neuronal distribution in the rat analog of L-DOPA-induced dyskinesia,” Journal of Neuroscience, vol. 29, no. 15, pp. 4829–4835, 2009. View at: Publisher Site | Google Scholar
  105. D. Frechilla, A. Cobreros, L. Saldise et al., “Serotonin 5-HT1A receptor expression is selectively enhanced in the striosomal compartment of chronic Parkinsonian monkeys,” Synapse, vol. 39, no. 4, pp. 288–296, 2001. View at: Publisher Site | Google Scholar
  106. M. Doder, E. A. Rabiner, N. Turjanski, A. J. Lees, and D. J. Brooks, “Tremor in Parkinson's disease and serotonergic dysfunction: an 11C-WAY 100635 PET study,” Neurology, vol. 60, no. 4, pp. 601–605, 2003. View at: Google Scholar
  107. S. J. Kish, “Biochemistry of Parkinson's disease: is a brain serotonergic deficiency a characteristic of idiopathic Parkinson's disease?” Advances in Neurology, vol. 91, pp. 39–49, 2003. View at: Google Scholar
  108. B. Scholtissen, F. R. J. Verhey, H. W. M. Steinbusch, and A. F. G. Leentjens, “Serotonergic mechanisms in Parkinson's disease: opposing results from preclinical and clinical data,” Journal of Neural Transmission, vol. 113, no. 1, pp. 59–73, 2006. View at: Publisher Site | Google Scholar
  109. K. A. Jellinger, “Pathology of Parkinson's disease: changes other than the nigrostriatal pathway,” Molecular and Chemical Neuropathology, vol. 14, no. 3, pp. 153–197, 1991. View at: Google Scholar
  110. G. M. Halliday, P. C. Blumbergs, R. G. H. Cotton, W. W. Blessing, and L. B. Geffen, “Loss of brainstem serotonin- and substance P-containing neurons in Parkinson's disease,” Brain Research, vol. 510, no. 1, pp. 104–107, 1990. View at: Publisher Site | Google Scholar
  111. G. G. Kovacs, S. Klöppel, I. Fischer et al., “Nucleus-specific alteration of raphe neurons in human neurodegenerative disorders,” NeuroReport, vol. 14, no. 1, pp. 73–76, 2003. View at: Publisher Site | Google Scholar
  112. C. P. L. H. Chen, J. T. Alder, L. Bray, A. E. Kingsbury, P. T. Francis, and O. J. F. Foster, “Post-synaptic 5-HT(1A) and 5-HT(2A) receptors are increased in Parkinson's disease neocortex,” Annals of the New York Academy of Sciences, vol. 861, pp. 288–289, 1998. View at: Publisher Site | Google Scholar
  113. S. J. Kish, J. Tong, O. Hornykiewicz et al., “Preferential loss of serotonin markers in caudate versus putamen in Parkinson's disease,” Brain, vol. 131, no. 1, pp. 120–131, 2008. View at: Publisher Site | Google Scholar
  114. M. E. Castro, J. Pascual, T. Romón, J. Berciano, J. Figols, and A. Pazos, “5-HT(1B) receptor binding in degenerative movement disorders,” Brain Research, vol. 790, no. 1-2, pp. 323–328, 1998. View at: Publisher Site | Google Scholar
  115. R. Quirion and J. Richard, “Differential effects of selective lesions of cholinergic and dopaminergic neurons on serotonin-type 1 receptors in rat brain,” Synapse, vol. 1, no. 1, pp. 124–130, 1987. View at: Google Scholar
  116. K. Ikeguchi and A. Kuroda, “Mianserin treatment of patients with psychosis induced by antiparkinsonian drugs,” European Archives of Psychiatry and Clinical Neuroscience, vol. 244, no. 6, pp. 320–324, 1995. View at: Publisher Site | Google Scholar
  117. F. Durif, M. Vidailhet, F. Assal, C. Roche, A. M. Bonnet, and Y. Agid, “Low-dose clozapine improves dyskinesias in Parkinson's disease,” Neurology, vol. 48, no. 3, pp. 658–662, 1997. View at: Google Scholar
  118. G. Di Giovanni, V. Di Matteo, M. Pierucci, A. Benigno, and E. Esposito, “Serotonin involvement in the basal ganglia pathophysiology: could the 5-HT2c receptor be a new target for therapeutic strategies?” Current Medicinal Chemistry, vol. 13, no. 25, pp. 3069–3081, 2006. View at: Publisher Site | Google Scholar
  119. P. De Deurwaerdère, L. Mignon, and M. F. Chesselet, “Physiological and pathophysiological aspects of 5-HT2C receptors in basal ganglia,” in The Pathophysiology of Central 5-HT2C Receptors, G. Di Giovanni and K. Neve, Eds., The receptors series, Humana Press, Springer, New York, NY, USA, 2010. View at: Google Scholar
  120. S. H. Fox, B. Moser, and J. M. Brotchie, “Behavioral effects of 5-HT(2C) receptor antagonism in the substantia nigra zona reticulata of the 6-hydroxydopamine-lesioned rat model of Parkinson's disease,” Experimental Neurology, vol. 151, no. 1, pp. 35–49, 1998. View at: Publisher Site | Google Scholar
  121. S. H. Fox and J. M. Brotchie, “5-HT(2C) receptor antagonists enhance the behavioural response to dopamine D1 receptor agonists in the 6-hydroxydopamine-lesioned rat,” European Journal of Pharmacology, vol. 398, no. 1, pp. 59–64, 2000. View at: Publisher Site | Google Scholar
  122. P. De Deurwaerdère and M. F. Chesselet, “Nigrostriatal lesions alter oral dyskinesia and c-Fos expression induced by the serotonin agonist 1-(m-chlorophenyl)piperazine in adult rats,” Journal of Neuroscience, vol. 20, no. 13, pp. 5170–5178, 2000. View at: Google Scholar
  123. M. Politis, K. Wu, C. Loane et al., “Staging of serotonergic dysfunction in Parkinson's Disease: an in vivo 11C-DASB PET study,” Neurobiology of Disease, vol. 40, no. 1, pp. 216–221, 2010. View at: Publisher Site | Google Scholar
  124. A. Muñoz, Q. Li, F. Gardoni et al., “Combined 5-HT1A and 5-HT1B receptor agonists for the treatment of L-DOPA-induced dyskinesia,” Brain, vol. 131, no. 12, pp. 3380–3394, 2008. View at: Publisher Site | Google Scholar
  125. G. M. Goodwin, R. J. De Souza, A. J. Wood, and A. R. Green, “The enhancement by lithium of the 5-HT(1A) mediated serotonin syndrome produced by 8-OH-DPAT in the rat: evidence for a post-synaptic mechanism,” Psychopharmacology, vol. 90, no. 4, pp. 488–493, 1986. View at: Google Scholar
  126. J. Yamada, Y. Sugimoto, and K. Horisaka, “The behavioural effects of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) in mice,” European Journal of Pharmacology, vol. 154, no. 3, pp. 299–304, 1988. View at: Google Scholar
  127. W. L. Kuan, J. W. Zhao, and R. A. Barker, “The role of anxiety in the development of levodopa-induced dyskinesias in an animal model of Parkinson's disease, and the effect of chronic treatment with the selective serotonin reuptake inhibitor citalopram,” Psychopharmacology, vol. 197, no. 2, pp. 279–293, 2008. View at: Publisher Site | Google Scholar
  128. L. F. Schettino, S. V. Adamovich, W. Hening, E. Tunik, J. Sage, and H. Poizner, “Hand preshaping in Parkinson's disease: effects of visual feedback and medication state,” Experimental Brain Research, vol. 168, no. 1-2, pp. 186–202, 2006. View at: Publisher Site | Google Scholar
  129. A. Dagher and A. Nagano-Saito, “Functional and anatomical magnetic resonance imaging in Parkinson's disease,” Molecular Imaging and Biology, vol. 9, no. 4, pp. 234–242, 2007. View at: Publisher Site | Google Scholar
  130. G. S. Robertson and H. A. Robertson, “Evidence that L-dopa-induced rotational behavior is dependent on both striatal and nigral mechanisms,” Journal of Neuroscience, vol. 9, no. 9, pp. 3326–3331, 1989. View at: Google Scholar
  131. A. Antonini, J. Schwarz, W. H. Oertel, O. Pogarell, and K. L. Leenders, “Long-term changes of striatal dopamine D2 receptors in patients with Parkinson's disease: a study with positron emission tomography and [11C]raclopride,” Movement Disorders, vol. 12, no. 1, pp. 33–38, 1997. View at: Publisher Site | Google Scholar
  132. R. Kuriakose and A. J. Stoessl, “Imaging the nigrostriatal system to monitor disease progression and treatment-induced complications,” Progress in Brain Research, vol. 184, pp. 177–192, 2010. View at: Publisher Site | Google Scholar
  133. E. V. Encarnacion and R. A. Hauser, “Levodopa-induced dyskinesias in Parkinson's disease: etiology, impact on quality of life, and treatments,” European Neurology, vol. 60, no. 2, pp. 57–66, 2008. View at: Publisher Site | Google Scholar
  134. J. J. Soghomonian, “L-DOPA-induced dyskinesia in adult rats with a unilateral 6-OHDA lesion of dopamine neurons is paralleled by increased c-fos gene expression in the subthalamic nucleus,” European Journal of Neuroscience, vol. 23, no. 9, pp. 2395–2403, 2006. View at: Publisher Site | Google Scholar
  135. P. Svenningsson, J. Arts, L. Gunne, and P. E. Andren, “Acute and repeated treatment with L-DOPA increase c-jun expression in the 6-hydroxydopamine-lesioned forebrain of rats and common marmosets,” Brain Research, vol. 955, no. 1-2, pp. 8–15, 2002. View at: Publisher Site | Google Scholar
  136. Y. Xu, S. Sun, and X. Cao, “Effect of levodopa chronic administration on behavioral changes and fos expression in basal ganglia in rat model of PD,” Journal of Huazhong University of Science and Technology. Medical sciences, vol. 23, no. 3, pp. 258–262, 2003. View at: Google Scholar
  137. A. Berthet and E. Bezard, “Dopamine receptors and L-dopa-induced dyskinesia,” Parkinsonism and Related Disorders, vol. 15, supplement 4, pp. S8–S12, 2009. View at: Google Scholar
  138. P. Calabresi, P. Giacomini, D. Centonze, and G. Bernardi, “Levodopa-induced dyskinesia: a pathological form of striatal synaptic plasticity?” Annals of Neurology, vol. 47, no. 4, supplement 1, pp. S60–S69, 2000. View at: Google Scholar
  139. C. Guigoni, Q. Li, I. Aubert et al., “Involvement of sensorimotor, limbic, and associative basal ganglia domains in L-3,4-dihydroxyphenylalanine-induced dyskinesia,” Journal of Neuroscience, vol. 25, no. 8, pp. 2102–2107, 2005. View at: Publisher Site | Google Scholar
  140. L. Gong, R. M. Kostrzewa, R. W. Fuller, and K. W. Perry, “Supersensitization of the oral response to SKF 38393 in neonatal 6-OHDA- lesioned rats is mediated through a serotonin system,” Journal of Pharmacology and Experimental Therapeutics, vol. 261, no. 3, pp. 1000–1007, 1992. View at: Google Scholar
  141. A. Beyeler, N. Kadiri, S. Navailles et al., “Stimulation of serotonin2C receptors elicits abnormal oral movements by acting on pathways other than the sensorimotor one in the rat basal ganglia,” Neuroscience, vol. 169, no. 1, pp. 158–170, 2010. View at: Publisher Site | Google Scholar
  142. S. Kapur and G. Remington, “Serotonin-dopamine interaction and its relevance to schizophrenia,” American Journal of Psychiatry, vol. 153, no. 4, pp. 466–476, 1996. View at: Google Scholar
  143. J. F. Liégeois, J. Ichikawa, and H. Y. Meltzer, “5-HT2A receptor antagonism potentiates haloperidol-induced dopamine release in rat medial prefrontal cortex and inhibits that in the nucleus accumbens in a dose-dependent manner,” Brain Research, vol. 947, no. 2, pp. 157–165, 2002. View at: Publisher Site | Google Scholar
  144. G. Meco, P. Stirpe, F. Edito et al., “Aripiprazole in l-dopa-induced dyskinesias: a one-year open-label pilot study,” Journal of Neural Transmission, vol. 116, no. 7, pp. 881–884, 2009. View at: Publisher Site | Google Scholar
  145. M. Carlsson and A. Carlsson, “Interactions between glutamatergic and monoaminergic systems within the basal ganglia—implications for schizophrenia and Parkinson's disease,” Trends in Neurosciences, vol. 13, no. 7, pp. 272–276, 1990. View at: Google Scholar
  146. E. Wolf, K. Seppi, R. Katzenschlager et al., “Long-term antidyskinetic efficacy of amantadine in Parkinson's disease,” Movement Disorders, vol. 25, no. 10, pp. 1357–1363, 2010. View at: Publisher Site | Google Scholar
  147. S. Navailles and P. De Deurwaerdère, “Presynaptic control of serotonin on striatal dopamine function,” Psychopharmacology, vol. 213, no. 2-3, pp. 213–242, 2010. View at: Publisher Site | Google Scholar
  148. B. Gomez-Mancilla and P. J. Bedard, “Effect of nondopaminergic drugs on L-DOPA-induced dyskinesias in MPTP- treated monkeys,” Clinical Neuropharmacology, vol. 16, no. 5, pp. 418–427, 1993. View at: Google Scholar
  149. C. G. Goetz, P. Damier, C. Hicking et al., “Sarizotan as a treatment for dyskinesias in Parkinson's disease: a double-blind placebo-controlled trial,” Movement Disorders, vol. 22, no. 2, pp. 179–186, 2007. View at: Publisher Site | Google Scholar
  150. K. L. Eskow, V. Gupta, S. Alam, J. Y. Park, and C. Bishop, “The partial 5-HT1A agonist buspirone reduces the expression and development of l-DOPA-induced dyskinesia in rats and improves l-DOPA efficacy,” Pharmacology Biochemistry and Behavior, vol. 87, no. 3, pp. 306–314, 2007. View at: Publisher Site | Google Scholar
  151. K. Kannari, K. Kurahashi, M. Tomiyama et al., “Tandospirone citrate, a selective 5-HT1A agonist, alleviates L-DOPA-induced dyskinesia in patients with Parkinson's disease,” Brain and Nerve, vol. 54, no. 2, pp. 133–137, 2002. View at: Google Scholar
  152. M. M. Iravani, K. Tayarani-Binazir, W. B. Chu, M. J. Jackson, and P. Jenner, “In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated primates, the selective 5-hydroxytryptamine 1a agonist (R)-(+)-8-OHDPAT inhibits levodopa-induced dyskinesia but only with\ increased motor disability,” Journal of Pharmacology and Experimental Therapeutics, vol. 319, no. 3, pp. 1225–1234, 2006. View at: Publisher Site | Google Scholar
  153. M. Tomiyama, T. Kimura, T. Maeda, K. Kannari, M. Matsunaga, and M. Baba, “A serotonin 5-HT1A receptor agonist prevents behavioral sensitization to L-DOPA in a rodent model of Parkinson's disease,” Neuroscience Research, vol. 52, no. 2, pp. 185–194, 2005. View at: Publisher Site | Google Scholar

Copyright © 2012 Sylvia Navailles and Philippe De Deurwaerdère. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


More related articles

 PDF Download Citation Citation
 Download other formatsMore
 Order printed copiesOrder
Views1675
Downloads758
Citations

Related articles

We are committed to sharing findings related to COVID-19 as quickly as possible. We will be providing unlimited waivers of publication charges for accepted research articles as well as case reports and case series related to COVID-19. Review articles are excluded from this waiver policy. Sign up here as a reviewer to help fast-track new submissions.