Véronique Sgambato-Faure

Glutamatergic mechanisms in the dyskinesias induced by pharmacological dopamine replacement and deep brain stimulation for the treatment of Parkinson's disease

Dyskinesias represent a major complication of dopamine replacement therapy in Parkinsons disease (PD) and have prompted a search for alternative treatments. The most radical advances in this field have been provided by surgical manipulations of the deep basal ganglia nuclei, and particularly by deep brain stimulation (DBS) of the subthalamic nucleus (STN). Although being very effective, high-frequency stimulation (HFS) of the STN is a poorly understood treatment. Besides its anti-akinetic activity, it can be pro-dyskinetic above a certain stimulation intensity. Accumulating evidence indicates that dyskinesias induced by STN-HFS and dopamine replacement therapy are linked to dysregulation of glutamate transmission in the basal ganglia. In rat models of PD, both types of dyskinesia are associated with increased concentrations of extracellular glutamate and altered expression of glutamate transporters in the substantia nigra pars reticulata and the striatum. Furthermore, a vast and ever growing literature has revealed changes in the expression, phosphorylation state, and/or subcellular distribution of specific subtypes of glutamate receptors in these dyskinetic conditions. Both types of dyskinesias are linked to an increased phosphorylation of NR2B-containing NMDA receptors in critical basal ganglia circuits. We conclude that disruption of glutamate homeostasis and activation of perisynaptic and extra-synaptic glutamate receptors are an important pathophysiological component of these treatment-induced dyskinesias in PD. These findings lay the ground for therapeutic development initiatives targeting dysfunctional components of glutamate transmission in the basal ganglia.

Distinct Changes in cAMP and Extracellular Signal-Regulated Protein Kinase Signalling in L-DOPA-Induced Dyskinesia

Background In rodents, the development of dyskinesia produced by L-DOPA in the dopamine-depleted striatum occurs in response to increased dopamine D1 receptor-mediated activation of the cAMP - protein kinase A and of the Ras-extracellular signal-regulated kinase (ERK) signalling pathways. However, very little is known, in non-human primates, about the regulation of these signalling cascades and their association with the induction, manifestation and/or maintenance of dyskinesia. Methodology/Results We here studied, in the gold-standard non-human primate model of Parkinsons disease, the changes in PKA-dependent phosphorylation of DARPP-32 and GluR1 AMPA receptor, as well as in ERK and ribosomal protein S6 (S6) phosphorylation, associated to acute and chronic administration of L-DOPA. Increased phosphorylation of DARPP-32 and GluR1 was observed in both L-DOPA first-ever exposed and chronically-treated dyskinetic parkinsonian monkeys. In contrast, phosphorylation of ERK and S6 was enhanced preferentially after acute L-DOPA administration and decreased during the course of chronic treatment. Conclusion Dysregulation of cAMP signalling is maintained during the course of chronic L-DOPA administration, while abnormal ERK signalling peaks during the initial phase of L-DOPA treatment and decreases following prolonged exposure. While cAMP signalling enhancement is associated with dyskinesia, abnormal ERK signalling is associated with priming.

Subthalamic Stimulation-Induced Forelimb Dyskinesias Are Linked to an Increase in Glutamate Levels in the Substantia Nigra Pars Reticulata

The neurobiological mechanisms by which high-frequency stimulation of the subthalamic nucleus (STN–HFS) alleviates the motor symptoms of Parkinsons disease (PD) remain unclear. In this study, we analyzed the effects of STN–HFS on motor behavior in intact or hemiparkinsonian rats (6-hydroxydopamine lesion of the substantia nigra pars compacta) and investigated the correlation between these effects and extracellular glutamate (Glu) and GABA levels, assessed by intracerebral microdialysis in the substantia nigra pars reticulata (SNr). STN–HFS at an intensity corresponding to the threshold inducing contralateral forelimb dyskinesia, increased Glu levels in the SNr of both intact and hemiparkinsonian rats. In contrast, STN–HFS at half this intensity did not affect Glu levels in the SNr in intact or hemiparkinsonian rats but increased GABA levels in hemiparkinsonian rats only. STN–HFS-induced forelimb dyskinesia was blocked by microinjection of the Glu receptor antagonist kynurenate into the SNr and facilitated by microinjection of a mixture of the Glu receptor agonists AMPA and NMDA into the SNr. These new neurochemical data suggest that STN–HFS-induced forelimb dyskinesia is mediated by glutamate, probably via the direct activation of STN axons, shedding light on the mechanisms of STN–HFS in PD.

Coordinated and spatial upregulation of arc in striatonigral neurons correlates with L-dopa-induced behavioral sensitization in dyskinetic rats.

Although oral administration of L-Dopa remains the best therapy for Parkinson disease, its long-term administration causes the appearance of abnormal involuntary movements such as dyskinesia. Although persistent striatal induction of some genes has already been associated with such pathologic profiles in hemiparkinsonian rats, molecular and cellular mechanisms underlying such long-term adaptations remain to be elucidated. In this study, using a rat model of L-Dopa-induced dyskinesia, we report that activity regulated cytoskeletal (Arc)-associated protein is strongly upregulated in the lesioned striatum and that the extent of its induction further varies according to the occurrence or absence of locomotor sensitization. Moreover, Arc is preferentially induced, along with FosB, nur77, and homer-1a, in striatonigral neurons, which express mRNA encoding the precursor of dynorphin. Given the likely importance of Arc in the regulation of cytoskeleton during synaptic plasticity, its upregulation supports the hypothesis that a relationship exists between cytoskeletal modifications and the longlasting action of chronically administrated L-Dopa.

High-Frequency Stimulation of the Subthalamic Nucleus Potentiates l-DOPA-Induced Neurochemical Changes in the Striatum in a Rat Model of Parkinson's Disease

This study examined the cellular changes produced in the striatum by chronic l-DOPA treatment and prolonged subthalamic nucleus high-frequency stimulation (STN–HFS) applied separately, successively, or in association, in the 6-hydroxydopamine-lesioned rat model of Parkinsons disease (PD). Only animals showing severe l-DOPA-induced dyskinesias (LIDs) were included, and STN–HFS was applied for 5 d at an intensity efficient for alleviating akinesia without inducing dyskinesias. l-DOPA treatment alone induced FosB/ΔFosB immunoreactivity, exacerbated the postlesional increase in preproenkephalin, reversed the decrease in preprotachykinin, and markedly increased mRNA levels of preprodynorphin and of the glial glutamate transporter GLT1, which were respectively decreased and unaffected by the dopamine lesion. STN–HFS did not affect per se the postlesion changes in any of these markers. However, when applied in association with l-DOPA treatment, it potentiated the positive modulation exerted by l-DOPA on all of the markers examined and tended to exacerbate LIDs. After 5 d of l-DOPA withdrawal, the only persisting drug-induced responses were an elevation in preprodynorphin mRNA levels and in the number of FosB/ΔFosB-immunoreactive neurons. Selective additional increases in these two markers were measured when STN–HFS was applied subsequently to l-DOPA treatment. These data provide the first evidence that STN–HFS exacerbates the responsiveness of striatal cells to l-DOPA medication and suggest that STN–HFS acts specifically through an l-DOPA-modulated signal transduction pathway associated with LIDs in the striatum. They point to striatal cells as a primary site for the complex interactions between these two therapeutic approaches in PD and argue against a direct anti-dyskinetic action of STN–HFS.

Role of serotonergic 1A receptor dysfunction in depression associated with Parkinson's disease.

Depression is frequent in Parkinsons disease, but its pathophysiology remains unclear. Two recent studies have investigated the role of serotonergic system at the presynaptic level. The objective of the present study was to use positron emission tomography and [18F]MPPF to investigate the role of postsynaptic serotonergic system dysfunction in the pathophysiology of depression in Parkinsons disease. Four parkinsonian patients with depression and 8 parkinsonian patients without depression were enrolled. Each patient underwent a scan using [18F]MPPF, a selective serotonin 1A receptor antagonist. Voxel‐by‐voxel statistical comparison of [18F]MPPF uptake of the 2 groups of parkinsonian patients and with 7 matched normal subjects was made using statistical parametric mapping (P uncorrected < .001). Compared with nondepressed parkinsonian patients, depressed patients exhibited reduced tracer uptake in the left hippocampus, the right insula, the left superior temporal cortex, and the orbitofrontal cortex. Compared with controls, nondepressed parkinsonian patients presented reduced [18F]MPPF uptake bilaterally in the inferior frontal cortex as well as in the right ventral striatum and insula. Compared with controls, [18F]MPPF uptake was decreased in depressed parkinsonian patients in the left dorsal anterior cingulate and orbitofrontal cortices, in the right hippocampic region, and in the temporal cortex. The present imaging study suggests that abnormalities in serotonin 1A receptor neurotransmission in the limbic system may be involved in the neural mechanisms underlying depression in patients with Parkinsons disease.

Impulse control disorders and levodopa-induced dyskinesias in Parkinson's disease: an update

Dopaminergic medications used in the treatment of patients with Parkinsons disease are associated with motor and non-motor behavioural side-effects, such as dyskinesias and impulse control disorders also known as behavioural addictions. Levodopa-induced dyskinesias occur in up to 80% of patients with Parkinsons after a few years of chronic treatment. Impulse control disorders, including gambling disorder, binge eating disorder, compulsive sexual behaviour, and compulsive shopping occur in about 17% of patients with Parkinsons disease on dopamine agonists. These behaviours reflect the interactions of the dopaminergic medications with the individuals susceptibility, and the underlying neurobiology of Parkinsons disease. Parkinsonian rodent models show enhanced reinforcing effects of chronic dopaminergic medication, and a potential role for individual susceptibility. In patients with Parkinsons disease and impulse control disorders, impairments are observed across subtypes of decisional impulsivity, possibly reflecting uncertainty and the relative balance of rewards and losses. Impairments appear to be more specific to decisional than motor impulsivity, which might reflect differences in ventral and dorsal striatal engagement. Emerging evidence suggests impulse control disorder subtypes have dissociable correlates, which indicate that individual susceptibility predisposes towards the expression of different behavioural subtypes and neurobiological substrates. Therapeutic interventions to treat patients with Parkinsons disease and impulse control disorders have shown efficacy in randomised controlled trials. Large-scale studies are warranted to identify individual risk factors and novel therapeutic targets for these diseases. Mechanisms underlying impulse control disorders and dyskinesias could provide crucial insights into other behavioural symptoms in Parkinsons disease and addictions in the general population.

The prominent role of serotonergic degeneration in apathy, anxiety and depression in de novo Parkinson’s disease

SEE SCHRAG AND POLITIS DOI101093/AWW190 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Apathy, which can occur separately or in combination with depression and anxiety, is one of the most frequently encountered neuropsychiatric symptoms in Parkinsons disease. Pathophysiological evidence suggests that parkinsonian apathy is primarily due to a mesolimbic dopaminergic denervation, but the role of the serotonergic alteration has never been examined, despite its well-known involvement in the pathogenesis of depression and anxiety. To fill this gap, we address here the pure model of de novo Parkinsons disease, without the confounding effects of antiparkinsonian treatment. Fifteen apathetic (Lille Apathy Rating Scale scores ≥ -21) and 15 non-apathetic (-36 ≤ Lille Apathy Rating Scale scores ≤ -22) drug-naïve de novo parkinsonian patients were enrolled in the present study and underwent detailed clinical assessment and positron emission tomography imaging, using both dopaminergic [(11)C-N-(3-iodoprop-2E-enyl)-2-beta-carbomethoxy-3-beta-(4-methylphenyl)-nortropane (PE2I)] (n = 29) and serotonergic [(11)C-N,N-dimethyl-2-(-2-amino-4-cyanophenylthio)-benzylamine (DASB)] (n = 27) presynaptic transporter radioligands. Apathetic parkinsonian patients presented higher depression (P = 0.0004) and anxiety (P = 0.004) scores - as assessed using the Beck Depression Inventory and the part B of the State-Trait Anxiety Inventory, respectively - compared to the non-apathetic ones - who were not different from the age-matched healthy subjects (n = 15). Relative to the controls, the non-apathetic parkinsonian patients mainly showed dopaminergic denervation (n = 14) within the right caudate nucleus, bilateral putamen, thalamus and pallidum, while serotonergic innervation (n = 15) was fairly preserved. Apathetic parkinsonian patients exhibited, compared to controls, combined and widespread dopaminergic (n = 15) and serotonergic (n = 12) degeneration within the bilateral caudate nuclei, putamen, ventral striatum, pallidum and thalamus, but also a specific bilateral dopaminergic disruption within the substantia nigra-ventral tegmental area complex, as well as a specific serotonergic alteration within the insula, the orbitofrontal and the subgenual anterior cingulate cortices. When comparing the two parkinsonian groups, the apathetic patients mainly displayed greater serotonergic alteration in the ventral striatum, the dorsal and the subgenual parts of the anterior cingulate cortices, bilaterally, as well as in the right-sided caudate nucleus and the right-sided orbitofrontal cortex. Regression analyses also revealed that the severity of apathy was moreover mainly related to specific serotonergic lesions within the right-sided anterior caudate nucleus and the orbitofrontal cortex, while the degree of both depression and anxiety was primarily linked to serotonergic disruption within the bilateral subgenual parts and/or the right dorsal part of the anterior cingulate cortex, without prominent role of the dopaminergic degeneration in the pathogenesis of these three non-motor signs. Altogether, these findings highlight a prominent role of the serotonergic degeneration in the expression of the neuropsychiatric symptoms occurring at the onset of Parkinsons disease.

De novo and long-term L-Dopa induce both common and distinct striatal gene profiles in the hemiparkinsonian rat

We compared for the first time the effects of de novo versus long-term l-Dopa treatment inducing abnormal involuntary movement on striatal gene profiles and related bio-associations in the 6-hydroxydopamine rat model of Parkinsons disease. We examined the pattern of striatal messenger RNA expression over 4854 genes in hemiparkinsonian rats treated acutely or chronically with l-Dopa, and subsequently verified some of the gene alterations by in situ hybridization or real-time quantitative PCR. We found that de novo and long-term l-Dopa share common gene regulation features involving phosphorylation, signal transduction, secretion, transcription, translation, homeostasis, exocytosis and synaptic transmission processes. We also found that the transcriptomic response is enhanced by long-term l-Dopa and that specific biological alterations are underlying abnormal motor behavior. Processes such as growth, synaptogenesis, neurogenesis and cell proliferation may be particularly relevant to the long-term action of l-Dopa.

Behavioural impact of a double dopaminergic and serotonergic lesion in the non-human primate

Serotonergic (5-HT) neurons degenerate in Parkinsons disease. To determine the role of this 5-HT injury-besides the dopaminergic one in the parkinsonian symptomatology-we developed a new monkey model exhibiting a double dopaminergic/serotonergic lesion by sequentially using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 3,4-methylenedioxy-N-methamphetamine (MDMA, better known as ecstasy). By positron emission tomography imaging and immunohistochemistry, we demonstrated that MDMA injured 5-HT nerve terminals in the brain of MPTP monkeys. Unexpectedly, this injury had no impact on tremor or on bradykinesia, but altered rigidity. It abolished the l-DOPA-induced dyskinesia and neuropsychiatric-like behaviours, without altering the anti-parkinsonian response. These data demonstrate that 5-HT fibres play a critical role in the expression of both motor and non-motor symptoms in Parkinsons disease, and highlight that an imbalance between the 5-HT and dopaminergic innervating systems is involved in specific basal ganglia territories for different symptoms.