Gregory Porras - Academia.edu (original) (raw)

Papers by Gregory Porras

Science Translational Medicine, 2010

Parkinson's disease is caused primarily by degeneration of brain dopaminergic neurons in the subs... more Parkinson's disease is caused primarily by degeneration of brain dopaminergic neurons in the substantia nigra and the consequent deficit of dopamine in the striatum. Dopamine replacement therapy with the dopamine precursor L-dopa is the mainstay of current treatment. After several years, however, the patients develop L-dopa-induced dyskinesia, or abnormal involuntary movements, thought to be due to excessive signaling via dopamine receptors. G protein-coupled receptor kinases (GRKs) control desensitization of dopamine receptors. We found that dyskinesia is attenuated by lentivirus-mediated overexpression of GRK6 in the striatum in rodent and primate models of Parkinson's disease. Conversely, reduction of GRK6 concentration by microRNA delivered with lentiviral vector exacerbated dyskinesia in parkinsonian rats. GRK6 suppressed dyskinesia in monkeys without compromising the antiparkinsonian effects of L-dopa and even prolonged the antiparkinsonian effect of a lower dose of L-dopa. Our finding that increased availability of GRK6 ameliorates dyskinesia and increases duration of the antiparkinsonian action of L-dopa suggests a promising approach for controlling both dyskinesia and motor fluctuations in Parkinson's disease.

PLoS ONE, 2010

Background: The A11 diencephalospinal pathway is crucial for sensorimotor integration and pain co... more Background: The A11 diencephalospinal pathway is crucial for sensorimotor integration and pain control at the spinal cord level. When disrupted, it is thought to be involved in numerous painful conditions such as restless legs syndrome and migraine. Its anatomical organization, however, remains largely unknown in the non-human primate (NHP). We therefore characterized the anatomy of this pathway in the NHP.

Acta Neuropathologica Communications, 2015

Introduction: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized ... more Introduction: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons as well as the presence of proteinaceous inclusions named Lewy bodies. α-synuclein (α-syn) is a major constituent of Lewy bodies, and the first disease-causing protein characterized in PD. Several α-syn-based animal models of PD have been developed to investigate the pathophysiology of PD, but none of them recapitulate the full picture of the disease. Ageing is the most compelling and major risk factor for developing PD but its impact on α-syn toxicity remains however unexplored. In this study, we developed and exploited a recombinant adeno-associated viral (AAV) vector of serotype 9 overexpressing mutated α-syn to elucidate the influence of ageing on the dynamics of PD-related neurodegeneration associated with α-syn pathology in different mammalian species. Results: Identical AAV pseudotype 2/9 vectors carrying the DNA for human mutant p.A53T α-syn were injected into the substantia nigra to induce neurodegeneration and synucleinopathy in mice, rats and monkeys. Rats were used first to validate the ability of this serotype to replicate α-syn pathology and second to investigate the relationship between the kinetics of α-syn-induced nigrostriatal degeneration and the progressive onset of motor dysfunctions, strikingly reminiscent of the impairments observed in PD patients. In mice, AAV2/9-hα-syn injection into the substantia nigra was associated with accumulation of α-syn and phosphorylated hα-syn, regardless of mouse strain. However, phenotypic mutants with either accelerated senescence or resistance to senescence did not display differential susceptibility to hα-syn overexpression. Of note, p-α-syn levels correlated with nigrostriatal degeneration in mice. In monkeys, hα-syn-induced degeneration of the nigrostriatal pathway was not affected by the age of the animals. Unlike mice, m onkeys did not exhibit correlations between levels of phosphorylated α-syn and neurodegeneration. Conclusions: In conclusion, AAV2/9-mediated hα-syn induces robust nigrostriatal neurodegeneration in mice, rats and monkeys, allowing translational comparisons among species. Ageing, however, neither exacerbated nigrostriatal neurodegeneration nor α-syn pathology per se. Our unprecedented multi-species investigation thus favours the multiple-hit hypothesis for PD wherein ageing would merely be an aggravating, additive, factor superimposed upon an independent disease process.

The Journal of Neuroscience : The Official Journal of the Society for Neuroscience

Chronic L-dopa treatment of Parkinson's disease (PD) often leads to debilitating involuntary ... more Chronic L-dopa treatment of Parkinson's disease (PD) often leads to debilitating involuntary movements, termed L-dopa-induced dyskinesia (LID), mediated by dopamine (DA) receptors. RGS9-2 is a GTPase accelerating protein that inhibits DA D2 receptor-activated G proteins. Herein, we assess the functional role of RGS9-2 on LID. In monkeys, Western blot analysis of striatal extracts shows that RGS9-2 levels are not altered by MPTP-induced DA denervation and/or chronic L-dopa administration. In MPTP monkeys with LID, striatal RGS9-2 overexpression--achieved by viral vector injection into the striatum--diminishes the involuntary movement intensity without lessening the anti-parkinsonian effects of the D1/D2 receptor agonist L-dopa. In contrasts, in these animals, striatal RGS9-2 overexpression diminishes both the involuntary movement intensity and the anti-parkinsonian effects of the D2/D3 receptor agonist ropinirole. In unilaterally 6-OHDA-lesioned rats with LID, we show that the ti...

Experimental neurology, 2008

Multiple targets and pathways may be amenable to the development of gene therapy approaches for P... more Multiple targets and pathways may be amenable to the development of gene therapy approaches for Parkinson's disease. This article discusses some of the cellular and brain circuit pathways relevant to Parkinson's disease that would be clinically amenable to gene therapy. Approaches could be classified according to two main categories, i.e. symptomatic vs. neuroprotective/neurorestorative strategies. Examples of the different possibilities currently in development are given and feature both dopaminergic and non-dopaminergic symptomatic treatments of parkinsonian symptoms and/or L-DOPA-induced side effects, anti-apoptotic neuroprotective strategies and growth-factor delivery for neuroprotection/neurorestoration. While gene therapy has been mostly used so far for enhancing the expression of the target gene, the use of dominant negative or siRNA opens new possibilities. This, combined with the key feature of gene delivery that offers access to intracellular signalling pathways, i...

Parkinson's disease 6-OHDA Serotonin 5-HT1A/1B agonists a b s t r a c t

Cold Spring Harbor perspectives in medicine, 2012

The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) primate models of Parkinson's disease... more The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) primate models of Parkinson's disease (PD) reproduce most, although not all, of the clinical and pathological hallmarks of PD. The present contribution presents the possibilities offered by the MPTP monkey models of PD to readers with minimal knowledge of PD, emphasizing the diversity of species, route and regimen of administration, symptoms and pathological features. Readers would eventually find out that there is not a single MPTP monkey model of PD but instead MPTP monkey models of PD, each addressing a specific experimental need.

Neuropharmacology, 2000

In this study, we use in vivo microdialysis to investigate the influence of endogenous serotonin ... more In this study, we use in vivo microdialysis to investigate the influence of endogenous serotonin (5-HT) on striatal dopamine (DA) and 5-hydroxyidoleacetic acid (5-HIAA) efflux in both basal and activated conditions. The selective serotonin reuptake inhibitors citalopram and fluoxetine were used to mobilize endogenous 5-HT.

Neuropsychopharmacology, 2004

During recent years, much attention has been devoted at investigating the modulatory role of cent... more During recent years, much attention has been devoted at investigating the modulatory role of central 5-HT 2C receptors on dopamine (DA) neuron activity, and it has been proposed that these receptors modulate selectively DA exocytosis associated with increased firing of DA neurons. In the present study, using in vivo microdialysis in the nucleus accumbens (NAc) and the striatum of halothaneanesthetized rats, we addressed this hypothesis by assessing the ability of 5-HT 2C agents to modulate the increase in DA outflow induced by haloperidol and cocaine, of which the effects on DA outflow are associated or not with an increase in DA neuron firing, respectively. The intraperitoneal administration of cocaine (10-30 mg/kg) induced a dose-dependent increase in DA extracellular levels in the NAc and the striatum. The effect of 15 mg/kg cocaine was potentiated by the mixed 5-HT 2C/2B antagonist SB 206553 (5 mg/kg i.p.) and the selective 5-HT 2C antagonist SB 242084 (1 mg/kg i.p.) in both brain regions. The mixed 5-HT 2C/2B agonist, Ro 60-0175 (1 mg/kg i.p.), failed to affect cocaine-induced DA outflow, but reduced significantly the increase in DA outflow induced by the subcutaneous administration of 0.1 mg/kg haloperidol. The obtained results provide evidence that 5-HT 2C receptors exert similar effects in both the NAc and the striatum, and they modulate DA exocytosis also when its increase occurs independently from an increase in DA neuron impulse activity. Furthermore, they show that 5-HT 2C agonists, at variance with 5-HT 2C antagonists, exert a preferential control on the impulse-stimulated release of DA.

Chronic L-dopa treatment of Parkinson&amp... more Chronic L-dopa treatment of Parkinson's disease (PD) often leads to debilitating involuntary movements, termed L-dopa-induced dyskinesia (LID), mediated by dopamine (DA) receptors. RGS9-2 is a GTPase accelerating protein that inhibits DA D2 receptor-activated G proteins. Herein, we assess the functional role of RGS9-2 on LID. In monkeys, Western blot analysis of striatal extracts shows that RGS9-2 levels are not altered by MPTP-induced DA denervation and/or chronic L-dopa administration. In MPTP monkeys with LID, striatal RGS9-2 overexpression--achieved by viral vector injection into the striatum--diminishes the involuntary movement intensity without lessening the anti-parkinsonian effects of the D1/D2 receptor agonist L-dopa. In contrasts, in these animals, striatal RGS9-2 overexpression diminishes both the involuntary movement intensity and the anti-parkinsonian effects of the D2/D3 receptor agonist ropinirole. In unilaterally 6-OHDA-lesioned rats with LID, we show that the time course of viral vector-mediated striatal RGS9-2 overexpression parallels the time course of improvement of L-dopa-induced involuntary movements. We also find that unilateral 6-OHDA-lesioned RGS9-/- mice are more susceptible to L-dopa-induced involuntary movements than unilateral 6-OHDA-lesioned RGS9+/+ mice, albeit the rotational behavior--taken as an index of the anti-parkinsonian response--is similar between the two groups of mice. Together, these findings suggest that RGS9-2 plays a pivotal role in LID pathophysiology. However, the findings also suggest that increasing RGS9-2 expression and/or function in PD patients may only be a suitable therapeutic strategy to control involuntary movements induced by nonselective DA agonist such as L-dopa.

L-dopa remains the mainstay treatment for Parkinson's disease (PD), although in later stages, tre... more L-dopa remains the mainstay treatment for Parkinson's disease (PD), although in later stages, treatment is complicated by L-dopa-induced dyskinesias (LID). Current evidence links LID to excessive striatal L-dopa-derived dopamine (DA) release, while the possibility of a direct involvement of L-dopa itself in LID has been largely ignored. Here we show that L-dopa can alter basal ganglia activity and produce LID without enhancing striatal DA release in parkinsonian non-human primates. These data may have therapeutic implications for the management of advanced PD since they suggest that LID could result from diverse mechanisms of action of L-dopa.

Handbook of Behavioral Neuroscience, 2010

Parkinsonism & Related Disorders, 2007

Objective: Chronic L-dopa treatment of Parkinson disease (PD) leads to debilitating involuntary m... more Objective: Chronic L-dopa treatment of Parkinson disease (PD) leads to debilitating involuntary movements, termed L-dopa-induced dyskinesia (LID), mediated in part by supersensitive dopamine (DA) receptors. The present experiments aimed at exploring the role of RGS9-2, a GTPase accelerating protein that potently inhibits DA D2 receptor-activated G proteins.

Journal of Neuroscience, 2009

We have associated behavioral, pharmacological, and quantitative immunohistochemical study in a r... more We have associated behavioral, pharmacological, and quantitative immunohistochemical study in a rat analog of L-DOPA-induced dyskinesia to understand whether alterations in dopamine receptor fate in striatal neurons may be involved in mechanisms leading to movement abnormalities. Detailed analysis at the ultrastructural level demonstrates specific alterations of dopamine D 1 receptor (D 1 R) subcellular localization in striatal medium spiny neurons in L-DOPA-treated 6-hydroxydopamine-lesioned rats with abnormal involuntary movements (AIMs). This includes exaggerated D 1 R expression at the plasma membrane. However, D 1 R retains ability of internalization, as a challenge with the potent D 1 R agonist SKF-82958 induces a strong decrease of labeling at membrane in animals with AIMs. Since a functional cross talk between D 1 R and D 3 R has been suggested, we hypothesized that their coactivation by dopamine derived from L-DOPA might anchor D 1 R at the membrane. Accordingly, cotreatment with L-DOPA and the D 3 R antagonist ST 198 restores normal level of membrane-bound D 1 R. Together, these results demonstrate that AIMs are related to abnormal D 1 R localization at the membrane and intraneuronal trafficking dysregulation, and suggest that strategies aiming at disrupting the D 1 R-D 3 R cross talk might reduce L-DOPAinduced dyskinesia by reducing D 1 R availability at the membrane.

Science Translational Medicine, 2010

Parkinson's disease is caused primarily by degeneration of brain dopaminergic neurons in the subs... more Parkinson's disease is caused primarily by degeneration of brain dopaminergic neurons in the substantia nigra and the consequent deficit of dopamine in the striatum. Dopamine replacement therapy with the dopamine precursor L-dopa is the mainstay of current treatment. After several years, however, the patients develop L-dopa-induced dyskinesia, or abnormal involuntary movements, thought to be due to excessive signaling via dopamine receptors. G protein-coupled receptor kinases (GRKs) control desensitization of dopamine receptors. We found that dyskinesia is attenuated by lentivirus-mediated overexpression of GRK6 in the striatum in rodent and primate models of Parkinson's disease. Conversely, reduction of GRK6 concentration by microRNA delivered with lentiviral vector exacerbated dyskinesia in parkinsonian rats. GRK6 suppressed dyskinesia in monkeys without compromising the antiparkinsonian effects of L-dopa and even prolonged the antiparkinsonian effect of a lower dose of L-dopa. Our finding that increased availability of GRK6 ameliorates dyskinesia and increases duration of the antiparkinsonian action of L-dopa suggests a promising approach for controlling both dyskinesia and motor fluctuations in Parkinson's disease.

Parkinsonism & Related Disorders, 2009

Background: The A11 diencephalospinal pathway is crucial for sensorimotor integration and pain co... more Background: The A11 diencephalospinal pathway is crucial for sensorimotor integration and pain control at the spinal cord level. When disrupted, it is thought to be involved in numerous painful conditions such as restless legs syndrome and migraine. Its anatomical organization, however, remains largely unknown in the non-human primate (NHP). We therefore characterized the anatomy of this pathway in the NHP.

Neuroscience Research, 2013

Parkinson's disease 6-OHDA Serotonin 5-HT1A/1B agonists a b s t r a c t

Neuroscience Letters, 2008

Dopamine agonists used to manage Parkinsonian motor symptoms have been suggested to be neuroprote... more Dopamine agonists used to manage Parkinsonian motor symptoms have been suggested to be neuroprotective. The study was designed to assess the neuroprotective potential of the D 3 /D 2 /D 1 dopamine receptor agonist rotigotine in the acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridinelesioned (MPTP) mouse model of Parkinson's disease by measuring mesencephalic degenerating neurons using FluoroJade staining and the remaining dopaminergic nerve endings in the striatum using dopamine transporter binding. Continuous administration of rotigotine at a dose of 3 mg/kg significantly attenuated MPTP-induced acute cell degeneration in the FluoroJade-staining paradigm. Rotigotine (0.3-3 mg/kg) partially protected dopamine nerve endings from MPTP-induced degeneration in a dose-dependent manner. These data suggest that rotigotine, at the doses employed, significantly protected dopamine neurons from degeneration in an acute mouse model of MPTP intoxication.

Neuropsychopharmacology, 2002

In vivo microdialysis and single-cell extracellular recordings were used to assess the involvemen... more In vivo microdialysis and single-cell extracellular recordings were used to assess the involvement of serotonin and serotonin 2C/2B (5-HT 2C/2B ) receptors in the effects induced by amphetamine and morphine on dopaminergic (DA) activity within the mesoaccumbal and nigrostriatal pathways. The increase in DA release induced by amphetamine (2 mg/kg i.p.) in the nucleus accumbens and striatum was significantly reduced by the selective 5-HT 2A antagonist SR 46349B (0.5 mg/kg s.c.), but not affected by the 5-HT 2C/2B antagonist SB 206553 (5 mg/kg i.p.). In contrast, the enhancement of accumbal and striatal DA output induced by morphine (2.5 mg/kg s.c.), while insensitive to SR 46349B, was significantly increased by SB 206553. Furthermore, morphine (0.1-10 mg/kg i.v.)-induced increase in DA neuron firing rate in both the ventral tegmental area and the substantia nigra pars compacta was unaffected by SR 46349B (0.1 mg/kg i.v.) but significantly potentiated by SB 206553 (0. . These results show that 5-HT 2A and 5-HT 2C receptors regulate specifically the activation of midbrain DA neurons induced by amphetamine and morphine, respectively. This differential contribution may be related to the specific mechanism of action of the drug considered and to the neuronal circuitry involved in their effect on DA neurons. Furthermore, these results suggest that 5-HT 2C receptors selectively modulate the impulse flow-dependent release of DA.

Science Translational Medicine, 2010

Parkinson's disease is caused primarily by degeneration of brain dopaminergic neurons in the subs... more Parkinson's disease is caused primarily by degeneration of brain dopaminergic neurons in the substantia nigra and the consequent deficit of dopamine in the striatum. Dopamine replacement therapy with the dopamine precursor L-dopa is the mainstay of current treatment. After several years, however, the patients develop L-dopa-induced dyskinesia, or abnormal involuntary movements, thought to be due to excessive signaling via dopamine receptors. G protein-coupled receptor kinases (GRKs) control desensitization of dopamine receptors. We found that dyskinesia is attenuated by lentivirus-mediated overexpression of GRK6 in the striatum in rodent and primate models of Parkinson's disease. Conversely, reduction of GRK6 concentration by microRNA delivered with lentiviral vector exacerbated dyskinesia in parkinsonian rats. GRK6 suppressed dyskinesia in monkeys without compromising the antiparkinsonian effects of L-dopa and even prolonged the antiparkinsonian effect of a lower dose of L-dopa. Our finding that increased availability of GRK6 ameliorates dyskinesia and increases duration of the antiparkinsonian action of L-dopa suggests a promising approach for controlling both dyskinesia and motor fluctuations in Parkinson's disease.

PLoS ONE, 2010

Background: The A11 diencephalospinal pathway is crucial for sensorimotor integration and pain co... more Background: The A11 diencephalospinal pathway is crucial for sensorimotor integration and pain control at the spinal cord level. When disrupted, it is thought to be involved in numerous painful conditions such as restless legs syndrome and migraine. Its anatomical organization, however, remains largely unknown in the non-human primate (NHP). We therefore characterized the anatomy of this pathway in the NHP.

Acta Neuropathologica Communications, 2015

Introduction: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized ... more Introduction: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons as well as the presence of proteinaceous inclusions named Lewy bodies. α-synuclein (α-syn) is a major constituent of Lewy bodies, and the first disease-causing protein characterized in PD. Several α-syn-based animal models of PD have been developed to investigate the pathophysiology of PD, but none of them recapitulate the full picture of the disease. Ageing is the most compelling and major risk factor for developing PD but its impact on α-syn toxicity remains however unexplored. In this study, we developed and exploited a recombinant adeno-associated viral (AAV) vector of serotype 9 overexpressing mutated α-syn to elucidate the influence of ageing on the dynamics of PD-related neurodegeneration associated with α-syn pathology in different mammalian species. Results: Identical AAV pseudotype 2/9 vectors carrying the DNA for human mutant p.A53T α-syn were injected into the substantia nigra to induce neurodegeneration and synucleinopathy in mice, rats and monkeys. Rats were used first to validate the ability of this serotype to replicate α-syn pathology and second to investigate the relationship between the kinetics of α-syn-induced nigrostriatal degeneration and the progressive onset of motor dysfunctions, strikingly reminiscent of the impairments observed in PD patients. In mice, AAV2/9-hα-syn injection into the substantia nigra was associated with accumulation of α-syn and phosphorylated hα-syn, regardless of mouse strain. However, phenotypic mutants with either accelerated senescence or resistance to senescence did not display differential susceptibility to hα-syn overexpression. Of note, p-α-syn levels correlated with nigrostriatal degeneration in mice. In monkeys, hα-syn-induced degeneration of the nigrostriatal pathway was not affected by the age of the animals. Unlike mice, m onkeys did not exhibit correlations between levels of phosphorylated α-syn and neurodegeneration. Conclusions: In conclusion, AAV2/9-mediated hα-syn induces robust nigrostriatal neurodegeneration in mice, rats and monkeys, allowing translational comparisons among species. Ageing, however, neither exacerbated nigrostriatal neurodegeneration nor α-syn pathology per se. Our unprecedented multi-species investigation thus favours the multiple-hit hypothesis for PD wherein ageing would merely be an aggravating, additive, factor superimposed upon an independent disease process.

The Journal of Neuroscience : The Official Journal of the Society for Neuroscience

Chronic L-dopa treatment of Parkinson's disease (PD) often leads to debilitating involuntary ... more Chronic L-dopa treatment of Parkinson's disease (PD) often leads to debilitating involuntary movements, termed L-dopa-induced dyskinesia (LID), mediated by dopamine (DA) receptors. RGS9-2 is a GTPase accelerating protein that inhibits DA D2 receptor-activated G proteins. Herein, we assess the functional role of RGS9-2 on LID. In monkeys, Western blot analysis of striatal extracts shows that RGS9-2 levels are not altered by MPTP-induced DA denervation and/or chronic L-dopa administration. In MPTP monkeys with LID, striatal RGS9-2 overexpression--achieved by viral vector injection into the striatum--diminishes the involuntary movement intensity without lessening the anti-parkinsonian effects of the D1/D2 receptor agonist L-dopa. In contrasts, in these animals, striatal RGS9-2 overexpression diminishes both the involuntary movement intensity and the anti-parkinsonian effects of the D2/D3 receptor agonist ropinirole. In unilaterally 6-OHDA-lesioned rats with LID, we show that the ti...

Experimental neurology, 2008

Multiple targets and pathways may be amenable to the development of gene therapy approaches for P... more Multiple targets and pathways may be amenable to the development of gene therapy approaches for Parkinson's disease. This article discusses some of the cellular and brain circuit pathways relevant to Parkinson's disease that would be clinically amenable to gene therapy. Approaches could be classified according to two main categories, i.e. symptomatic vs. neuroprotective/neurorestorative strategies. Examples of the different possibilities currently in development are given and feature both dopaminergic and non-dopaminergic symptomatic treatments of parkinsonian symptoms and/or L-DOPA-induced side effects, anti-apoptotic neuroprotective strategies and growth-factor delivery for neuroprotection/neurorestoration. While gene therapy has been mostly used so far for enhancing the expression of the target gene, the use of dominant negative or siRNA opens new possibilities. This, combined with the key feature of gene delivery that offers access to intracellular signalling pathways, i...

Parkinson's disease 6-OHDA Serotonin 5-HT1A/1B agonists a b s t r a c t

Cold Spring Harbor perspectives in medicine, 2012

The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) primate models of Parkinson's disease... more The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) primate models of Parkinson's disease (PD) reproduce most, although not all, of the clinical and pathological hallmarks of PD. The present contribution presents the possibilities offered by the MPTP monkey models of PD to readers with minimal knowledge of PD, emphasizing the diversity of species, route and regimen of administration, symptoms and pathological features. Readers would eventually find out that there is not a single MPTP monkey model of PD but instead MPTP monkey models of PD, each addressing a specific experimental need.

Neuropharmacology, 2000

In this study, we use in vivo microdialysis to investigate the influence of endogenous serotonin ... more In this study, we use in vivo microdialysis to investigate the influence of endogenous serotonin (5-HT) on striatal dopamine (DA) and 5-hydroxyidoleacetic acid (5-HIAA) efflux in both basal and activated conditions. The selective serotonin reuptake inhibitors citalopram and fluoxetine were used to mobilize endogenous 5-HT.

Neuropsychopharmacology, 2004

During recent years, much attention has been devoted at investigating the modulatory role of cent... more During recent years, much attention has been devoted at investigating the modulatory role of central 5-HT 2C receptors on dopamine (DA) neuron activity, and it has been proposed that these receptors modulate selectively DA exocytosis associated with increased firing of DA neurons. In the present study, using in vivo microdialysis in the nucleus accumbens (NAc) and the striatum of halothaneanesthetized rats, we addressed this hypothesis by assessing the ability of 5-HT 2C agents to modulate the increase in DA outflow induced by haloperidol and cocaine, of which the effects on DA outflow are associated or not with an increase in DA neuron firing, respectively. The intraperitoneal administration of cocaine (10-30 mg/kg) induced a dose-dependent increase in DA extracellular levels in the NAc and the striatum. The effect of 15 mg/kg cocaine was potentiated by the mixed 5-HT 2C/2B antagonist SB 206553 (5 mg/kg i.p.) and the selective 5-HT 2C antagonist SB 242084 (1 mg/kg i.p.) in both brain regions. The mixed 5-HT 2C/2B agonist, Ro 60-0175 (1 mg/kg i.p.), failed to affect cocaine-induced DA outflow, but reduced significantly the increase in DA outflow induced by the subcutaneous administration of 0.1 mg/kg haloperidol. The obtained results provide evidence that 5-HT 2C receptors exert similar effects in both the NAc and the striatum, and they modulate DA exocytosis also when its increase occurs independently from an increase in DA neuron impulse activity. Furthermore, they show that 5-HT 2C agonists, at variance with 5-HT 2C antagonists, exert a preferential control on the impulse-stimulated release of DA.

Chronic L-dopa treatment of Parkinson&amp... more Chronic L-dopa treatment of Parkinson's disease (PD) often leads to debilitating involuntary movements, termed L-dopa-induced dyskinesia (LID), mediated by dopamine (DA) receptors. RGS9-2 is a GTPase accelerating protein that inhibits DA D2 receptor-activated G proteins. Herein, we assess the functional role of RGS9-2 on LID. In monkeys, Western blot analysis of striatal extracts shows that RGS9-2 levels are not altered by MPTP-induced DA denervation and/or chronic L-dopa administration. In MPTP monkeys with LID, striatal RGS9-2 overexpression--achieved by viral vector injection into the striatum--diminishes the involuntary movement intensity without lessening the anti-parkinsonian effects of the D1/D2 receptor agonist L-dopa. In contrasts, in these animals, striatal RGS9-2 overexpression diminishes both the involuntary movement intensity and the anti-parkinsonian effects of the D2/D3 receptor agonist ropinirole. In unilaterally 6-OHDA-lesioned rats with LID, we show that the time course of viral vector-mediated striatal RGS9-2 overexpression parallels the time course of improvement of L-dopa-induced involuntary movements. We also find that unilateral 6-OHDA-lesioned RGS9-/- mice are more susceptible to L-dopa-induced involuntary movements than unilateral 6-OHDA-lesioned RGS9+/+ mice, albeit the rotational behavior--taken as an index of the anti-parkinsonian response--is similar between the two groups of mice. Together, these findings suggest that RGS9-2 plays a pivotal role in LID pathophysiology. However, the findings also suggest that increasing RGS9-2 expression and/or function in PD patients may only be a suitable therapeutic strategy to control involuntary movements induced by nonselective DA agonist such as L-dopa.

L-dopa remains the mainstay treatment for Parkinson's disease (PD), although in later stages, tre... more L-dopa remains the mainstay treatment for Parkinson's disease (PD), although in later stages, treatment is complicated by L-dopa-induced dyskinesias (LID). Current evidence links LID to excessive striatal L-dopa-derived dopamine (DA) release, while the possibility of a direct involvement of L-dopa itself in LID has been largely ignored. Here we show that L-dopa can alter basal ganglia activity and produce LID without enhancing striatal DA release in parkinsonian non-human primates. These data may have therapeutic implications for the management of advanced PD since they suggest that LID could result from diverse mechanisms of action of L-dopa.

Handbook of Behavioral Neuroscience, 2010

Parkinsonism & Related Disorders, 2007

Objective: Chronic L-dopa treatment of Parkinson disease (PD) leads to debilitating involuntary m... more Objective: Chronic L-dopa treatment of Parkinson disease (PD) leads to debilitating involuntary movements, termed L-dopa-induced dyskinesia (LID), mediated in part by supersensitive dopamine (DA) receptors. The present experiments aimed at exploring the role of RGS9-2, a GTPase accelerating protein that potently inhibits DA D2 receptor-activated G proteins.

Journal of Neuroscience, 2009

We have associated behavioral, pharmacological, and quantitative immunohistochemical study in a r... more We have associated behavioral, pharmacological, and quantitative immunohistochemical study in a rat analog of L-DOPA-induced dyskinesia to understand whether alterations in dopamine receptor fate in striatal neurons may be involved in mechanisms leading to movement abnormalities. Detailed analysis at the ultrastructural level demonstrates specific alterations of dopamine D 1 receptor (D 1 R) subcellular localization in striatal medium spiny neurons in L-DOPA-treated 6-hydroxydopamine-lesioned rats with abnormal involuntary movements (AIMs). This includes exaggerated D 1 R expression at the plasma membrane. However, D 1 R retains ability of internalization, as a challenge with the potent D 1 R agonist SKF-82958 induces a strong decrease of labeling at membrane in animals with AIMs. Since a functional cross talk between D 1 R and D 3 R has been suggested, we hypothesized that their coactivation by dopamine derived from L-DOPA might anchor D 1 R at the membrane. Accordingly, cotreatment with L-DOPA and the D 3 R antagonist ST 198 restores normal level of membrane-bound D 1 R. Together, these results demonstrate that AIMs are related to abnormal D 1 R localization at the membrane and intraneuronal trafficking dysregulation, and suggest that strategies aiming at disrupting the D 1 R-D 3 R cross talk might reduce L-DOPAinduced dyskinesia by reducing D 1 R availability at the membrane.

Science Translational Medicine, 2010

Parkinson's disease is caused primarily by degeneration of brain dopaminergic neurons in the subs... more Parkinson's disease is caused primarily by degeneration of brain dopaminergic neurons in the substantia nigra and the consequent deficit of dopamine in the striatum. Dopamine replacement therapy with the dopamine precursor L-dopa is the mainstay of current treatment. After several years, however, the patients develop L-dopa-induced dyskinesia, or abnormal involuntary movements, thought to be due to excessive signaling via dopamine receptors. G protein-coupled receptor kinases (GRKs) control desensitization of dopamine receptors. We found that dyskinesia is attenuated by lentivirus-mediated overexpression of GRK6 in the striatum in rodent and primate models of Parkinson's disease. Conversely, reduction of GRK6 concentration by microRNA delivered with lentiviral vector exacerbated dyskinesia in parkinsonian rats. GRK6 suppressed dyskinesia in monkeys without compromising the antiparkinsonian effects of L-dopa and even prolonged the antiparkinsonian effect of a lower dose of L-dopa. Our finding that increased availability of GRK6 ameliorates dyskinesia and increases duration of the antiparkinsonian action of L-dopa suggests a promising approach for controlling both dyskinesia and motor fluctuations in Parkinson's disease.

Parkinsonism & Related Disorders, 2009

Background: The A11 diencephalospinal pathway is crucial for sensorimotor integration and pain co... more Background: The A11 diencephalospinal pathway is crucial for sensorimotor integration and pain control at the spinal cord level. When disrupted, it is thought to be involved in numerous painful conditions such as restless legs syndrome and migraine. Its anatomical organization, however, remains largely unknown in the non-human primate (NHP). We therefore characterized the anatomy of this pathway in the NHP.

Neuroscience Research, 2013

Parkinson's disease 6-OHDA Serotonin 5-HT1A/1B agonists a b s t r a c t

Neuroscience Letters, 2008

Dopamine agonists used to manage Parkinsonian motor symptoms have been suggested to be neuroprote... more Dopamine agonists used to manage Parkinsonian motor symptoms have been suggested to be neuroprotective. The study was designed to assess the neuroprotective potential of the D 3 /D 2 /D 1 dopamine receptor agonist rotigotine in the acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridinelesioned (MPTP) mouse model of Parkinson's disease by measuring mesencephalic degenerating neurons using FluoroJade staining and the remaining dopaminergic nerve endings in the striatum using dopamine transporter binding. Continuous administration of rotigotine at a dose of 3 mg/kg significantly attenuated MPTP-induced acute cell degeneration in the FluoroJade-staining paradigm. Rotigotine (0.3-3 mg/kg) partially protected dopamine nerve endings from MPTP-induced degeneration in a dose-dependent manner. These data suggest that rotigotine, at the doses employed, significantly protected dopamine neurons from degeneration in an acute mouse model of MPTP intoxication.

Neuropsychopharmacology, 2002

In vivo microdialysis and single-cell extracellular recordings were used to assess the involvemen... more In vivo microdialysis and single-cell extracellular recordings were used to assess the involvement of serotonin and serotonin 2C/2B (5-HT 2C/2B ) receptors in the effects induced by amphetamine and morphine on dopaminergic (DA) activity within the mesoaccumbal and nigrostriatal pathways. The increase in DA release induced by amphetamine (2 mg/kg i.p.) in the nucleus accumbens and striatum was significantly reduced by the selective 5-HT 2A antagonist SR 46349B (0.5 mg/kg s.c.), but not affected by the 5-HT 2C/2B antagonist SB 206553 (5 mg/kg i.p.). In contrast, the enhancement of accumbal and striatal DA output induced by morphine (2.5 mg/kg s.c.), while insensitive to SR 46349B, was significantly increased by SB 206553. Furthermore, morphine (0.1-10 mg/kg i.v.)-induced increase in DA neuron firing rate in both the ventral tegmental area and the substantia nigra pars compacta was unaffected by SR 46349B (0.1 mg/kg i.v.) but significantly potentiated by SB 206553 (0. . These results show that 5-HT 2A and 5-HT 2C receptors regulate specifically the activation of midbrain DA neurons induced by amphetamine and morphine, respectively. This differential contribution may be related to the specific mechanism of action of the drug considered and to the neuronal circuitry involved in their effect on DA neurons. Furthermore, these results suggest that 5-HT 2C receptors selectively modulate the impulse flow-dependent release of DA.