The Experts below are selected from a list of 1107 Experts worldwide ranked by ideXlab platform
Paolo Calabresi - One of the best experts on this subject based on the ideXlab platform.
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dopamine drives binge like consumption of a palatable food in Experimental Parkinsonism
Movement Disorders, 2019Co-Authors: Desiree Mineo, Paolo Calabresi, Fabrizio Cacace, Maria Mancini, Anna Vannelli, Federica Campanelli, Giuseppina Natale, Gioia Marino, Antonella Cardinale, Barbara PicconiAbstract:Background Prolonged dopaminergic replacement therapy in PD results in pulsatile dopamine receptors stimulation in both dorsal and ventral striatum causing wearing off, motor fluctuations, and nonmotor side effects such as behavioral addictions. Among impulse control disorders, binge eating can be easily modeled in laboratory animals. Objectives We hypothesize that manipulation of dopamine levels in a 6-hydroxydopamine-lesioned rats, as a model of PD characterized by a different extent of dopamine denervation between dorsal and ventral striatum, would influence both synaptic plasticity of the nucleus accumbens and binge-like eating behavior. Methods Food preference, food intake, and weight gain were monitored in sham-operated and unilaterally lesioned rats, subjected to a modified version of Corwin's limited access protocol, modelling binge eating disorder. Electrophysiological properties and long-term potentiation of GABAergic spiny projection neurons of the nucleus accumbens core were studied through ex vivo intracellular and patch-clamp recordings from corticostriatal slices of naive and l-dopa-treated rats. Results Sham-operated animals with intact nucleus accumbens core plasticity reliably developed food-addiction-like behavior when exposed to intermittent access to a highly palatable food. In contrast, parkinsonian rats were unresponsive to such restriction regimens, and also plasticity was lost in ventral spiny neurons. Chronic l-dopa reestablished long-term potentiation and compulsive eating, but with a different temporal dynamic that follows that of drug administration. Conclusions Our data indicate that endogenous and exogenous dopamine drive binge-like consumption of a palatable food in healthy and parkinsonian rats with distinct temporal dynamics, providing new insights into the complexity of l-dopa effects on the mesolimbic dopaminergic system. © 2019 International Parkinson and Movement Disorder Society.
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region specific restoration of striatal synaptic plasticity by dopamine grafts in Experimental Parkinsonism
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Daniella Rylander, Paolo Calabresi, Vincenza Bagetta, Valentina Pendolino, Elisa Zianni, Shane Grealish, Fabrizio Gardoni, Monica Di Luca, Angela M Cenci, Barbara PicconiAbstract:Intrastriatal transplantation of dopaminergic neurons can restore striatal dopamine levels and improve parkinsonian deficits, but the mechanisms underlying these effects are poorly understood. Here, we show that transplants of dopamine neurons partially restore activity-dependent synaptic plasticity in the host striatal neurons. We evaluated synaptic plasticity in regions distal or proximal to the transplant (i.e., dorsolateral and ventrolateral striatum) and compared the effects of dopamine- and serotonin-enriched grafts using a rat model of Parkinson disease. Naive rats showed comparable intrinsic membrane properties in the two subregions but distinct patterns of long-term synaptic plasticity. The ventrolateral striatum showed long-term potentiation using the same protocol that elicited long-term depression in the dorsolateral striatum. The long-term potentiation was linked to higher expression of postsynaptic AMPA and N2B NMDA subunits (GluN2B) and was dependent on the activation of GluN2A and GluN2B subunits and the D1 dopamine receptor. In both regions, the synaptic plasticity was abolished after a severe dopamine depletion and could not be restored by grafted serotonergic neurons. Solely, dopamine-enriched grafts could restore the long-term potentiation and partially restore motor deficits in the rats. The restoration could only be seen close to the graft, in the ventrolateral striatum where the graft-derived reinnervation was denser, compared with the distal dorsolateral region. These data provide proof of concept that dopamine-enriched transplants are able to functionally integrate into the host brain and restore deficits in striatal synaptic plasticity after Experimental Parkinsonism. The region-specific restoration might impose limitations in symptomatic improvement following neural transplantation.
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Region-specific restoration of striatal synaptic plasticity by dopamine grafts in Experimental Parkinsonism
'Proceedings of the National Academy of Sciences', 2013Co-Authors: Daniella Rylander, Paolo Calabresi, Vincenza Bagetta, Valentina Pendolino, Elisa Zianni, Shane Grealish, Fabrizio Gardoni, Monica Di Luca, M. Cenci, Barbara PicconiAbstract:Intrastriatal transplantation of dopaminergic neurons can restore striatal dopamine levels and improve parkinsonian deficits, but the mechanisms underlying these effects are poorly understood. Here, we show that transplants of dopamine neurons partially restore activity-dependent synaptic plasticity in the host striatal neurons. We evaluated synaptic plasticity in regions distal or proximal to the transplant (i.e., dorsolateral and ventrolateral striatum) and compared the effects of dopamine- and serotonin-enriched grafts using a rat model of Parkinson disease. Na\uefve rats showed comparable intrinsic membrane properties in the two subregions but distinct patterns of long-term synaptic plasticity. The ventrolateral striatum showed long-term potentiation using the same protocol that elicited long-term depression in the dorsolateral striatum. The long-term potentiation was linked to higher expression of postsynaptic AMPA and N2B NMDA subunits (GluN2B) and was dependent on the activation of GluN2A and GluN2B subunits and the D1 dopamine receptor. In both regions, the synaptic plasticity was abolished after a severe dopamine depletion and could not be restored by grafted serotonergic neurons. Solely, dopamine-enriched grafts could restore the long-term potentiation and partially restore motor deficits in the rats. The restoration could only be seen close to the graft, in the ventrolateral striatum where the graft-derived reinnervation was denser, compared with the distal dorsolateral region. These data provide proof of concept that dopamine-enriched transplants are able to functionally integrate into the host brain and restore deficits in striatal synaptic plasticity after Experimental Parkinsonism. The region-specific restoration might impose limitations in symptomatic improvement following neural transplantation
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theta burst stimulation and striatal plasticity in Experimental Parkinsonism
Experimental Neurology, 2012Co-Authors: Veronica Ghiglieri, Barbara Picconi, Vincenza Bagetta, Valentina Pendolino, Carmelo Sgobio, Paolo CalabresiAbstract:Repetitive transcranial magnetic stimulation (rTMS) in humans increases levels of dopamine (DA) in the vicinity of highly active corticostriatal terminals suggesting its use to alleviate symptoms in Parkinson's disease (PD). However, the effects of rTMS on corticostriatal plasticity have not been explored. Here we show that a single-session of cortical rTMS using intermittent theta-burst stimulation (iTBS) pattern increases striatal excitability and rescues corticostriatal long-term depression (LTD) in a significant number of field excitatory postsynaptic potentials (fEPSP) recorded from hemiparkinsonian rats. These data indicate that cortical iTBS affects neuronal activity of subcortical regions, providing Experimental evidence for its use in clinical settings.
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Striatal synaptic changes in Experimental Parkinsonism: role of NMDA receptor trafficking in PSD.
Parkinsonism & Related Disorders, 2008Co-Authors: Barbara Picconi, Vincenza Bagetta, Veronica Ghiglieri, Carmelo Sgobio, Ilaria Barone, Paolo CalabresiAbstract:Abstract Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive degeneration of dopaminergic terminals from substantia nigra pars compacts, which leads to the motor symptoms observed in this disorder. l -Dopa administration represents the most effective therapeutic treatment of PD, but the development of disabling dyskinetic movements is a dramatic consequence of the treatment. The organization and functional interactions of glutamate receptors within the striatum appear to be crucial both in the pathogenesis of PD and in the development of dyskinesia. At the molecular level, it has become increasingly evident that the glutamatergic NMDA receptor complex is a dynamic structure that is involved in the regulation of corticostriatal long-term synaptic changes, which is altered in Experimental PD and in dyskinesia.
Barbara Picconi - One of the best experts on this subject based on the ideXlab platform.
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dopamine drives binge like consumption of a palatable food in Experimental Parkinsonism
Movement Disorders, 2019Co-Authors: Desiree Mineo, Paolo Calabresi, Fabrizio Cacace, Maria Mancini, Anna Vannelli, Federica Campanelli, Giuseppina Natale, Gioia Marino, Antonella Cardinale, Barbara PicconiAbstract:Background Prolonged dopaminergic replacement therapy in PD results in pulsatile dopamine receptors stimulation in both dorsal and ventral striatum causing wearing off, motor fluctuations, and nonmotor side effects such as behavioral addictions. Among impulse control disorders, binge eating can be easily modeled in laboratory animals. Objectives We hypothesize that manipulation of dopamine levels in a 6-hydroxydopamine-lesioned rats, as a model of PD characterized by a different extent of dopamine denervation between dorsal and ventral striatum, would influence both synaptic plasticity of the nucleus accumbens and binge-like eating behavior. Methods Food preference, food intake, and weight gain were monitored in sham-operated and unilaterally lesioned rats, subjected to a modified version of Corwin's limited access protocol, modelling binge eating disorder. Electrophysiological properties and long-term potentiation of GABAergic spiny projection neurons of the nucleus accumbens core were studied through ex vivo intracellular and patch-clamp recordings from corticostriatal slices of naive and l-dopa-treated rats. Results Sham-operated animals with intact nucleus accumbens core plasticity reliably developed food-addiction-like behavior when exposed to intermittent access to a highly palatable food. In contrast, parkinsonian rats were unresponsive to such restriction regimens, and also plasticity was lost in ventral spiny neurons. Chronic l-dopa reestablished long-term potentiation and compulsive eating, but with a different temporal dynamic that follows that of drug administration. Conclusions Our data indicate that endogenous and exogenous dopamine drive binge-like consumption of a palatable food in healthy and parkinsonian rats with distinct temporal dynamics, providing new insights into the complexity of l-dopa effects on the mesolimbic dopaminergic system. © 2019 International Parkinson and Movement Disorder Society.
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region specific restoration of striatal synaptic plasticity by dopamine grafts in Experimental Parkinsonism
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Daniella Rylander, Paolo Calabresi, Vincenza Bagetta, Valentina Pendolino, Elisa Zianni, Shane Grealish, Fabrizio Gardoni, Monica Di Luca, Angela M Cenci, Barbara PicconiAbstract:Intrastriatal transplantation of dopaminergic neurons can restore striatal dopamine levels and improve parkinsonian deficits, but the mechanisms underlying these effects are poorly understood. Here, we show that transplants of dopamine neurons partially restore activity-dependent synaptic plasticity in the host striatal neurons. We evaluated synaptic plasticity in regions distal or proximal to the transplant (i.e., dorsolateral and ventrolateral striatum) and compared the effects of dopamine- and serotonin-enriched grafts using a rat model of Parkinson disease. Naive rats showed comparable intrinsic membrane properties in the two subregions but distinct patterns of long-term synaptic plasticity. The ventrolateral striatum showed long-term potentiation using the same protocol that elicited long-term depression in the dorsolateral striatum. The long-term potentiation was linked to higher expression of postsynaptic AMPA and N2B NMDA subunits (GluN2B) and was dependent on the activation of GluN2A and GluN2B subunits and the D1 dopamine receptor. In both regions, the synaptic plasticity was abolished after a severe dopamine depletion and could not be restored by grafted serotonergic neurons. Solely, dopamine-enriched grafts could restore the long-term potentiation and partially restore motor deficits in the rats. The restoration could only be seen close to the graft, in the ventrolateral striatum where the graft-derived reinnervation was denser, compared with the distal dorsolateral region. These data provide proof of concept that dopamine-enriched transplants are able to functionally integrate into the host brain and restore deficits in striatal synaptic plasticity after Experimental Parkinsonism. The region-specific restoration might impose limitations in symptomatic improvement following neural transplantation.
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Region-specific restoration of striatal synaptic plasticity by dopamine grafts in Experimental Parkinsonism
'Proceedings of the National Academy of Sciences', 2013Co-Authors: Daniella Rylander, Paolo Calabresi, Vincenza Bagetta, Valentina Pendolino, Elisa Zianni, Shane Grealish, Fabrizio Gardoni, Monica Di Luca, M. Cenci, Barbara PicconiAbstract:Intrastriatal transplantation of dopaminergic neurons can restore striatal dopamine levels and improve parkinsonian deficits, but the mechanisms underlying these effects are poorly understood. Here, we show that transplants of dopamine neurons partially restore activity-dependent synaptic plasticity in the host striatal neurons. We evaluated synaptic plasticity in regions distal or proximal to the transplant (i.e., dorsolateral and ventrolateral striatum) and compared the effects of dopamine- and serotonin-enriched grafts using a rat model of Parkinson disease. Na\uefve rats showed comparable intrinsic membrane properties in the two subregions but distinct patterns of long-term synaptic plasticity. The ventrolateral striatum showed long-term potentiation using the same protocol that elicited long-term depression in the dorsolateral striatum. The long-term potentiation was linked to higher expression of postsynaptic AMPA and N2B NMDA subunits (GluN2B) and was dependent on the activation of GluN2A and GluN2B subunits and the D1 dopamine receptor. In both regions, the synaptic plasticity was abolished after a severe dopamine depletion and could not be restored by grafted serotonergic neurons. Solely, dopamine-enriched grafts could restore the long-term potentiation and partially restore motor deficits in the rats. The restoration could only be seen close to the graft, in the ventrolateral striatum where the graft-derived reinnervation was denser, compared with the distal dorsolateral region. These data provide proof of concept that dopamine-enriched transplants are able to functionally integrate into the host brain and restore deficits in striatal synaptic plasticity after Experimental Parkinsonism. The region-specific restoration might impose limitations in symptomatic improvement following neural transplantation
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theta burst stimulation and striatal plasticity in Experimental Parkinsonism
Experimental Neurology, 2012Co-Authors: Veronica Ghiglieri, Barbara Picconi, Vincenza Bagetta, Valentina Pendolino, Carmelo Sgobio, Paolo CalabresiAbstract:Repetitive transcranial magnetic stimulation (rTMS) in humans increases levels of dopamine (DA) in the vicinity of highly active corticostriatal terminals suggesting its use to alleviate symptoms in Parkinson's disease (PD). However, the effects of rTMS on corticostriatal plasticity have not been explored. Here we show that a single-session of cortical rTMS using intermittent theta-burst stimulation (iTBS) pattern increases striatal excitability and rescues corticostriatal long-term depression (LTD) in a significant number of field excitatory postsynaptic potentials (fEPSP) recorded from hemiparkinsonian rats. These data indicate that cortical iTBS affects neuronal activity of subcortical regions, providing Experimental evidence for its use in clinical settings.
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Striatal synaptic changes in Experimental Parkinsonism: role of NMDA receptor trafficking in PSD.
Parkinsonism & Related Disorders, 2008Co-Authors: Barbara Picconi, Vincenza Bagetta, Veronica Ghiglieri, Carmelo Sgobio, Ilaria Barone, Paolo CalabresiAbstract:Abstract Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive degeneration of dopaminergic terminals from substantia nigra pars compacts, which leads to the motor symptoms observed in this disorder. l -Dopa administration represents the most effective therapeutic treatment of PD, but the development of disabling dyskinetic movements is a dramatic consequence of the treatment. The organization and functional interactions of glutamate receptors within the striatum appear to be crucial both in the pathogenesis of PD and in the development of dyskinesia. At the molecular level, it has become increasingly evident that the glutamatergic NMDA receptor complex is a dynamic structure that is involved in the regulation of corticostriatal long-term synaptic changes, which is altered in Experimental PD and in dyskinesia.
Francisco Ciruela - One of the best experts on this subject based on the ideXlab platform.
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triglyceride form of docosahexaenoic acid mediates neuroprotection in Experimental Parkinsonism
Frontiers in Neuroscience, 2018Co-Authors: Maricel Gomezsoler, Victor Fernandezduenas, Begona Cordobilla, Xavier Morato, Joan Carles Domingo, Francisco CiruelaAbstract:Parkinson's disease (PD) is a neurodegenerative disorder of unknown etiology. The main treatment of PD consists of medication with dopamine-based drugs, which palliate the symptoms but may produce adverse effects after chronic administration. Accordingly, there is a need to develop novel neuroprotective therapies. Several studies suggest that omega-3 polyunsaturated fatty acids (n-3 PUFA) might provide protection against brain damage. Here, we studied several Experimental models of PD, using striatal neuronal cultures, striatal slices, and mice, to assess the neuroprotective effects of docosahexaenoic acid (DHA), the main n-3 PUFA in the brain, administered in its triglyceride form (TG-DHA). Hence, we determined the beneficial effects of TG-DHA on neural viability following 6-hydroxydopamine (6-OHDA)-induced neurotoxicity, a well-established PD model. We also implemented a novel mouse behavioral test, the beam walking test, to finely assess mouse motor skills following dopaminergic denervation. This test showed potential as a useful behavioral tool to assess novel PD treatments. Our results indicated that TG-DHA-mediated neuroprotection was independent of the net incorporation of PUFA into the striatum, thus suggesting a tight control of brain lipid homeostasis both in normal and pathological conditions.
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uncovering caffeine s adenosine a2a receptor inverse agonism in Experimental Parkinsonism
ACS Chemical Biology, 2014Co-Authors: Victor Fernandezduenas, Jaume Taura, Catherine Ledent, Masahiko Watanabe, Jean-pierre Vilardaga, Maricel Gomezsoler, Marc Lopezcano, Francisco CiruelaAbstract:Caffeine, the most consumed psychoactive substance worldwide, may have beneficial effects on Parkinson’s disease (PD) therapy. The mechanism by which caffeine contributes to its antiparkinsonian effects by acting as either an adenosine A2A receptor (A2AR) neutral antagonist or an inverse agonist is unresolved. Here we show that caffeine is an A2AR inverse agonist in cell-based functional studies and in Experimental Parkinsonism. Thus, we observed that caffeine triggers a distinct mode, opposite to A2AR agonist, of the receptor’s activation switch leading to suppression of its spontaneous activity. These inverse agonist-related effects were also determined in the striatum of a mouse model of PD, correlating well with increased caffeine-mediated motor effects. Overall, caffeine A2AR inverse agonism may be behind some of the well-known physiological effects of this substance both in health and disease. This information might have a critical mechanistic impact for PD pharmacotherapeutic design.
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Uncovering Caffeine’s Adenosine A2A Receptor Inverse Agonism in Experimental Parkinsonism
ACS chemical biology, 2014Co-Authors: Víctor Fernández-dueñas, Maricel Gómez-soler, Marc López-cano, Jaume Taura, Catherine Ledent, Masahiko Watanabe, Jean-pierre Vilardaga, Francisco CiruelaAbstract:Caffeine, the most consumed psychoactive substance worldwide, may have beneficial effects on Parkinson’s disease (PD) therapy. The mechanism by which caffeine contributes to its antiparkinsonian effects by acting as either an adenosine A2A receptor (A2AR) neutral antagonist or an inverse agonist is unresolved. Here we show that caffeine is an A2AR inverse agonist in cell-based functional studies and in Experimental Parkinsonism. Thus, we observed that caffeine triggers a distinct mode, opposite to A2AR agonist, of the receptor’s activation switch leading to suppression of its spontaneous activity. These inverse agonist-related effects were also determined in the striatum of a mouse model of PD, correlating well with increased caffeine-mediated motor effects. Overall, caffeine A2AR inverse agonism may be behind some of the well-known physiological effects of this substance both in health and disease. This information might have a critical mechanistic impact for PD pharmacotherapeutic design.
Per Svenningsson - One of the best experts on this subject based on the ideXlab platform.
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non dopaminergic alterations in depression like fsl rats in Experimental Parkinsonism and l dopa responses
Frontiers in Pharmacology, 2020Co-Authors: Nicoletta Schintu, Xiaoqun Zhang, Nikolas Stroth, Aleksander A Mathe, Per E Andren, Per SvenningssonAbstract:Depression is a common comorbid condition in Parkinson's disease (PD). Patients with depression have a two-fold increased risk to develop PD. Further, depression symptoms often precede motor sympto ...
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genetic deletion of gpr88 enhances the locomotor response to l dopa in Experimental Parkinsonism while counteracting the induction of dyskinesia
Neuropharmacology, 2020Co-Authors: Ioannis Mantas, Xiaoqun Zhang, Yunting Yang, Clotilde Mannourylacour, Millan Mark, Per SvenningssonAbstract:Parkinson's disease (PD) is characterized by progressive loss of midbrain dopaminergic neurons and treated with the dopamine precursor, 3,4-dihydroxy-l-phenylalanine (L-DOPA). Prolonged L-DOPA treatment is however associated with waning efficacy and the induction of L-DOPA induced dyskinesia (LID). GPR88 is an orphan G-protein Coupled Receptor (GPCR) expressed in dopaminoceptive striatal medium spiny neurons (MSNs) and their afferent corticostriatal glutamatergic neurons. Here, we studied the role of GPR88 in Experimental Parkinsonism and LID. Chronic L-DOPA administration to male GPR88 KO mice, subjected to unilateral 6-hydroxydopamine (6-OHDA) lesions of the medial forebrain bundle, resulted in more rotations than in their WT counterparts. Conversely, GPR88 KO mice had a lower abnormal involuntary movements (AIMs) score. These behavioral responses were accompanied by altered transcription of L-DOPA upregulated genes in lesioned GPR88 KO compared to WT striata. In accordance with a role for serotonin neurons in LID development, WT but not GPR88 KO striata exhibited 5-hydroxytryptamine displacement upon repeated L-DOPA treatment. Intact male GPR88 KO mice showed diminished tacrine-induced PD-like tremor and spontaneous hyperlocomotion. Dopamine and its metabolites were not increased in male GPR88 KO mice, but biosensor recordings revealed increased spontaneous/basal and evoked glutamate release in striata of male GPR88 KO mice. In conclusion, genetic deletion of GPR88 promotes l-DOPA-induced rotation and spontaneous locomotion yet suppresses the induction of LIDs and also reduces tremor. These data provide behavioral, neurochemical and molecular support that GPR88 antagonism may favour motor relief in PD patients without aggravating the induction of motor side effects.
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asymmetric dopaminergic degeneration and levodopa alter functional corticostriatal connectivity bilaterally in Experimental Parkinsonism
Experimental Neurology, 2017Co-Authors: Cyril Monnot, Xiaoqun Zhang, Sahar Nikkhouaski, Peter Damberg, Per SvenningssonAbstract:Asymmetric dopamine loss is commonly found in early Parkinson's disease (PD), but its effects on functional networks have been difficult to delineate in PD patients because of variations in age, disease duration and therapy. Here we used unilateral 6-hydroxydopamine-lesioned (6-OHDA) rats and controls and treated them with a single intraperitoneal injection of levodopa (L-DOPA) before performing diffusion weighted MRI and resting state functional MRI (rs-fMRI). In accordance with a neurodegeneration of the nigrostriatal dopaminergic pathway, diffusion tensor imaging showed increased radial diffusivity and decreased fractional anisotropy in the lesioned substantia nigra. Likewise a deterministic connectometry approach showed increase of isotropic diffusion values in the medial forebrain bundle. rs-fMRI showed reduced interhemispheric functional connectivity (FC) between the intact and the 6-OHDA lesioned caudate-putamen. Unexpectedly, there was an increased FC between the 6-OHDA lesioned caudate-putamen and sensorimotor cortices of both hemispheres. L-DOPA reversed the FC changes between the dopamine denervated caudate-putamen and the sensorimotor cortices, but not the reduced interhemispheric FC between caudate-putamina. Similarly, L-DOPA induced c-fos expression in both sensorimotor cortices, but only in the dopamine-depleted caudate-putamen. Taken together, these data suggest that asymmetric degeneration of the nigrostriatal dopamine pathway results in functional asynchrony between the intact and 6-OHDA-lesioned caudate-putamen and increased interhemispheric synchrony between sensorimotor cortices. The results also indicate that the initial effect of L-DOPA is to restore functional corticostriatal connectivity rather than synchronize caudate-putamina.
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p11 modulates l dopa therapeutic effects and dyskinesia via distinct cell types in Experimental Parkinsonism
Proceedings of the National Academy of Sciences of the United States of America, 2016Co-Authors: Nicoletta Schintu, Alexandra Alvarsson, Xiaoqun Zhang, Roberta Marongiu, Michael G Kaplitt, Paul Greengard, Per SvenningssonAbstract:The reduced movement repertoire of Parkinson's disease (PD) is mainly due to degeneration of nigrostriatal dopamine neurons. Restoration of dopamine transmission by levodopa (L-DOPA) relieves motor symptoms of PD but often causes disabling dyskinesias. Subchronic L-DOPA increases levels of adaptor protein p11 (S100A10) in dopaminoceptive neurons of the striatum. Using Experimental mouse models of Parkinsonism, we report here that global p11 knockout (KO) mice develop fewer jaw tremors in response to tacrine. Following L-DOPA, global p11KO mice show reduced therapeutic responses on rotational motor sensitization, but also develop less dyskinetic side effects. Studies using conditional p11KO mice reveal that distinct cell populations mediate these therapeutic and side effects. Selective deletion of p11 in cholinergic acetyltransferase (ChAT) neurons reduces tacrine-induced tremor. Mice lacking p11 in dopamine D2R-containing neurons have a reduced response to L-DOPA on the therapeutic parameters, but develop dyskinetic side effects. In contrast, mice lacking p11 in dopamine D1R-containing neurons exhibit tremor and rotational responses toward L-DOPA, but develop less dyskinesia. Moreover, coadministration of rapamycin with L-DOPA counteracts L-DOPA-induced dyskinesias in wild-type mice, but not in mice lacking p11 in D1R-containing neurons. 6-OHDA lesioning causes an increase of evoked striatal glutamate release in wild type, but not in global p11KO mice, indicating that altered glutamate neurotransmission could contribute to the reduced L-DOPA responsivity. These data demonstrate that p11 located in ChAT or D2R-containing neurons is involved in regulating therapeutic actions in Experimental PD, whereas p11 in D1R-containing neurons underlies the development of L-DOPA-induced dyskinesias.
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modulation by trace amine associated receptor 1 of Experimental Parkinsonism l dopa responsivity and glutamatergic neurotransmission
The Journal of Neuroscience, 2015Co-Authors: Alexandra Alvarsson, Mark J Millan, Xiaoqun Zhang, Tiberiu Loredan Stan, Nicoletta Schintu, Banafsheh Kadkhodaei, Thomas Perlmann, Per SvenningssonAbstract:Parkinson9s disease (PD) is a movement disorder characterized by a progressive loss of nigrostriatal dopaminergic neurons. Restoration of dopamine transmission by l-DOPA relieves symptoms of PD but causes dyskinesia. Trace Amine-Associated Receptor 1 (TAAR1) modulates dopaminergic transmission, but its role in Experimental Parkinsonism and l-DOPA responses has been neglected. Here, we report that TAAR1 knock-out (KO) mice show a reduced loss of dopaminergic markers in response to intrastriatal 6-OHDA administration compared with wild-type (WT) littermates. In contrast, the TAAR1 agonist RO5166017 aggravated degeneration induced by intrastriatal 6-OHDA in WT mice. Subchronic l-DOPA treatment of TAAR1 KO mice unilaterally lesioned with 6-OHDA in the medial forebrain bundle resulted in more pronounced rotational behavior and dyskinesia than in their WT counterparts. The enhanced behavioral sensitization to l-DOPA in TAAR1 KO mice was paralleled by increased phosphorylation of striatal GluA1 subunits of AMPA receptors. Conversely, RO5166017 counteracted both l-DOPA-induced rotation and dyskinesia as well as AMPA receptor phosphorylation. Underpinning a role for TAAR1 receptors in modulating glutamate neurotransmission, intrastriatal application of RO5166017 prevented the increase of evoked corticostriatal glutamate release provoked by dopamine deficiency after 6-OHDA-lesions or conditional KO of Nurr1. Finally, inhibition of corticostriatal glutamate release by TAAR1 showed mechanistic similarities to that effected by activation of dopamine D 2 receptors. These data unveil a role for TAAR1 in modulating the degeneration of dopaminergic neurons, the behavioral response to l-DOPA, and presynaptic and postsynaptic glutamate neurotransmission in the striatum, supporting their relevance to the pathophysiology and, potentially, management of PD. SIGNIFICANCE STATEMENT Parkinson9s disease (PD) is characterized by a progressive loss of nigrostriatal dopaminergic neurons. Restoration of dopamine transmission by l-DOPA relieves symptoms of PD but causes severe side effects. Trace Amine-Associated Receptor 1 (TAAR1) modulates dopaminergic transmission, but its role in PD and l-DOPA responses has been neglected. Here, we report that TAAR1 potentiates the degeneration of dopaminergic neurons and attenuates the behavioral response to l-DOPA and presynaptic and postsynaptic glutamate neurotransmission in the striatum, supporting the relevance of TAAR1 to the pathophysiology and, potentially, management of PD.
Catherine Ledent - One of the best experts on this subject based on the ideXlab platform.
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Untangling dopamine-adenosine receptor-receptor assembly in Experimental Parkinsonism in rats
Disease Models & Mechanisms, 2015Co-Authors: Víctor Fernández-dueñas, Maricel Gómez-soler, Marc López-cano, Catherine Ledent, Jeanphilippe Pin, J. J. Taura, Martin Cottet, M. Watanabe, E. Trinquet, R. LujanAbstract:Parkinson's disease (PD) is a dopaminergic-related pathology in which functioning of the basal ganglia is altered. It has been postulated that a direct receptor-receptor interaction - i.e. of dopamine D2 receptor (D2R) with adenosine A2A receptor (A2AR) (forming D2R-A2AR oligomers) - finely regulates this brain area. Accordingly, elucidating whether the pathology prompts changes to these complexes could provide valuable information for the design of new PD therapies. Here, we first resolved a long-standing question concerning whether D2R-A2AR assembly occurs in native tissue: by means of different complementary Experimental approaches (i.e. immunoelectron microscopy, proximity ligation assay and TR-FRET), we unambiguously identified native D2R-A2AR oligomers in rat striatum. Subsequently, we determined that, under pathological conditions (i.e. in a rat PD model), D2R-A2AR interaction was impaired. Collectively, these results provide definitive evidence for alteration of native D2R-A2AR oligomers in Experimental Parkinsonism, thus conferring the rationale for appropriate oligomer-based PD treatments.
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uncovering caffeine s adenosine a2a receptor inverse agonism in Experimental Parkinsonism
ACS Chemical Biology, 2014Co-Authors: Victor Fernandezduenas, Jaume Taura, Catherine Ledent, Masahiko Watanabe, Jean-pierre Vilardaga, Maricel Gomezsoler, Marc Lopezcano, Francisco CiruelaAbstract:Caffeine, the most consumed psychoactive substance worldwide, may have beneficial effects on Parkinson’s disease (PD) therapy. The mechanism by which caffeine contributes to its antiparkinsonian effects by acting as either an adenosine A2A receptor (A2AR) neutral antagonist or an inverse agonist is unresolved. Here we show that caffeine is an A2AR inverse agonist in cell-based functional studies and in Experimental Parkinsonism. Thus, we observed that caffeine triggers a distinct mode, opposite to A2AR agonist, of the receptor’s activation switch leading to suppression of its spontaneous activity. These inverse agonist-related effects were also determined in the striatum of a mouse model of PD, correlating well with increased caffeine-mediated motor effects. Overall, caffeine A2AR inverse agonism may be behind some of the well-known physiological effects of this substance both in health and disease. This information might have a critical mechanistic impact for PD pharmacotherapeutic design.
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Uncovering Caffeine’s Adenosine A2A Receptor Inverse Agonism in Experimental Parkinsonism
ACS chemical biology, 2014Co-Authors: Víctor Fernández-dueñas, Maricel Gómez-soler, Marc López-cano, Jaume Taura, Catherine Ledent, Masahiko Watanabe, Jean-pierre Vilardaga, Francisco CiruelaAbstract:Caffeine, the most consumed psychoactive substance worldwide, may have beneficial effects on Parkinson’s disease (PD) therapy. The mechanism by which caffeine contributes to its antiparkinsonian effects by acting as either an adenosine A2A receptor (A2AR) neutral antagonist or an inverse agonist is unresolved. Here we show that caffeine is an A2AR inverse agonist in cell-based functional studies and in Experimental Parkinsonism. Thus, we observed that caffeine triggers a distinct mode, opposite to A2AR agonist, of the receptor’s activation switch leading to suppression of its spontaneous activity. These inverse agonist-related effects were also determined in the striatum of a mouse model of PD, correlating well with increased caffeine-mediated motor effects. Overall, caffeine A2AR inverse agonism may be behind some of the well-known physiological effects of this substance both in health and disease. This information might have a critical mechanistic impact for PD pharmacotherapeutic design.
