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Marc Savasta

Publications and source records attributed to Marc Savasta.

10 recordsLinked to original sources
PubMed2006

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 Parkinson's 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.

Animals↗
PubMed2006

Benefit of tianeptine and morphine in a transgenic model of familial amyotrophic lateral sclerosis.

The familial form of amyotrophic lateral sclerosis (FALS) has been linked in some cases to dominant mutations in the gene encoding the Cu/Zn superoxide dismutase (SOD1) mutation. Transgenic mice bearing the G93A SOD1 mutation develop clinical symptoms and pathological features similar to those described in the human disease and represent a good model to explore the potential benefit of therapeutic agents. Using this animal model, we tested the efficacy of morphine and tianeptine treatments, separately and in association, on both disease progression and survival. Acute injection of either of them, administered daily and before the onset of the disease, significantly prolonged the survival of the transgenic mice.

Amyotrophic Lateral Sclerosis↗
PubMed2005

Functional reinnervation from remaining DA terminals induced by GDNF lentivirus in a rat model of early Parkinson's disease.

Glial cell-line derived neurotrophic factor (GDNF) is a good candidate agent for restoring functional reinnervation and/or neuroprotection of dopamine (DA) nigrostriatal system and thus for the treatment of Parkinson's disease (PD). Viral delivery is currently the most likely in vivo strategy for delivery of the therapeutic protein into the brain for treatment of neurological diseases. However, one of the important unresolved issues for this strategy is the threshold number of DA nigral neurons and/or of striatal DA terminals necessary for optimal benefit from GDNF therapy. In this study, we examined the intrastriatal neurotrophic effects of long-term GDNF delivery using a lentiviral vector in a new rat model of early PD. Lenti-GDNF was injected into the striatum 4 weeks after partial substantia nigra pars compacta 6-hydroxydopamine-induced lesion. Striatal denervation was evaluated by assessing tyrosine hydroxylase-positive DA fiber density and corroborated by testing motor deficit by means of a staircase test. GDNF treatment restored complete striatal DA innervation in the previously denervated area and this was associated with significant behavioral improvements.

Animals↗
PubMed2005

Pallidal origin of GABA release within the substantia nigra pars reticulata during high-frequency stimulation of the subthalamic nucleus.

High-frequency stimulation of the subthalamic nucleus (HFS-STN) is an effective treatment for alleviating the motor symptoms of parkinsonian patients. However, the neurochemical basis of its effects remains unknown. We showed previously that 1 h of HFS-STN in normal rats increases extracellular glutamate (Glu) level in the output nuclei of the STN, the globus pallidus (GP), and the substantia nigra pars reticulata (SNr), consistent with an increase in the activity of STN neurons. HFS-STN also increases GABA levels in the SNr, but the origin of this increase is unclear. We investigated the effectiveness of HFS-STN for improving Parkinson's disease symptoms, using intracerebral microdialysis to determine the extracellular Glu and GABA levels of the GP and SNr in response to HFS-STN in anesthetized hemiparkinsonian rats [6-hydroxydopamine lesion of the substantia nigra pars compacta (SNc)]. Basal levels of Glu and GABA in the GP and SNr were significantly higher in hemiparkinsonian than in intact rats. HFS-STN did not affect extracellular Glu level in the SNr of hemiparkinsonian rats but doubled the level of GABA. Ibotenic acid lesion of the GP abolished the increase in GABA levels in the SNr induced by HFS-STN in SNc-lesioned rats. These results provide neurochemical confirmation of the hyperactivity of the STN after dopaminergic denervation and suggest that the therapeutic effects of HFS-STN may result partly from the stimulation of pallidonigral fibers, thereby revealing a potential role for pallidal GABA in the inhibition of basal ganglial output structures during HFS-STN.

Animals↗
PubMed2004

Uncovering the mechanism(s) of action of deep brain stimulation: activation, inhibition, or both.

High-frequency deep brain stimulation (DBS) of the thalamus or basal ganglia represents an effective clinical technique for the treatment of several medically refractory movement disorders. However, understanding of the mechanisms responsible for the therapeutic action of DBS remains elusive. The goal of this review is to address our present knowledge of the effects of high-frequency stimulation within the central nervous system and comment on the functional implications of this knowledge for uncovering the mechanism(s) of DBS. Four general hypotheses have been developed to explain the mechanism(s) of DBS: depolarization blockade, synaptic inhibition, synaptic depression, and stimulation-induced modulation of pathological network activity. Using the results from functional imaging, neurochemistry, neural recording, and neural modeling experiments we address the general hypotheses and attempt to reconcile what have been considered conflicting results from these different research modalities. Our analysis suggests stimulation-induced modulation of pathological network activity represents the most likely mechanism of DBS; however, several open questions remain to explicitly link the effects of DBS with therapeutic outcomes.

Animals↗
PubMed2004

Glutamatergic-receptors blockade does not regularize the slow wave sleep bursty pattern of subthalamic neurons.

The subthalamic nucleus (STN) has been implicated in movement disorders observed in Parkinson's disease because of its pathological mixed burst firing mode and hyperactivity. In physiological conditions, STN bursty pattern has been shown to be dependent on slow wave cortical activity. Indeed, cortical ablation abolished STN bursting activity in urethane-anaesthetized intact or dopamine depleted rats. Thus, glutamate afferents might be involved in STN bursting activity during slow wave sleep (SWS) when thalamic and cortical cells oscillate in a low-frequency range. The present work was aimed to test, on non-anaesthetized rats, if it was possible to regularize the SWS STN bursty pattern by microiontophoresis of kynurenate, a broad-spectrum glutamate ionotropic receptors antagonist. As glutamatergic effects might be masked by GABAergic inputs arriving tonically and during the entire sleep-wake cycle on STN neurons, kynurenate was also co-iontophoresed with bicuculline, a GABA(A) receptors antagonist. Kynurenate iontophoretic applications had a weak inhibitory effect on the discharge rate of STN neurons whatever the vigilance state, and did not regularize the SWS STN bursty pattern. But, the robust bursty bicuculline-induced pattern was impaired by kynurenate, which elicited the emergence of single spikes between remaining bursts. These data indicate that the bursty pattern exhibited by STN neurons specifically in SWS, does not seem to exclusively depend on glutamatergic inputs to STN cells. Furthermore, GABA(A) receptors may play a critical role in regulating the influence of excitatory inputs on STN cells.

Action Potentials↗
PubMed2003

Influence of the frequency parameter on extracellular glutamate and gamma-aminobutyric acid in substantia nigra and globus pallidus during electrical stimulation of subthalamic nucleus in rats.

High-frequency stimulation (HFS) of the subthalamic nucleus (STN) proves to be an efficient treatment for alleviating motor symptoms in Parkinson's disease (PD). However, the mechanisms of HFS underlying these clinical effects remain unknown. Using intracerebral microdialysis, we previously reported that HFS induces, in normal rats, a significant increase of extracellular glutamate (Glu) in the globus pallidus (GP in rats or GPe in primates) and the substantia nigra pars reticulata (SNr), whereas gamma-aminobutyric acid (GABA) was increased only in the SNr. Bradykinesia can be improved by STN stimulation in a frequency-dependent manner, a plateau being reached around 130 Hz. The aim of the present study was to determine whether neurochemical changes are also frequency dependent. Electrical STN stimulation was applied at various frequencies (10, 60, 130, and 350 Hz) in normal rats. The results show that, for Glu, the amplitude of increase detected in GP and SNr is maximal at 130 Hz and is maintained at 350 Hz. No modifications of GABA were observed in GP whatever the frequency applied, whereas, in SNr, GABA increased from 60 to 350 Hz. Our results provide new neurochemical data implicating STN target structures in deep-brain-stimulation mechanisms.

Animals↗
PubMed2003

Neurochemical mechanisms induced by high frequency stimulation of the subthalamic nucleus: increase of extracellular striatal glutamate and GABA in normal and hemiparkinsonian rats.

High frequency stimulation (HFS) (130 Hz) of the subthalamic nucleus (STN) provides beneficial effects in patients suffering from severe parkinsonism, but the mechanisms underlying these clinical results remain to be clarified. To date, very little is known concerning the effects of STN-HFS on neurochemical transmission in the different basal ganglia nuclei and in particular the striatum. This study examines the effects of STN-HFS in intact and hemiparkinsonian rats on extracellular striatal glutamate (Glu) and GABA levels by means of intracerebral microdialysis. Unilateral STN-HFS was found to induce a significant bilateral increase of striatal Glu and GABA both in intact and in dopamine-lesioned animals. In intact rats, these increases were reversed by local administration of the D1 antagonist SCH 23390, but were potentiated by the D2 antagonist sulpiride. Potentiation was also observed after local administration of both D1 and D2 antagonists whose amplitude was similar to that measured in hemiparkinsonian rats. These data furnish the first evidence that STN-HFS influences striatal amino-acid transmission and that this influence is modulated by dopamine. They provide evidence that the effects of STN-HFS are not only restricted to the direct STN targets, but also involve adaptive changes within other structures of the basal ganglia circuitry.

Animals↗
PubMedDate not supplied

How does deep brain stimulation work? Present understanding and future questions.

High-frequency deep brain stimulation (DBS) of the thalamus or basal ganglia represents an effective clinical technique for the treatment of several medically refractory movement disorders (e.g., Parkinson's disease, essential tremor, and dystonia). In addition, new clinical applications of DBS for other neurologic and psychiatric disorders (e.g., epilepsy and obsessive-compulsive disorder) have been vaulted forward. Although DBS has been effective in the treatment of movement disorders and is rapidly being explored for the treatment of other neurologic disorders, the scientific understanding of its mechanisms of action remains unclear and continues to be debated in the scientific community. Optimization of DBS technology for present and future therapeutic applications will depend on identification of the therapeutic mechanism(s) of action. The goal of this review is to address the present knowledge of the effects of high frequency stimulation within the central nervous system and comment on the functional implications of this knowledge for uncovering the mechanism(s) of DBS. Four general hypotheses have been developed to explain the mechanism(s) of DBS: depolarization blockade, synaptic inhibition, synaptic depression, and stimulation-induced modulation of pathologic network activity. Using the results from microdialysis, neural recording, functional imaging, and neural modeling experiments, the authors address the main hypotheses and attempt to reconcile what have been considered conflicting results from different research modalities.

Basal Ganglia↗