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Simpli®ed block diagram of basal ganglia circuitry. (A) Simpli®ed block diagram of basal ganglia (within grey box) illustrating the major GABAergic (dark boxes and arrows) and glutamatergic (light boxes and arrows) connections. The projection from the neostriatum (striatum) to the substantia nigra constitutes the direct pathway. The projection from the neostriatum to the substantia nigra which includes the globus pallidus and the subthalamic nucleus constitutes the indirect pathway. The major sources of GABA collected in the striatal probes are the local collaterals of striatonigral and striatopallidal neurons and local GABAergic interneurons. Glutamate and aspartate are likely to be derived from the corticostriatal and the thalamostriatal afferents. The major source of GABA in the substantia nigra and globus pallidus is likely to be the terminals of striatal projection neurons and the local axon collaterals of nigral and pallidal neurons, respectively. The major source of glutamate/aspartate is likely to be the terminals of neurons of the subthalamic nucleus. (B) Following lesion of the dopaminergic nigrostriatal pathway there is a marked reduction in the release of GABA in the substantia nigra following stimulation of the neostriatum. Although stimulated release of GABA in the globus pallidus was unaltered in lesioned animals there was an enhanced basal release of GABA. GP, globus pallidus; SNr, substantia nigra pars reticulata ; STN, subthalamic nucleus.
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The loss of dopaminergic neurons of the substantia nigra in Parkinson's disease and in animal models of Parkinson's disease is associated with an imbalance in the activity of the so-called 'direct' and 'indirect' pathways of information flow through the basal ganglia. The aim of the present study was to determine whether the imbalance is reflected...
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... disease, is re ̄ected in an imbalance in the release of GABA in these pathways. To this end we performed dual probe microdialysis analyses in vivo to examine the release, primarily of GABA but also of other amino acids, in the direct (striatonigral) and the indirect (striatopallidal) pathways. The essential ®ndings are that, indeed, there are imbalances in the release of GABA under both basal and stimulated conditions in the direct and indirect pathways of 6- OHDA-lesioned rats. Firstly, under basal conditions there was a signi®cantly greater release of GABA in the GP, whereas the release was not altered in the SN ( Fig. 7). Secondly, following stimulation of the two pathways by infusion of the glutamate receptor agonists, KA or AMPA, into the neostriatal microdialysis probe, the imbalance was evident as reduced release in the direct pathway (Fig. 7). Thus there were no changes in the enhanced release in the striatopallidal pathway but the enhanced release of GABA that occurs in the SN following stimulation of the neostriatum in control animals was abolished in the 6-OHDA-lesioned animals. Thirdly, GABA release in both the neostriatum and GP, but not in the SN, was much more sensitive to the local application of a high-potassium solution in the 6-OHDA-lesioned animals. Thus in these three situations the imbalance was in favour of the indirect pathway and is therefore consistent with the direct± indirect pathways model of basal ganglia function and dysfunction. Many studies of Parkinson's disease and animal models of Parkinson's disease have reported imbalances in the levels of peptides, neurotransmitter markers, receptors and metabolic activity that are consistent with a down-regulation of the direct pathway and up-regulation of the indirect pathway (for reviews see Gerfen, 2000; Hirsch et al ., 2000; Obeso et al ., 2000). Furthermore, changes in the physiological activity in the indirect pathway consistent with increased activity (and altered patterns of activity) have been reported to be associated with the loss of dopamine (for reviews see Wichmann & DeLong, 1996; Bergman et al ., 1998). The present study now demonstrates alterations in ...
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... disease, is re ̄ected in an imbalance in the release of GABA in these pathways. To this end we performed dual probe microdialysis analyses in vivo to examine the release, primarily of GABA but also of other amino acids, in the direct (striatonigral) and the indirect (striatopallidal) pathways. The essential ®ndings are that, indeed, there are imbalances in the release of GABA under both basal and stimulated conditions in the direct and indirect pathways of 6- OHDA-lesioned rats. Firstly, under basal conditions there was a signi®cantly greater release of GABA in the GP, whereas the release was not altered in the SN ( Fig. 7). Secondly, following stimulation of the two pathways by infusion of the glutamate receptor agonists, KA or AMPA, into the neostriatal microdialysis probe, the imbalance was evident as reduced release in the direct pathway (Fig. 7). Thus there were no changes in the enhanced release in the striatopallidal pathway but the enhanced release of GABA that occurs in the SN following stimulation of the neostriatum in control animals was abolished in the 6-OHDA-lesioned animals. Thirdly, GABA release in both the neostriatum and GP, but not in the SN, was much more sensitive to the local application of a high-potassium solution in the 6-OHDA-lesioned animals. Thus in these three situations the imbalance was in favour of the indirect pathway and is therefore consistent with the direct± indirect pathways model of basal ganglia function and dysfunction. Many studies of Parkinson's disease and animal models of Parkinson's disease have reported imbalances in the levels of peptides, neurotransmitter markers, receptors and metabolic activity that are consistent with a down-regulation of the direct pathway and up-regulation of the indirect pathway (for reviews see Gerfen, 2000; Hirsch et al ., 2000; Obeso et al ., 2000). Furthermore, changes in the physiological activity in the indirect pathway consistent with increased activity (and altered patterns of activity) have been reported to be associated with the loss of dopamine (for reviews see Wichmann & DeLong, 1996; Bergman et al ., 1998). The present study now demonstrates alterations in ...
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... of GABA in the two pathways that are consistent with these ®ndings. The present experiments were carried out on `freely moving', behaving rats. One would predict that during normal behaviour, the direct and indirect pathways would be functioning appropriately and playing their roles in the control of movement and behaviour in general. Thus the `basal release' in these experiments, unlike that in anaesthetized animals, is a re ̄ection of ongoing activity in the striatofugal pathways. In this situation we observed an increase in the basal release of GABA in the GP in the 6-OHDA-treated rats, which presumably re ̄ects the overactivity which is predicted by the direct±indirect pathway model (Fig. 7). Similar ®ndings have been made by others in behaving (Robertson et al ., 1991; Ochi et al ., 2000) but not anaesthetized (Segovia et al ., 1986; Tossman et al ., 1986) animals. In contrast to the observations in the striatopallidal experiments, the basal release of GABA in the SN was not altered in the 6-OHDA-lesioned animals. This ®nding is consistent with some studies in anaesthetized and freely moving animals (Lindefors et al ., 1989; Sarre et al ., 2001) but contradicts another, where increased release of GABA was observed in the SN in anaesthetized rats (You et al ., 1994), although it is not clear what the contribution of the direct pathway is to the basal release of GABA in the SN (Bianchi et al ., 1994, 1998). It should be remembered, however, that the source of the GABA in the GP and in the SN is not solely neostriatal neurons giving rise to the indirect or direct pathways. Thus in the GP, in addition to terminals derived from neostriatal neurons of the indirect pathway, the local collaterals of ...
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... to the output nuclei of the basal ganglia, the entopeduncular nucleus (EP) (or internal segment of the globus pallidus in primates) and the substantia nigra pars reticulata (SNr), by direct and indirect pathways and thence to the ventral thalamus and/or subcortical premotor regions ( Albin et al., 1989;Bergman et al., 1990;DeLong, 1990) (Fig. 7A). The direct pathway consists of a monosynaptic g-aminobutyric acid (GABA)ergic projection from the neostriatum to the output nuclei, activation of which leads to inhibition of neurons in the output nuclei which in turn leads to disinhibition of the targets of the basal ganglia. Disinhibition of the targets of the basal ganglia is ...
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... pathways. The essential ®ndings are that, indeed, there are imbalances in the release of GABA under both basal and stimulated conditions in the direct and indirect pathways of 6-OHDA-lesioned rats. Firstly, under basal conditions there was a signi®cantly greater release of GABA in the GP, whereas the release was not altered in the SN (Fig. 7). Secondly, following stimulation of the two pathways by infusion of the glutamate receptor agonists, KA or AMPA, into the neostriatal microdialysis probe, the imbalance was evident as reduced release in the direct pathway (Fig. 7). Thus there were no changes in the enhanced release in the striatopallidal pathway but the enhanced ...
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... conditions there was a signi®cantly greater release of GABA in the GP, whereas the release was not altered in the SN (Fig. 7). Secondly, following stimulation of the two pathways by infusion of the glutamate receptor agonists, KA or AMPA, into the neostriatal microdialysis probe, the imbalance was evident as reduced release in the direct pathway (Fig. 7). Thus there were no changes in the enhanced release in the striatopallidal pathway but the enhanced release of GABA that occurs in the SN following stimulation of the neostriatum in control animals was abolished in the 6-OHDA-lesioned animals. Thirdly, GABA release in both the neostriatum and GP, but not in the SN, was much more ...
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... release' in these experiments, unlike that in anaesthetized animals, is a re¯ection of ongoing activity in the striatofugal pathways. In this situation we observed an increase in the basal release of GABA in the GP in the 6-OHDA-treated rats, which presumably re¯ects the overactivity which is predicted by the direct±indirect pathway model (Fig. 7). Similar ®ndings have been made by others in behaving (Robertson et al., 1991;Ochi et al., 2000) but not anaesthetized ( Segovia et al., 1986;Tossman et al., 1986) animals. In contrast to the observations in the striatopallidal experiments, the basal release of GABA in the SN was not altered in the 6-OHDA-lesioned animals. This ®nding ...
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... the 6-OHDA-lesioned rats the KA-enhanced release of amino acids was largely unaltered in the neostriatum and GP but both the KAand AMPA-enhanced release of GABA in the SN was abolished (Fig. 7B). The abolition of the release of GABA in the distal probe in the SN following the 6-OHDA lesions was unlikely to be due to a nonspeci®c reduced responsiveness of striatonigral neurons as enhanced release of GABA still occurred in response to glutamate receptor stimulation within the neostriatum after the 6-OHDA lesions. However, local ...
Citations
... Excessive inhibition of GPe neurons by striatal GABAergic neurons of the indirect pathway is considered a critical mechanism underlying the pathological overactivity of the subthalamic nucleus and BG output structures and thus the expression of the motor symptoms [1,6,22,23]. While electrophysiological and neurochemical studies in patients and animal models of PD provide support for this view [24][25][26][27][28], few studies have explored the behavioral effects of global GPe stimulations in the context of dopamine (DA) depletion, and the reported results are controversial. Pharmacological and global chemogenetic GPe activations ameliorate motor deficits in reserpine-treated rats and in mice with bilateral medial forebrain bundle (MFB) lesions, respectively [29][30][31]. ...
... Numerous electrophysiological studies demonstrated a reduction of GPe neuronal firings in animal models and PD patients [3,24,26,28]. GPe hypoactivity has been attributed to an abnormal elevation of extracellular GABA concentrations caused by the overactivity of the striato-pallidal pathway [23,25,49] and to local changes at the level of pallidal GABAergic synapses [27,50]. Our study provides new behavioral evidence that GPe activity is altered upon DA depletion. ...
... Further, striatal inputs of Npas1 + -expressing neurons, which suppress locomotor behavior, have been shown to be strengthened upon DA lesion [56]. Finally, it should be noted that motor symptoms of PD were linked not only to changes in local firing rates but also to abnormal rhythmic activity in BG and cortex manifested by enhanced oscillations in the beta frequency range (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) [61,62]. Pathological beta-oscillations are thought to compromise information flow and processing in the cortico-basal ganglia (CBC) network, thereby leading to the impairment of motor functions. ...
Excessive inhibition of the external globus pallidus (GPe) by striatal GABAergic neurons is considered a central mechanism contributing to motor symptoms of Parkinson’s disease (PD). While electrophysiological findings support this view, behavioral studies assessing the beneficial effects of global GPe activations are scarce and the reported results are controversial. We used an optogenetic approach and the standard unilateral 6-hydroxydopamine nigrostriatal dopamine (DA) lesion model of PD to explore the effects of GPe photostimulation on motor deficits in mice. Global optogenetic GPe inhibition was used in normal mice to verify whether it reproduced the typical motor impairment induced by DA lesions. GPe activation improved ipsilateral circling, contralateral forelimb akinesia, locomotor hypoactivity, and bradykinesia in 6-OHDA-lesioned mice at ineffective photostimulation parameters (532 nm, 5 Hz, 3 mW) in normal mice. GPe photoinhibition (450 nm, 12 mW) had no effect on locomotor activity and forelimb use in normal mice. Bilateral photoinhibition (450 nm, 6 mW/side) reduced directed exploration and improved working memory performances indicating that recruitment of GPe in physiological conditions may depend on the behavioral task involved. Collectively, these findings shed new light on the functional role of GPe and suggest that it is a promising target for neuromodulatory restoration of motor deficits in PD.
... Despite some variability in experimental observations, more active iSN cells seem to be a very consistent finding in experimental studies. Increased firing rates were measured in PD animal models (Kita & Kita, 2011;Mallet, Ballion, Le Moine, & Gonon, 2006;Sharott, Vinciati, Nakamura, & Magill, 2017), and further findings on synapse density (Day et al., 2006), increased metabolism in GPe (Crossman, Mitchell, & Sambrook, 1985;Mitchell, Cross, Sambrook, & Crossman, 1986;Schwartzman & Alexander, 1985) and increased GABA levels in GPe (Bianchi, Galeffi, Bolam, & Della Corte, 2003;Robertson, Graham, Sambrook, & Crossman, 1991) indicate increased activity of the iSN cells. Only a few studies did not reproduce an increased iSN firing rate in PD (Ketzef et al., 2017;Ryan, Bair-Marshall, & Nelson, 2018). ...
Previous computational model‐based approaches for understanding the dynamic changes related to Parkinson’s disease made particular assumptions about Parkinson’s disease related activity changes or specified dopamine‐dependent activation or learning rules. Inspired by recent model‐based analysis of resting‐state fMRI, we have taken a data‐driven approach. We fit the free parameters of a spiking neuro‐computational model to match correlations of blood‐oxygen‐level‐dependent signals between different basal ganglia nuclei and obtain subject‐specific neurocomputational models of two subject groups: Parkinson patients and matched controls. When comparing mean firing rates at rest and connectivity strengths between the control and Parkinsonian model groups, several significant differences were found that are consistent with previous experimental observations. We discuss the implications of our approach and compare its results also with the popular “rate model” of the basal ganglia. Our study suggests that a model‐based analysis of imaging data from healthy and Parkinsonian subjects is a promising approach for the future to better understand Parkinson related changes in the basal ganglia and corresponding treatments.
... Also in PD, levels of GABA in the SNr have been reported to be either increased (Windels et al., 2005) or unchanged (Bianchi et al., 2003;Ochi et al., 2004). Changes in GABAergic transmission have been evaluated with measurements of mRNA or protein levels for the GABA-synthesizing enzyme glutamate acid decarboxylase (GAD). ...
The substantia nigra pars reticulate (SNr) is the main output structure of the basal ganglia (BG), a subcortical network controlling the elaboration of motor programs as well as cognitive and associative learning functions. The identification of distinct cell-types within the BG has played a key role for understanding the properties and functions of this circuit. Recent studies suggest that the SNr is composed of several cell types but until now this neuronal diversity has never been taken into consideration regarding normal and pathological functioning of this nucleus, particularly in Parkinson’s disease (PD). By combining immunohistochemical and electrophysiological approaches in the PVCre::Ai9T mouse line, we have demonstrated that SNr neurons expressing the protein parvalbumin (PV+) exhibit different anatomical and electrophysiological properties than non PV-expressing (PV-) neurons. Our anatomical analysis reveal that PV+ and PV- neurons are present in equal proportion in the SNr, but with a distinct distribution, PV+ being enriched in the lateral part of the SNr, while PV- are found in the medial portion of the nucleus. In vitro electrophysiological recordings from identified PV+ and PV- neurons in the SNr also revealed that PV+ neurons fired at relatively higher rates than PV- cells. Additionally, our data revealed that DA loss and subsequent L-DOPA treatment induce a profound reduction of the excitability of PV+ SNr neurons in a 6-OHDA mouse model of PD while activity of PV- remains unchanged by these treatments.It is well known that the activity of SNr neurons is controlled by GABAergic inputs from striatal dSPN and the GP. We performed optogenetic manipulation of STR-SNr and GP-SNr inputs in order to determine whether PV+ and PV- SNr neurons received equivalent inputs from these two nuclei. We tested the impact of STR-SNr or GP-SNr activation on the activity of SNr neurons in cell-attached configuration and then switched to whole-cell voltage-clamp to characterize short-term plasticity of these synapses. Our results show that both PV+ and PV- SNr neurons are innervated by the STR and the GP. They also revealed that inhibition from dSPN was more powerful to silence activity of both subtypes of SNr neurons. Indeed, we observed that both STR-SNr and GP-SNr synapses displayed short-term depression in PV+ and PV- SNr neurons. DA loss affected GABA transmission in a different manner in PV+ and PV- SNr cells. On one hand, PV+ neurons were more sensible to striatal synaptic inhibition than PV- cells after DA depletion. On the other hand, PV-GP inputs were reduced on PV+ neurons and increased in PV- cells after DA loss suggesting a disequilibrium in pallidal inhibition between these two SNr populations.Furthermore, considering that rodent models of PD have shown elevated extracellular levels of GABA in the SNr which can exert a tonic extrasynaptic inhibition on SNr neurons, we decided to characterize GABAergic extrasynaptic transmission in the SNr of control and 6-OHDA lesioned mice. We studied GABAA mediated tonic inhibition by performing whole-cell patch-clamp recordings of PV+ and PV- SNr neurons in acute slices. We observed that PV- SNr neurons displayed larger GABAA receptor-mediated tonic currents than PV+ cells in the SNr of control mice. The presence and involvement of δ and/or α5 extrasynaptic subunits in GABAA receptors mediating this type of transmission was also studied, revealing a major presence and effect of α5-subunits on PV- neurons probably mediating the tonic currents observed in these neurons. However, contrary to expected, chronic DA-depletion did not trigger any increase in tonic inhibition neither in PV+ cells nor in PV- SNr neurons.All these findings highlight the importance of differentiating cell populations in the SNr to a better knowledge of the BG circuit in normal and pathological states such as in PD.
... 1,2 The degeneration of dopaminergic neurons in the substantia nigra is the primary cause of PD. 3−5 It is thought to induce an imbalance between the direct and indirect basal ganglia circuit pathways. 6,7 Electrical stimulation of the target is accepted in clinical therapy. 8,9 Chemical therapies like levodopa also remain effective in treating symptoms. ...
Apomorphine (APO) is often used to treat Parkinson’s Disease (PD) while the mechanism in PD treatment remains unclear. In this study, a four-shank microelectrode array (MEA) was fabricated to monitor cortex (two shorter shanks) and Caudate Putamen (CPu) (two longer shanks) signals simultaneously. Dopamine (DA) concentration and neural spike firing in the bilateral targets were recorded in the unilateral 6-OHDA PD rats treated by APO. Electroplating platinum black and reduced graphene oxide nanocomposites onto the electrodes surface significantly improved their performance with higher sensitivity, selectivity, linearity and lower impedance. The DA level and neural spike firing rate were regulated to the normal level. On the lesioned side, the mean DA concentration increased and the firing rate decreased significantly in the cortex and CPu. Synchronous spike oscillation and typical periodic firing appeared on the lesioned side but were significantly reduced after APO treatment. This represents a substantial contribution to PD treatment and effective recovery of movement. The nanotechnology-enhanced MEA biosensing interface provides an elaborate platform for detecting neuron activities and helps to reveal the abnormal signals between neurons.
... Therefore, the dopaminergic system required manipulation to elicit motor impairment in our PD model, observed by comparing open field test with and without haloperidol, corroborating prior findings (Barnéoud et al., 2000;Jaskiw and Popli, 2004;Johnson and McFarland, 1993;Kirik et al., 1998). Disturbance of the GABAergic system has been suggested in the SN of hemiparkinsonian rats (di Michele et al., 2013;Galeffi et al., 2003;Rangel-Barajas et al., 2008) and PD patients (Anglade et al., 1995;Błaszczyk, 2016), resulting in overactivity of the remaining dopaminergic neurons in the SN (Błaszczyk, 2016;Zigmond et al., 1984). We did not observe these phenomena since GABA labeling did not change and decreased neuronal activation was observed in the SN in our PD model. ...
Parkinson's disease (PD) is a neurodegenerative disorder that causes progressive dysfunction of dopaminergic and non-dopaminergic neurons, generating motor and nonmotor signs and symptoms. Pain is reported as the most bothersome nonmotor symptom in PD; however, pain remains overlooked and poorly understood. In this study, we evaluated the nociceptive behavior and the descending analgesia circuitry in a rat model of PD. Three independent experiments were performed to investigate: i) thermal nociceptive behavior; ii) mechanical nociceptive behavior and dopaminergic repositioning; and iii) modulation of the pain control circuitry. The rat model of PD, induced by unilateral striatal 6-hydroxydopamine (6-OHDA), did not interfere with thermal nociceptive responses; however, the mechanical nociceptive threshold was decreased bilaterally compared to that of naive or striatal saline-injected rats. This response was reversed by apomorphine or levodopa treatment. Striatal 6-OHDA induced motor impairments and reduced dopaminergic neuron immunolabeling as well as the pattern of neuronal activation (c-Fos) in the substantia nigra ipsilateral (IPL) to the lesion. In the midbrain periaqueductal gray (PAG), 6-OHDA-induced lesion increased IPL and decreased contralateral PAG GABAergic labeling compared to control. In the dorsal horn of the spinal cord, lesioned rats showed bilateral inhibition of enkephalin and μ-opioid receptor labeling. Taken together, we demonstrated that the unilateral 6-OHDA-induced PD model induces bilateral mechanical hypernociception, which is reversed by dopamine restoration, changes in the PAG circuitry, and inhibition of spinal opioidergic regulation, probably due to impaired descending analgesic control. A better understanding of pain mechanisms in PD patients is critical for developing better therapeutic strategies to improve their quality of life.
... Dopamine-depleted (DD) rodents show morphological changes at striato-pallidal synaptic terminals (Ingham et al., 1997), increased striato-pallidal synaptic transmission (Cui et al., 2016), and GP astrocytosis (Charron et al., 2014), supporting iSPN hyperactivity as well as local synaptic dysfunctions. While these modifications can account for the elevated extracellular concentrations of GABA observed in the GP of the DD rodents (Galeffi et al., 2003;Ochi et al., 2000), the underlying synaptic mechanism(s) remains unknown. In this study, we used patch-clamp electro-physiology, biochemistry, and in vivo pharmacology in behaving rodents to investigate the alteration of GABA uptake by GATs in the GP of DD rodents. ...
... GATs represent the main buffering system to control extracellular levels of GABA and to shape GABAergic transmission (Scimemi, 2014b). In the GP, extracellular GABA concentrations are abnormally elevated in the DD condition (Galeffi et al., 2003;Ochi et al., 2000), suggesting that GABA uptake is deficient. Electron microscopy analysis has shown that GAT-1 is present in unmyelinated axons as well as in GP glial processes (Galvan et al., 2005(Galvan et al., , 2010. ...
The external globus pallidus (GP) is a key GABAergic hub in the basal ganglia (BG) circuitry, a neuronal network involved in motor control. In Parkinson's disease (PD), the rate and pattern of activity of GP neurons are profoundly altered and contribute to the motor symptoms of the disease. In rodent models of PD, the striato-pallidal pathway is hyperactive, and extracellular GABA concentrations are abnormally elevated in the GP, supporting the hypothesis of an alteration of neuronal and/or glial clearance of GABA. Here, we discovered the existence of persistent GABAergic tonic inhibition in GP neurons of dopamine-depleted (DD) rodent models. We showed that glial GAT-3 transporters are downregulated while neuronal GAT-1 function remains normal in DD rodents. Finally, we showed that blocking GAT-3 activity in vivo alters the motor coordination of control rodents, suggesting that GABAergic tonic inhibition in the GP contributes to the pathophysiology of PD.
... Furthermore, several studies have indicated that there was an increase of releasing glutamate in the regions such as entopeduncular nucleus and striatum as well as an enhancement of Fos expression in the shell and core regions of nucleus accumbens, dorsolateral striatum, and lateral septal nucleus in dopaminergic hemilesioned rats or dopamine-depleted rats [85]. 5-HT1A receptor agonists inhibited the cortico-striatal glutamate pathway and reduced extracellular glutamate levels in the striatum, and tandospirone significantly reduced haloperidol-induced Fos expression in the dorsolateral striatum [86,87]. ...
5-hydroxytryptamine (5-HT, serotonin) is an important neurotransmitter in the modulation of the cognitive, behavioral and psychological functions in animals and humans. Among the fourteen subtypes of 5-HT receptor, 5-HT1A receptor has been extensively studied. Tandospirone, an azapirone derivative with strong and selective agonist effect on 5-HT1A receptor, has been used for the treatment of anxiety disorders especially generalized anxiety disorder for decades. Recently, tandospirone showed the efficacy in relieving the syndromes of social anxiety disorder and posttraumatic stress disorder as well as in potentiating the effect of antidepressants in the treatment of depression in both preclinical and clinical studies. More impressively, the beneficial effect of tandospirone has been revealed on improvement of motor dysfunction of Parkinson's disease and cognitive deficits of schizophrenia either in monotherapy or in combination with other drugs. This review discusses the superiority of tandospirone in the treatment of the disorders and associated mechanisms in central nervous system from the literature.
... Parkinson's Disease (PD) is characterized by loss of nigrostriatal dopamine (DA) neurons and tyrosine hydroxylase (TH) 1-3 with nigrostriatal terminal fields being more vulnerable early in the disease process 3 . With progressive degeneration of DA neurons, evidence for concomitant increases in glutamatergic tone have been observed [4][5][6][7][8][9][10][11] ; including decreased striatal glutamate uptake and changes in glutamate transporter GLT-1 function [11][12][13] . High concentrations of synaptic glutamate increase Ca 2+ influx through the glutamate receptors triggering activation of Ca 2+− -dependent enzymes that can lead to excitotoxic cell death [14][15][16][17][18][19][20] . ...
... Therefore, increased GLT-1 and glutamate uptake may reduce LID severity by reducing excess glutamatergic neurotransmission, as seen with observations showing reduced LID in association with reduced glutamate release 49,50 . To the converse, others have not reported any difference in striatal glutamate concentrations in the lesioned nigrostriatal pathway 10,74,75 , which may be attributed to time-dependent changes in release and uptake and their contributions to extracellular glutamate concentration and when these determinations were made after lesion induction or the lesion site 4,5,40,75 . As a result, post-lesion time points and lesion topography are relevant metrics for timing therapeutic strategies. ...
Background: Increased extracellular glutamate may contribute to l-dopa induced dyskinesia, a debilitating side effect faced by Parkinson's disease patients 5 to 10 years after l-dopa treatment. Therapeutic strategies targeting postsynaptic glutamate receptors to mitigate dyskinesia may have limited success because of significant side effects. Increasing glutamate uptake may be another approach to attenuate excess glutamatergic neurotransmission to mitigate dyskinesia severity or prolong the time prior to onset. Initiation of a ceftriaxone regimen at the time of nigrostriatal lesion can attenuate tyrosine hydroxylase loss in conjunction with increased glutamate uptake and glutamate transporter GLT-1 expression in a rat 6-hydroxydopamine model. In this article, we examined if a ceftriaxone regimen initiated 1 week after nigrostriatal lesion, but prior to l-dopa, could reduce l-dopa–induced dyskinesia in an established dyskinesia model.
Methods: Ceftriaxone (200 mg/kg, intraperitoneal, once daily, 7 consecutive days) was initiated 7 days post-6-hydroxydopamine lesion (days 7-13) and continued every other week (days 21-27, 35-39) until the end of the study (day 39 postlesion, 20 days of l-dopa).
Results: Ceftriaxone significantly reduced abnormal involuntary movements at 5 time points examined during chronic l-dopa treatment. Partial recovery of motor impairment from nigrostriatal lesion by l-dopa was unaffected by ceftriaxone. The ceftriaxone-treated l-dopa group had significantly increased striatal GLT-1 expression and glutamate uptake. Striatal tyrosine hydroxylase loss in this group was not significantly different when compared with the l-dopa alone group.
Conclusions: Initiation of ceftriaxone after nigrostriatal lesion, but prior to and during l-dopa, may reduce dyskinesia severity without affecting l-dopa efficacy or the reduction of striatal tyrosine hydroxylase loss. © 2017 International Parkinson and Movement Disorder Society
... It is known that the balance between the neurotransmitters DA, glutamate and GABA is critical in maintaining normal function of the basal ganglia. Moreover, an imbalance between GABAergic neurons activated by D1 receptors and glutamate neurons inhibited by D2 receptors probably plays a major role in the pathogenesis of movement disorder [72][73][74][75]. The increase in glutamate activity in the subthalamic nucleus is responsible for overactivity of basal ganglia output structures, which are also directly under the control of the striatum [76,77]. ...
... In experimental models, mirroring PD, 6-OHDA lesions of the SNpc enhance and reduce levels of mRNA encoding vesicular GABA transporter in striatopallidal and striatonigral neurons, respectively (Wang et al., 2007). Further, employing intracellular microdialysis, it has repeatedly been reported that extracellular levels of GABA in the D 2 receptor-controlled striatopallidal GPe are increased in 6-OHDA-lesioned rats and MPTP-treated monkeys, presumably due to loss of D 2 receptor inhibition (Galeffi et al., 2003;Robertson et al., 1991;Segovia et al., 1986;Windels et al., 2005). Regarding the D 1 receptor-coordinated striatonigral pathway, the results are less clearcut. ...
... Regarding the D 1 receptor-coordinated striatonigral pathway, the results are less clearcut. Basal extracellular levels of GABA are not altered in the SNpr of 6-OHDA-lesioned freely moving rats (Galeffi et al., 2003;Lindefors et al., 1989;Ochi et al., 2004) or even enhanced in anesthetized rats (Windels et al., 2005), at odds with the expected lower activity of the striatonigral pathway. Nonetheless, compared to sham-lesioned rats, evoked GABA release in the SNpr was lower (Galeffi et al., 2003) or similar (Lindefors et al., 1989) in 6-OHDA-lesioned rats. ...
... Basal extracellular levels of GABA are not altered in the SNpr of 6-OHDA-lesioned freely moving rats (Galeffi et al., 2003;Lindefors et al., 1989;Ochi et al., 2004) or even enhanced in anesthetized rats (Windels et al., 2005), at odds with the expected lower activity of the striatonigral pathway. Nonetheless, compared to sham-lesioned rats, evoked GABA release in the SNpr was lower (Galeffi et al., 2003) or similar (Lindefors et al., 1989) in 6-OHDA-lesioned rats. Of note, nigral GABA extracellular levels were reduced after the injections of reserpine or the DA receptor antagonist haloperidol, two conditions leading to motor impairment Volta et al., 2010). ...
