Globus pallidus internus neuronal activity: a comparative study of linear and non-linear features in patients with dystonia or Parkinson's disease.

Movement disorders such as Parkinson's disease (PD) and dystonia are associated with alterations of basal ganglia motor circuits and abnormal neuronal activity in the output nucleus, the globus pallidus internus (GPi). This study aims to compare the electrophysiological hallmarks for PD and dystonia in the linear and non-linear time stamp domains in patients who underwent microelectrode recordings during functional stereotactic surgery for deep brain stimulation (DBS) or pallidotomy. We analyzed single-unit neuronal activity in the posteroventral lateral region of the GPi in awake patients prior to pallidotomy or the implantation of DBS electrodes in 29 patients with PD (N = 83 neurons) and 13 patients with dystonia (N = 41 neurons) under comparable conditions. The discharge rate and the instantaneous frequency of the GPi in dystonia patients were significantly lower than in PD patients (P < 0.001), while the total number of bursts, the percentage of spikes in bursts and the mean duration of bursts were higher (P < 0.001). Further, non-linear analysis revealed higher irregularity or entropy in the data streams of GPi neurons of PD patients compared to the dystonia patients group (P < 0.001). This study indicates that both linear and non-linear features of neuronal activity in the human GPi differ between PD and dystonia. Our results may serve as the basis for future studies on linear and non-linear analysis of neuronal firing patterns in various movement disorders.

Dopaminergic control of striatal 5-HT level at normobaric condition and at pressure.

High pressure of helium-oxygen (He-O2) increases the extracellular levels in both serotonine and dopamine in the rat striatum. Some motor symptoms evoked by high pressure (i.e., LMA) are known to be reduced by intrastriatal infusions of D1-like (SCH23390, 1 microM) or D2-like (Sulpiride, 1 microM) dopaminergic antagonists. Other studies have also reported that serotoninergic antagonists reduce the motor perturbation at pressure. However, it remains unknown whether the changes in serotoninergic neurotransmission may contribute to the beneficial effects of intrastriatal administration of a dopaminergic antagonist. The present study reports the effects of SCH23390 and sulpiride on serotonin levels in the striatum of rats exposed to 8 MPa of He-O2. Both sulpiride and SCH23390 reduced pressure-induced striatal 5-HT increase. Our data suggest that D1-like and D2-like receptors have similar effects on a pressure-evoked striatal 5-HT increase. Thus, reduction in serotoninergic neurotransmission may be one mechanism by which dopaminergic antagonists reduce motor symptoms at pressure.

High pressure enhanced NMDA activity in the striatum and the globus pallidus: relationships with myoclonia and locomotor and motor activity in rat.

In mammals high pressure of helium-oxygen (He-O2) breathing mixture leads to the high pressure neurological syndrome (HPNS) which includes a set of behavioural disorders such as locomotor and motor hyperactivity (LMA) and myoclonia. In rats, i.c.v. administrations of competitive NMDA antagonists decrease some of these symptoms suggesting that He-O2 pressure could enhance NMDA neurotransmission within the central nervous system. More recently, we have shown using microdialysis that the extracellular glutamate level is increased in the striatum by He-O2 pressure. Neurochemical data have suggested that this structure is probably involved in the LMA development but not in the myoclonia expression. When considering myoclonia, recent neuropathological studies performed at normal pressure in humans suggest that the globus pallidus extern (equivalent to the globus pallidus in the rat) could be involved in this behavioural disorder. The aim of this study was to compare the role of striatal and pallidal NMDA activity on the LMA development and the myoclonia expression in the model of rat exposed to 8 MPa of He-O2 mixture. The intrastriatal administration of D(-)-2-amino-7-phosphonoheptanoic acid (2-APH) (10 nmol/slide) reduced the LMA development but only slightly reduced myoclonia. In contrast, the intrapallidal administration of 2-APH (10 nmol/slide) reduced both LMA and myoclonia. These results suggest that the LMA development requires NMDA activity at both striatal and pallidal level. In contrast, the myoclonia expression mainly requires NMDA activity at pallidal level. Consequently, NMDA neurotransmission at input and output levels of the striato-pallidal pathway play different roles in some of the behavioural disorders induced by He-O2 pressure.

In vivo study of tumor metabolism: an application of new multi-probe microdialysis system in the striatum of freely moving rats grafted with C6 cells.

The purpose of this study is to investigate the in vivo tumoral brain metabolism in free moving rats using microdialysis. Cells from C6 glioma cell line were inoculated in one striatum 15 days before the microdialysis experimentation. Then, using a new system allowing perfusion of several microdialysis probes in free moving rat, normalised dialysate levels of glucose, lactate and pyruvate were monitored in both glioma and control striatum. At the end of the procedure, animals were sacrificed for histological study. Data shows that probe functioning is similar in both tissues. The results for normalised glucose level were in striatum control: 2.14 mM, in tumoral striatum: 1.71 mM (P>0.1); for lactate, respectively, 0.86 and 1.65 mM (P<0.05) and for pyruvate, respectively, 65.56 and 140. 94 microM (P<0.05). This data clearly shows a significant increase of pyruvate and lactate in tumoral striatum compared to normal striatum, correlating previous in vitro studies on glioma metabolism. We conclude that this microdialysis technique is of value in tumoral brain and could constitute an interesting tool for a better understanding of glioma metabolism.

Helium-oxygen pressure induces striatal glutamate increase: a microdialysis study in freely-moving rats.

In rat, helium pressures induce locomotor and motor activity which requires dopaminergic and N-methyl-D-aspartate (NMDA) receptor activities at striatal level. However, biochemical studies have suggested that pressure exposure may increase striatal glutamate level. We used microdialysis technique to study the effects of pressure on glutamate level in the striatum and the effects of local administration of D1 (SCH23390) or D2 (sulpiride) on these changes. Pressures increase both glutamate and glutamine levels in striatal microdialysates. Administration of sulpiride (1 microM) or SCH23390 (1 microM) by reverse microdialysis did not affect significantly pressure induced glutamate increase. So, protective effects of D1 and D2 antagonists against locomotor and motor hyperactivity (LMA) are probably independent of the processes involved in the striatal glutamate increase evoked by pressure.

The full expression of locomotor and motor hyperactivities induced by pressure requires both striatal dopaminergic and N-methyl-D-aspartate receptor activities in the rat.

High pressure induced locomotor and motor hyperactivities (LMA), tremor and myoclonia in rat. The LMA has been reported to be reduced by intracerebroventricular (i.c.v.) administration of dopaminergic receptor antagonists. Moreover, the LMA but not myoclonia correlate with pressure induced striatal dopamine increase. Nevertheless the role of dopaminergic and NMDA receptor activities at striatal level in the development of LMA remained unclear. In this study, the microdialysis technique associated to a behavioural device was used to test the effects of intra-striatal administration of D1 antagonist SCH23390 (1 microM), D2 antagonist sulpiride (1 microM) and NMDA antagonist AP-5 (10 microM) on LMA, tremor and myoclonia expression. Data clearly showed that LMA was drastically reduced by each treatment. In contrast, tremor and myoclonia were poorly affected. These data suggest that both dopaminergic and NMDA receptor activities at striatal level are needed for the full expression of the pressure-induced LMA and confirm that striatal neurotransmission changes are principally involved in this behavioural disorders. At the light of recent studies on dopaminergic neurotransmission and glutamate evoked-NMDA activity, we suggest that blockage of D1 or D2 receptors should reduced the LMA by reducing glutamate-evoked activity.

Pressure induces striatal serotonin and dopamine increases: a simultaneous analysis in free-moving microdialysed rats.

High pressure is known as a basic etiological factor underlying central nervous system changes known as the high pressure neurological syndrome (HPNS). In the rat, HPNS includes behavioural disturbances including locomotor and motor hyperactivities (LMA) linked to a striatal dopamine (DA) increase. Recent findings have shown that intracerebroventricular administration of 5-HT3 or 5-HT1b antagonists decrease both LMA and striatal DA increase suggesting that pressure could enhance the serotonin (5-HT) neurotransmission. In this study, for the first time, the striatal levels of DA and 5-HT were simultaneously monitored using microdialysis in free-moving rats exposed to high pressure. Our results show that the striatal 5-HT level increases during pressure exposure. These data suggest that pressure-induced striatal 5-HT increase could participate in the increasing DA release. Nevertheless, the lack of correlation between striatal DA and 5-HT changes suggests that other processes are involved in the pressure-induced striatal DA increase.

Effects of hypothermic deep-anaesthesia on energy metabolism at brain and peripheral levels: a multi-probe microdialysis study in free-moving rat.

Reduction of central energy metabolism is a strategy to protect brain against neurotoxic events. The aim of this microdialysis study in rats is to evaluate changes in energy metabolite levels at central level (striatum) comparatively to peripheral level (subcutaneous adipose tissue) during hypothermic barbituric deep-anaesthesia (sodium pentobarbital 60 mg/kg intraperitoneally). At brain level, extracellular glucose increases (+14.9%) while lactate decreases (-16.6%); opposite results were observed at subcutaneous level (-29.2% for glucose and +68.3% for lactate). Lactate/pyruvate ratio remains unchanged at brain level, but increases at subcutaneous level (+73.5%). In light of previous studies on the effects of pentobarbital on regional blood flow and tissue glucose consumption, our data correlates the fact that pentobarbital reduces preferentially brain energetic metabolism. We suggest that those regional effects are explained, at least for a part, by the fact that central isoform glucose transporters (Glut1 and Glut3) are known to be more sensitive to pentobarbital than peripheral isoforms. Such facts can be involved in the protection of brain tissue against ischemic risk due to decreased cerebral blood flow decrease.

Alteration of striatal dopaminergic function induced by glioma development: a microdialysis and immunohistological study in the rat striatum.

Tumoral growth effects on brain circuitry and neurochemical activities remain poorly documented. This study evaluates C6 graft effects on striatal dopaminergic afferent projections at both anatomical and functional levels. Immunohistochemistry was performed to investigate changes in neurofilament (NF), tyrosine hydroxylase (TH) and dopamine transporter (DAT) expression. Dopaminergic turnover was assessed using multiprobe microdialysis in freely-moving rat. In C6 graft striatum, dopamine (DA) catabolites were reduced in glioblastoma (DOPAC: -61%, HVA: -62%). In contrast, the DA level remained unchanged. Staining for NF, TH and DAT was drastically decreased inside the tumor. Our histological data report that striatal tumoral growth is associated with a decrease in the density of dopaminergic endings which can explain, at least in part, the decrease in DA turnover. The decrease in DAT transporter expression and the lack of change in DA level may result from an increase in DA diffusion from the peripheral areas of the tumor. In conclusion, glioblastoma growth has major consequences on the local neuronal circuitry and its neurochemistry. Changes in inter-connections and neurotransmitter turnover may result in abnormal neuronal firing activity and participate in clinical disorders associated with glioblastoma diagnosis.

A new system analysis of motor and locomotor activities associated with a microdialysis study of pressure-induced dopamine increase in rats.

In this work, we report a new analysis system to quantify the behavioral disorders observed in the model of the rat submitted to high pressure and monitored by piezoelectric sensor. The major advance consists in a spectral 3D representation of LMA and tremor, which provides a better selectivity than previous systems. This behavioral processing indicated that tremor is characterized by a 7-14 Hz frequency band and LMA by a 20-35 Hz frequency band. The association of this system to the microdialysis technique to simultaneously evaluate the striatal DA level confirms that pressure-induced striatal DA increase is in great part linked to the LMA, and supports the concept of a complex ethiology for this symptom. We conclude that this new behavioral system analysis associated with microdialysis study constitutes a powerful tool to investigate the role of different neurotransmitters in the occurrence of the behavioral components described in the HPNS of rats.

Pallidal administrations of gabazine and 5-AVA affect pressure-induced behavioral disorders in rats.

The aim of this work was to study the role of pallidal GABAa and GABAb neurotransmission in the behavioral disorders induced by pressure. The effects of GABAb antagonist 5-aminovalleric acid (5-AVA) or GABAa antagonist gabazine administrations in the globus pallidus (GP) on locomotor and motor hyperactivity (LMA) and myoclonia expressions in the model of the rat submitted to 8 MPa of helium-oxygen breathing mixture were analyzed. The administration of GABAa antagonist gabazine enhances the occurrence of the epileptic seizures, slightly increases LMA but decreases myoclonia. In contrast, the administration of GABAb antagonist 5-AVA decreases both LMA and myoclonia during the compression and the beginning of the holding time at 8 MPa. These data indicate that some behavioral disorders induced by pressure are in relation with GABAergic neurotransmission and establish clearly that GABAa and GABAb receptor mediations have distinct functions in the GP of the rat.

Striatal energetic homeostasis under anaesthetic conditions.

The effects of anesthetics on central energetic metabolism remain poorly documented. In this study, the authors have investigated changes in energetic metabolism in the rat striatum following the systemic administration of either pentobarbital or ketamine. Changes in subcortical energetic homeostasis were compared to those in peripheral adipocyte tissue and correlated to both EEG and vital parameters (heart period, respiratory period, body temperature, glycemia). Pentobarbital induced a decrease in glucose utilisation in the striatum and peripheral tissue. Both EEG activities and vital functions were drastically affected by this treatment. Interestingly, energetics were depleted in the peripheral adipose tissue but not in the striatum. Ketamine, which increased low frequencies in EEG activities and sustained vital functions, increased glucose utilisation in the striatum. Our data, obtained in vivo, established that striatal changes in energetics following anaesthesia are drug-specific and rely on tissue-specific mechanisms. In the subcortical nucleus, energetic response to anaesthetics appears to be affected by changes in both cortical activities and autonomic status. In regard to the peri-operative treatments administrated to patients, our study stresses the importance of the choice of drug anaesthetics in order to avoid adverse effects on brain energetic homeostasis.

Apomorphine reduces subthalamic neuronal entropy in parkinsonian patients.

Dopamine depletion in Parkinson's disease (PD) alters the neuronal activity in basal ganglia circuits. Characterizing these changes in network activity is an important step in understanding the disease and how therapies mitigate symptoms. Non-linear analysis methods can complement the traditional description of neuronal firing characteristics. Here we examine the entropy of subthalamic neurons in PD patients undergoing stereotactic surgery for deep brain stimulation (DBS). The activity of 8 neurons was recorded prior to, during, and following systemic administration of the dopamine agonist apomorphine at clinically effective doses. Apomorphine induced a decrease in entropy measured in the inter-spike intervals of sub-thalamic neurons in 6 of the 8 neurons. This is the first report that anti-parkinsonian drugs affect non-linear features of neuronal firing in the basal ganglia of parkinsonian patients.

Pharmacologic evidence for a parasympathetic role in seizure-induced neurocardiac regulatory abnormalities.

PURPOSE: We evaluated whether postictal cardiac arrhythmia can be prevented by pharmacologic blockage of peripheral muscarinic receptors in an experimental model of epilepsy in rats. METHODS: Rats were prepared for chronic electrocardiograph recording and pretreated with atropine methyl bromide (2 or 10mg/kg i.p.) or saline prior to exposure to maximal electroshock (MES). The resulting seizure severity and duration of cardiac arrhythmia were measured. RESULTS: Atropine methyl bromide did not significantly affect seizure severity in comparison to control animals but reduced the arrhythmia at a dose of 2mg/kg, and completely suppressed arrhythmia at 10mg/kg. CONCLUSIONS: Postictal arrhythmia following MES-induced seizures may be blocked by pretreatment with atropine methyl bromide, a peripherally acting parasympatholytic agent. Our findings support previous observations that suggest strong participation of the parasympathetic system in postictal arrhythmia. This may be important for clinical suppression of cardiac arrhythmia in persons with uncontrolled epilepsy, who are at risk for sudden unexpected death.

Effects of seizure severity and seizure repetition on postictal cardiac arrhythmia following maximal electroshock.

Convulsive seizures triggered by maximal electroshock (MES) induce profound abnormalities in neural regulation of cardiac rhythm that are manifested by a period of marked cardiac arrhythmia in the immediate postictal state. It is not known whether seizure severity or seizure experience may influence the duration of cardiac arrhythmia in the postictal state. We varied the duration of MES administered to rats to vary seizure severity, as measured by the extensor to flexion (E/F) ratio. In separate experiments, rats were subjected to daily MES. Finally, we pretreated rats with ketamine prior to MES to block seizures hindlimb extension. In all animals, the R-R interval was plotted on the tachogram, and the duration of the arrhythmia was measured. Increases in MES duration increased significantly the E/F ratio and prolonged significantly the postictal cardiac arrhythmia. Repetition of MES caused a kindling effect with respect to seizure severity resulting in a significant increase of the E/F ratio and significant increases in the duration of postictal arrhythmia. Blocking of the hindlimb extension by ketamine abolished arrhythmia suggesting that the arrhythmia is not caused directly by MES. Severity of tonic convulsive seizures is a determinant of disordered cardiac autonomic regulation and directly influences the duration of cardiac arrhythmia during the immediate postictal state following MES. Seizure repetition also increases abnormalities of postictal neural regulation of the heart, but further studies are needed to determine whether this effect is independent of seizure severity increases.