Depression of extra-cellular GABA and increase of NMDA-induced nitric oxide following acute intra-nuclear administration of alcohol in the cerebellar nuclei of the rat.

Gamma-aminobutyric acid (GABA) and nitric oxide are two key-transmitters in cerebellar nuclei, the major output of cerebellar circuitry. The aims of this study were to investigate the effects of acute intra-cerebellar administration of ethanol (20 mM) on extra-cellular levels of GABA and on the NMDA-induced nitric oxide (NO) production using microdialysis in the rat. We also studied: (i) the effects of a pre-administration of DNQX, a specific antagonist of AMPA receptors, on NO production, (ii) the effects of a pre-administration of 7-NI (7-nitroindazole, an inhibitor of neuronal nitric oxide synthase NOS) and APV (D-2-amino-5-phosphonovaleric acid, a specific blocker of the NMDA type glutamate receptors) on the actions of alcohol/NMDA on glutamate receptors, and (iii) the in vivo interaction between DNQX, ethanol and NMDA receptor activation. We found that ethanol decreased the amount of extra-cellular GABA, and that this effect was counterbalanced by administration of tiagabine 1 mg/kg, a potent inhibitor of GAT-1 GABA transporter, given by the i.p. route. In loco administration of NMDA increased the levels of NO, as previously reported. A pre-administration of DNQX (500 microM) increased significantly the production of NO up to toxic levels, as well as ethanol administration. A pre-administration of 7-NI or APV reduced significantly the amounts of NO when NMDA and alcohol were infused simultaneously. The combination of ethanol with DNQX was associated with a marked enhancement of the concentrations of NO. The activity of GAT-1 in cerebellar nuclei and around this target, including in glial cells expressing GAT-1 activated by ambient GABA, seems to be spared by ethanol. Tiagabine could be considered as a candidate for future investigational treatments of acute ethanol-induced dysfunction of cerebellar nuclei. We found a potentiation of the production of NO when AMPA antagonists are given simultaneously to ethanol. The hypothesis of AMPA neurotoxicity, which has convincing arguments during chronic exposure, is challenged in this model of acute cerebellar nuclear toxicity of alcohol.Journal Articleinfo:eu-repo/semantics/publishe

Pergolide potentiates L-DOPA-induced dopamine release in rat striatum after lesioning with 6-hydroxydopamine.

We used intrastriatal microdialysis to study the effect of pergolide, a D1/D2 dopamine (DA) receptor agonist on biotransformation of exogenous L-DOPA in hemi-Parkinsonian rats. DA and metabolites were assayed by microbore liquid chromatography. Pergolide (50 micrograms/kg, i.p.) caused a 67% and 87% decrease in striatal EC levels of DA in intact and denervated striatum respectively. In intact striatum but not in denervated striatum, pergolide decreased EC levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) (53% and 42% decrease, respectively). L-DOPA (100 mg/kg, i.p.) produced significant increase in EC levels of DA, DOPAC and HVA in intact and denervated striatum with and without local perfusion of 10(-4) M pergolide. In denervated striatum, L-DOPA-induced DA increase was significantly higher in rats with pergolide. Our results suggest that, in an animal model of Parkinson's disease, pergolide in association with L-DOPA favors the restoration of striatal EC DA levels.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Sleep deprivation decreases phase-shift responses of circadian rhythms to light in the mouse: role of serotonergic and metabolic signals.

The circadian pacemaker in the suprachiasmatic nuclei is primarily synchronized to the daily light-dark cycle. The phase-shifting and synchronizing effects of light can be modulated by non-photic factors, such as behavioral, metabolic or serotonergic cues. The present experiments examine the effects of sleep deprivation on the response of the circadian pacemaker to light and test the possible involvement of serotonergic and/or metabolic cues in mediating the effects of sleep deprivation. Photic phase-shifting of the locomotor activity rhythm was analyzed in mice transferred from a light-dark cycle to constant darkness, and sleep-deprived for 8 h from Zeitgeber Time 6 to Zeitgeber Time 14. Phase-delays in response to a 10-min light pulse at Zeitgeber Time 14 were reduced by 30% in sleep-deprived mice compared to control mice, while sleep deprivation without light exposure induced no significant phase-shifts. Stimulation of serotonin neurotransmission by fluoxetine (10 mg/kg), a serotonin reuptake inhibitor that decreases light-induced phase-delays in non-deprived mice, did not further reduce light-induced phase-delays in sleep-deprived mice. Impairment of serotonin neurotransmission with p-chloroamphetamine (three injections of 10 mg/kg), which did not increase light-induced phase-delays in non-deprived mice significantly, partially normalized light-induced phase-delays in sleep-deprived mice. Injections of glucose increased light-induced phase-delays in control and sleep-deprived mice. Chemical damage of the ventromedial hypothalamus by gold-thioglucose (600 mg/kg) prevented the reduction of light-induced phase-delays in sleep-deprived mice, without altering phase-delays in control mice. Taken together, the present results indicate that sleep deprivation can reduce the light-induced phase-shifts of the mouse suprachiasmatic pacemaker, due to serotonergic and metabolic changes associated with the loss of sleep.Journal ArticleResearch Support, Non-U.S. Gov'tResearch Support, U.S. Gov't, P.H.S.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

The cerebellum modulates rodent cortical motor output after repetitive somatosensory stimulation.

OBJECTIVE: To analyze the possible role of the cerebellum in the modulation of cortical motor output associated with repetitive electrical stimulation of the sciatic nerve in the rat. METHODS: A sustained somatosensory stimulation induces an increase in the intensity of the response of the rodent motor cortex. Wistar rats were anesthetized for surgical preparation using a continuous infusion of chloral hydrate. We analyzed the response evoked by electrical stimulation of the right motor cortex before (basal condition) and after peripheral electrical stimulation of the left sciatic nerve in rats with no cerebellar intervention (n = 6), and in control rats with Ringer's infusion via a microdialysis probe (n = 8) implanted in the left cerebellar nuclei. In addition, we investigated the effects of 1) the administration of ethanol (20 mmol/L) in the left cerebellar nuclei (n = 5); 2) the administration of tetrodotoxin (10 micromol/L), a sodium channel blocker, in the left cerebellar nuclei (n = 5); 3) electrical stimulation by deep cerebellar stimulation (frequency 100 Hz) on the left side (n = 5); or 4) electrical stimulation of the cerebellar nuclei on the right side (100 Hz; n = 6). For peripheral stimulation, all of the animals received 1 hour of electrical stimulation. Trains of stimulation consisted of five stimuli (duration of 1 stimulus, 1 ms) at a rate of 10 Hz. During stimulation of the motor cortex, peak-to-peak amplitudes in responses of the left calf muscle were analyzed. Motor threshold was defined as the lowest intensity eliciting at least 5 of 10 evoked responses with an amplitude greater than 20 muV. The intensity used was 130% of the motor threshold. RESULTS: In the basal condition (before repetitive stimulation), amplitudes of motor responses were similar in the six groups of rats (P = 0.40). In rats without cerebellar intervention, peripheral electrical stimulation was associated with an increase of motor response to 147.4 +/- 8.5% of baseline (P < 0.001). In rats with Ringer's infusion, the motor response increased to 141.6 +/- 7.9% of baseline (P < 0.001). The administration of ethanol in the cerebellum prevented the enhancement of the response ipsilaterally. The mean +/- standard deviation (SD) of motor responses was 105.7 +/- 6.2% of baseline measurements after stimulation of the sciatic nerve (P = 0.36). The same observation was made after the infusion of tetrodotoxin (mean +/- SD of motor responses: 107.1 +/- 7.4% after peripheral stimulation [P = 0.19] and after electrical stimulation of the cerebellum on the left side [mean +/- SD of motor responses, 104.3 +/- 8.5% after peripheral stimulation, P = 0.40]). However, electrical stimulation of cerebellar nuclei on the right side did not impair the modulation of cortical motor output by sciatic nerve stimulation (mean +/- SD of motor responses, 148.4 +/- 5.8% after peripheral stimulation, P < 0.001). CONCLUSION: Until now, the increase of motor output after peripheral nerve stimulation has been considered as a plasticity directly and solely dependent on cortical structures. We demonstrate that the cerebellum plays a key role in this form of neural plasticity.Journal Articleinfo:eu-repo/semantics/publishe

Interaction between repetitive stimulation of the sciatic nerve and functional ablation of cerebellar nucleus interpositus in the rat.

It is established that cerebellar nuclei exert a significant effect on the excitability of spinal neurons. However, their output is heterogeneous. Conditioning trains of dentate nucleus stimuli are known to modify the post-synaptic potentials evoked in motoneurons by stimulation of group Ia and Ib afferents in appropriate peripheral nerves. The role of the interpositus nucleus in the modulation of the excitability of rat spinal cord remains unclear. We investigated the interactions between tetrodotoxin (TTX)-induced inactivation of the interpositus cerebellar nuclei and repetitive electrical stimulation of the ipsilateral sciatic nerve (proximal segment) in the anesthetized rat. TTX (10 microM) was administered in cerebellar nuclei by the technique of microdialysis (coordinates of the extremity of the guide related to bregma: AP: -11.6, L: +2.3, V: -4.6). Peripheral stimulation consisted of trains of electric stimuli at a rate of 10 Hz, which were repeated every second during 1 hour. Stimulus intensity was adjusted to produce constant somatosensory evoked potentials. H-reflex, F-wave and M responses of the plantaris muscles were analysed ipsilaterally. H-reflex recruitment curve, Hmax/Mmax ratios, F-wave persistence and mean F/mean M ratios were studied. Functional blockade of cerebellar interpositus nucleus reduced the slope of H-reflex recruitment curve without affecting the Hmax/Mmax ratio, and depressed both F-waves persistence and mean F/mean M ratios. Concomitant repetitive stimulation of the sciatic nerve counteracted the depression of the H-reflex recruitment curve, without interacting with F-waves depression. Our results (1) show that TTX-sensitive sodium channels in cerebellar nucleus interpositus modulate the H-reflex recruitment, and (2) reveal an interaction between TTX-sensitive sodium channels in cerebellar nuclei and afferent repetitive activity not described so far.Comparative StudyJournal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Microdialysis-HPLC for plasma levodopa and metabolites monitoring in parkinsonian patients.

We used in vitro microdialysis-HPLC to determine L-3,4-dihydroxyphenylalanine (L-DOPA) and its metabolites in plasma of patients with advanced Parkinson disease. Blood samples and clinical evaluations were obtained 0, 30, 60, 90, 120, and 150 min after oral administration of carbidopa/L-DOPA (25/100 mg, 12.5/125 mg, and 50/200 mg). In vitro recoveries for L-DOPA and metabolites ranged from 22% to 36%. Linear correlation was found between metabolite concentrations in the dialysate and in the surrounding medium. There was a significant positive correlation between L-DOPA dose and plasma concentration of L-DOPA and homovanillic acid (P < 0.04). Clinical response was maximum 60 min after L-DOPA administration. Threshold L-DOPA plasma concentration averaged 7.74 +/- 3.3 mumol/L. Motor effect is longer with the highest L-DOPA peak concentration (P < 0.01). Microdialysis-HPLC is readily applicable, reproducible, and allows monitoring of plasma L-DOPA and metabolites in parkinsonian patients.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Cerebellar spongiform degeneration induced by acute lithium intoxication in the rat.

Cerebellar syndrome has been described after acute lithium intoxication in human. Neuropathological studies have demonstrated neuronal loss and spongiosis in the cerebellum. We describe an animal model of acute lithium-induced cerebellar degeneration. Five hours following administration of lithium chloride (250 mg/kg, i.p.), the cerebellar white matter of seven rats out 14 exhibited extensive spongiform changes. Microdialysis study in the rat cerebellar cortex demonstrated basal concentrations of dopamine (DA), hydroxy-3-methoxyphenylacetic acid (HVA) and 5-hydroxy-3-indolacetic acid (5-HIAA). These metabolites were unaffected by acute lithium intoxication suggesting that the cerebellar toxicity is not due to a modification of dopaminergic or serotoninergic neurotransmission.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Recent advances in transgenic models of ALS - Electrophysiological, morphological and neurochemical characterization of hSOD-1 G93A transgenic rats

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Systemic and intrastriatal theophylline have opposite effects on dopamine and dopamine metabolites measured by intrastriatal microdialysis in the rat.

Using a model of intrastriatal microdialysis, we studied the effect of theophylline, an A1 and A2A adenosine receptor antagonist on striatal dopamine (DA) and DA metabolites. Systemic administration of theophylline (10 and 50 mg/kg) significantly reduced striatal extracellular (EC) levels of DA and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and 4-hydroxy-3-methoxy-phenylacetic acid (HVA). Intrastriatal administration of theophylline (10(-2) M) significantly increased DA and its metabolites (DA1 + 120%; DOPAC, +28%; HVA, +30%). Contradictory effects of systemic and intrastriatal theophylline point to theophylline interactions with different receptors possibly at different locations.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Effects of levetiracetam on the production of nitric oxide--an in vivo study.

Comparative StudyLetterinfo:eu-repo/semantics/publishe