Jean-Marie Miquet

Effects of complete and partial lesions of the dopaminergic mesotelencephalic system on skilled forelimb use in the rat

This study compares certain behavioural consequences of partial and complete unilateral lesions of the dopaminergic mesotelencephalic system. We investigated skilled forelimb use, rotations induced by apomorphine and amphetamine, and dopaminergic metabolism of the nigrostriatal system of rats that had received a unilateral injection of 6-hydroxydopamine into the medial forebrain bundle. The rats classified Apo(+), that rotated after the administration of apomorphine, had a complete lesion of the nigrostriatal system, whereas those classified Apo(-), that did not rotate after the administration of apomorphine, had a partial lesion of the nigrostriatal system. In the Apo(+) rats, 99.8% of the dopamine in the striatum was depleted, as was 85% of that in the substantia nigra. For the Apo(-) rats, 72% of the dopamine in the striatum was depleted as was 56% of that in the substantia nigra. When investigated with the staircase test, the animals with the most severe dopamine depletions were those most impaired in the paw reaching task. Complete and partial unilateral depletions of the dopaminergic mesotelencephalic system impaired the hierarchic phases of paw reaching differently. A complete dopamine depletion, but not a partial one, decreased the number of attempts made with the contralateral paw, and induced a bias towards the ipsilateral paw. A partial dopamine lesion impaired the sensorimotor co-ordination of both paws, whereas the complete dopamine lesion had a greater effect on the contralateral paw than on the ipsilateral paw. The mild paw reaching impairments observed in animals with moderate depletions of dopamine are proposed as a model of the early symptoms of Parkinsons disease that may be useful for the development of protective or restorative therapies.

Neuroprotective effects of riluzole on a model of Parkinson's disease in the rat.

The aim of the present study was to analyse whether riluzole, a compound that interacts with the voltage-dependent sodium channel and impairs glutamatergic transmission, would exhibit a neuroprotective activity in a model of Parkinsons disease in the rat. Impaired skilled forelimb use, circling behavior, and altered dopaminergic metabolism of the mesotelencephalic system were evaluated in unilaterally 6-hydroxydopamine-lesioned rats. Riluzole was administered twice 15 min before, and 24 h after, the lesion. Riluzole reduced both the contralateral rotations induced by apomorphine and the ipsilateral ones elicited by amphetamine. Moreover, the decreased dopaminergic metabolism seen after 6-hydroxydopamine injection was attenuated in the riluzole-treated animals, at both the striatal and nigral levels. These biochemical and behavioral results demonstrate the ability of riluzole partially to protect the degeneration of the nigrostriatal dopaminergic neurons induced by the toxin 6-hydroxydopamine. Perhaps, the most striking evidence for the protective effect of riluzole was that this compound improved the skilled paw use, a complex sensorimotor behavior which is not easily ameliorated by palliative therapies such as dopaminergic grafts. These results extend previous data showing that riluzole counteracts the toxicity induced by 1-methyl-4-1,2,3,6-tetrahydropyridine and 1-methyl-4-phenylpyridinium in rodent dopaminergic neurons. The use of riluzole may be considered of potential interest for the neuroprotective therapy of Parkinsons disease.

Riluzole and experimental parkinsonism : antagonism of MPTP-induced decrease in central dopamine levels in mice

We have investigated whether riluzole, a compound that interferes with glutamatergic (GLUergic) transmission, would protect central dopaminergic (DAergic) neurones from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced toxicity in the striatum in mice. MPTP decreased DA, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels. Riluzole protected against the MPTP-induced decrease in DA levels. The utilization of DA ([DOPAC+HVA]/DA) was increased after MPTP treatment, but returned to control values in mice given riluzole in combination with MPTP. Riluzole did not confer protection by inhibiting either monoamine oxidase type B activity or DA uptake. Possible mechanisms involved in the protective action of riluzole are discussed. Our results show that riluzole antagonizes the DAergic neurotoxicity of MPTP, a pro-parkinsonian neurotoxin, in mice.

Riluzole and experimental parkinsonism : partial antagonism of MPP+-induced increase in striatal extracellular dopamine in rats in vivo

SUPERFUSION of the rat striatum with 100 μM of 1-methyl-4-phenylpyridinium (MPP+) induced a 70-fold increase in dopamine (DA) release and a decrease in the extracellular levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). Pretreatment with riluzole (8 mg kg-1, i.p.), a compound that interferes with glutamatergic transmission, partially antagonized the effect of MPP+ on the release of DA, but did not change the effects of this toxin on the efflux of DOPAC and HVA. Riluzole did not affect the increase in DA release induced by MPP+ in vitro. The in vivo efficacy of riluzole on MPP+-induced DA release could be due to its central interference with glutamatergic transmission. Our data point to a protective role of riluzole with regard to DA release, a marker of the neuronal impairment induced by MPP+, a pro-parkinsonian neurotoxin.

A Rapid Filtration Assay for the Glycine Binding Site on the NMDA Receptor in Rat Cortical Membranes using [3H]Dichlorokynurenic Acid

Abstract— A nitration binding assay using [3H]dichlorokynurenic acid to label the glycine binding site on the N‐methyl‐d‐aspartic acid receptor has been evaluated on rat cortical membranes. This ligand binds to a single population of binding sites following mass action kinetics with a Kd of 29 Nm and a capacity of 5·73 pmol (mg protein)−1. The pharmacological specificity of the binding site is identical to that previously reported for this binding site using [3H]glycine as a radioligand. Agonists showed lower affinity and antagonists higher affinity when [3H]dichlorokynurenic acid was used compared with [3H]glycine. The higher affinity of [3H]dichlorokynurenic acid compared with [3H]glycine make it the more suitable compound with which to label the glycine site.

Differential Effects of Potassium Channel Blockers on Dopamine Release from Rat Striatal Slices

Abstract— The effects of different potassium channel blockers on tritiated dopamine ([3H]DA) release were investigated in rat striatal slices in the presence of pargyline and nomifensine (10 μM each). 4‐Aminopyridine (4‐AP; 10 and 30 μM) and 3,4‐diaminopyridine (3,4‐DAP; 30 μM) markedly increased the basal tritium outflow, whereas tetraethylammonium (TEA; 100–1000 μM) was without effect. The facilitating effect of 4‐AP (10 μM) on spontaneous release was Ca2+‐ and K+‐dependent. Moreover, the 4‐AP‐induced increase in spontaneous release was abolished in the presence of tetrodotoxin, indicating that voltage‐dependent Na+ channels were involved in the release mechanism. 4‐AP (10 and 30 μM) induced a dose‐dependent decrease in K+‐evoked [3H]DA release. This effect was confirmed with 3,4‐DAP (30 μM). When striatal slices were depolarized with veratridine (5 μM), these two aminopyridines increased the evoked release of [3H]DA. TEA increased both K+‐ and veratridine‐evoked [3H]DA release. These biochemical results are consistent with electrophysiological differences between the mechanism of action of aminopyridines and that of TEA.

KATP channels modulate GABA release in hippocampal slices in the absence of glucose

Summary— We studied the effects of KATP channel blockers on [3H]GABA release in the absence of glucose in rat hippocampal slices. The omission of glucose induced a marked increase in the efflux of [3H]GABA, which was antagonized by TTX (1 μM), but not by MK 801 (1 μM) or DNQX (100 μM). Glibenclamide (10–100 μM) increased dose‐dependently the release of [3H]GABA evoked in the absence of glucose. An increase in [3H]GABA release was also observed with gliquidone (100–300 μM), another sulfonylurea. The potentiation of [3H]GABA release induced by glibenclamide (100 μM) was antagonized by DNQX but not by MK 801. Thus, in the absence of glucose, KATP channel blockers enhance the release of GABA from rat hippocampal slices; this effect seems to be mediated by an overstimulation of non‐NMDA glutamate receptors. On the basis of results reported in the present paper, we suggest that KATP channels may play a role in the regulation of GABAergic activity during hypoglycemia.

Neurotensin modulates differently potassium, veratridine and 4-aminopyridine-evoked release of dopamine in rat striatal slices

Summary— We have studied the effects of neurotensin (NT) on the release of [3H]dopamine ([3H]DA) evoked by terminal depolarization with either K+, veratridine or 4‐aminopyridine (4‐AP). NT (1–1000 nM) induced a net potentiation (up to 170%) of the K+ (25 mM) ‐evoked release of [3H]DA. The capacity of NT to potentiate the effect of K+ ions decreased as the K+ concentration rose from 25 to 50 mM and totally disappeared at this high K+ concentration. NT (100 nM; 1000 nM) had no significant effect on the veratridine (1.5; 5μM) or 4‐AP (20 μM) ‐evoked release of [3H]DA. The relevance of these experimental models of DA release to physiological transmitter release remains to be established. Those data highlight the complexity of the modulation of evoked neurotransmitter release by pharmacological agents.

Potassium markedly potentiates the effect of veratridine on dopamine release from rat superfused striatal ribbons

Abstract— The effects of veratridine‐induced depolarization on [3H]dopamine ([3H]DA) release in the presence of a physiological (5 Mm) or a depolarizing (25 Mm) concentration of K+ were studied in‐vitro in rat superfused striatal ribbons. A combination of the two depolarizing agents induced a marked potentiation in the overflow of [3H]DA, giving an overall 3‐ to 5‐fold increase in veratridine activity. This potentiation was completely antagonized by tetrodotoxin (100 Nm). These studies indicated that K+‐induced depolarization can increase the potency of veratridine in releasing dopamine from terminals.