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See detailA NEW APPROACH FOR THE TREATMENT OF MALARIA THROUGH SK CHANNEL MODULATION ?
Taouba, Hossein ULiege; Vitello, Romain ULiege; Lumb, Jean-Philip et al

Poster (2021, November 19)

See abstract

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See detailThe gating pore blocker 1-(2,4-xylyl)guanidinium selectively inhibits pacemaking of midbrain dopaminergic neurons
Jehasse, Kevin; Massotte, Laurent ULiege; Hartmann, Sebastian et al

in Neuropharmacology (2021), 197

Detailed reference viewed: 33 (9 ULiège)
See detailBenzhydrol analogues of bis-isoquinoliniums : chiral entities with potential to interact with SK channels
Vitello, Romain ULiege; Seutin, Vincent ULiege; Badarau, Eduard et al

Conference (2021, May 28)

SK channels are appealing targets but need better pharmacological tools. Here, we present a work highlighting a new synthesis pathway for bis-quinolinium blockers allowing for further extension and ... [more ▼]

SK channels are appealing targets but need better pharmacological tools. Here, we present a work highlighting a new synthesis pathway for bis-quinolinium blockers allowing for further extension and evaluationg the chiral aspect of target interaction with SK channels [less ▲]

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See detailCould Bis-THIQ compounds inhibit plasmodial growth through SK channel interaction ?
Taouba, Hossein ULiege; Vitello, Romain ULiege; Lumb, Jean-Philip et al

Poster (2021, May 26)

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See detailFunctional analysis of the F337C mutation in the CLCN1 gene associated with dominant myotonia congenita reveals an alteration of the macroscopic conductance and voltage dependence
Jehasse, Kevin ULiege; Jacquerie, Kathleen ULiege; de Froidmont, Alice ULiege et al

in Molecular Genetics and Genomic Medicine (2021)

Background: Myotonia congenita (MC) is a common channelopathy affecting skeletal muscle and which is due to pathogenic variants within the CLCN1 gene. Various alterations in the function of the channel ... [more ▼]

Background: Myotonia congenita (MC) is a common channelopathy affecting skeletal muscle and which is due to pathogenic variants within the CLCN1 gene. Various alterations in the function of the channel have been reported and we here illustrate a novel one. Methods: A patient presenting the symptoms of myotonia congenita was shown to bear a new heterozygous missense variant in exon 9 of the CLCN1 gene (c.1010 T > G, p.(Phe337Cys)). Confocal imaging and patch clamp recordings of transiently transfected HEK293 cells were used to functionally analyze the effect of this variant on channel properties. Results: Confocal imaging showed that the F337C mutant incorporated as well as the WT channel into the plasma membrane. However, in patch clamp, we observed a smaller conductance for F337C at −80 mV. We also found a marked reduction of the fast gating component in the mutant channels, as well as an overall reduced voltage dependence. Conclusion: To our knowledge, this is the first report of a mixed alteration in the biophysical properties of hClC-1 consisting of a reduced conductance at resting potential and an almost abolished voltage dependence.channel gating, CLCN1, microscopy, myotonia, patch clamp [less ▲]

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See detailThe atypical chemokine receptor ACKR3/CXCR7 is a broad-spectrum scavenger for opioid peptides.
Meyrath, Max Marc Roger ULiege; Szpakowska, Martyna; Zeiner, Julian et al

in Nature Communications (2020), 11(1), 3033

Endogenous opioid peptides and prescription opioid drugs modulate pain, anxiety and stress by activating opioid receptors, currently classified into four subtypes. Here we demonstrate that ACKR3/CXCR7 ... [more ▼]

Endogenous opioid peptides and prescription opioid drugs modulate pain, anxiety and stress by activating opioid receptors, currently classified into four subtypes. Here we demonstrate that ACKR3/CXCR7, hitherto known as an atypical scavenger receptor for chemokines, is a broad-spectrum scavenger of opioid peptides. Phylogenetically, ACKR3 is intermediate between chemokine and opioid receptors and is present in various brain regions together with classical opioid receptors. Functionally, ACKR3 is a scavenger receptor for a wide variety of opioid peptides, especially enkephalins and dynorphins, reducing their availability for the classical opioid receptors. ACKR3 is not modulated by prescription opioids, but we show that an ACKR3-selective subnanomolar competitor peptide, LIH383, can restrain ACKR3's negative regulatory function on opioid peptides in rat brain and potentiate their activity towards classical receptors, which may open alternative therapeutic avenues for opioid-related disorders. Altogether, our results reveal that ACKR3 is an atypical opioid receptor with cross-family ligand selectivity. [less ▲]

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See detailOn the path to understanding pacemaking of dopaminergic neurons
Jehasse, Kevin ULiege; Massotte, Laurent ULiege; Hartmann, Sébastian et al

Poster (2020, May 22)

Despite many years of investigations by many researchers, the mechanism of pacemaking of midbrain dopaminergic (DA) neurons remains unknown. Several groups found that the Ih current, which is prominent in ... [more ▼]

Despite many years of investigations by many researchers, the mechanism of pacemaking of midbrain dopaminergic (DA) neurons remains unknown. Several groups found that the Ih current, which is prominent in a majority of these neurons, enhances pacemaking in a subgroup of DA neurons, but this is not its core mechanism. We and others have been able to rule out various types of Cav channels as pacemaking generators. In our hands, NALCN channels do not seem to contribute either, because the (admittedly non-selective) blocker Gd3+ does not reliably affect pacemaking of DA neurons at 100 µM, whereas it stops fast pacemaking of reticulata GABAergic neurons (Lutas et al., 2016). Because we know that slow pacemaking of DA neurons necessitates only a very small inward current (1-6 pA) (Khaliq and Bean, 2008), we tested the hypothesis that their pacemaking is due to many membrane proteins with a very low unitary conductance. To do this, we investigated the effect of 1-(2,4-xylyl) guanidinium (XG) on their firing. This compound had been shown to block a so-called gating pore current in pathological Nav1.4 channels (Sokolov et al., 2010). In the presence of synaptic blockers (including 1 µM sulpiride), XG completely stopped the firing of DA neurons in a concentration-dependent manner (IC50 was 485 µM, Hill coefficient was 1.28), suggesting a one-to-one interaction. The effect of XG was only weakly reversible, but the firing in the partially inhibited neurons (200-600 µM) remained extremely stable after superfusion of the drug, arguing against a toxic effect. The effect of XG was similar in young and adult rat DA neurons, and was also seen in mouse DA neurons (SH and JR). Because the commercially available XG salt is poorly water-soluble, we (RV and JFL) synthesized a much more soluble salt (XG-M) which yielded the same effect (IC50 was 427 µM). XG inhibited the firing of DA neurons without affecting their conductance and without inducing a hyperpolarization, contrary to D2 agonists. In addition, in the presence of XG, DA neurons could be induced to fire with a small amount of positive current (10 to 30 pA), and their action potential properties were unaffected by the drug. Finally, XG did not affect the pacemaking of fast GABAergic pacemakers. Using pacemaker clamp (imposing in voltage clamp the waveform of spontaneous firing), we isolated a small XG-sensitive inward current which operates from ~-60 to ~-20 mV, but is not seen at more hyperpolarized potentials, arguing against a gating pore current. Molecular biology experiments (BL and KJ) also ruled out an editing of mRNAs coding for the main voltage-dependent channels of these neurons in their S4 segments (this could have been the mechanism of a « physiological » gating pore). In ion substitution experiments, we found that the XG-sensitive current is carried by Na+ and Cl- ions, but not Ca2+ or K+ ions. Given these characteristics, we recently checked whether the dopamine transporter would be involved, since it had been shown to depolarize cultured DA neurons (Ingram et al., 2002). However, we recently ruled out this hypothesis. What could be the nature of this elusive XG-sensitive current? [less ▲]

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See detailKetamine selectively enhances AMPA neurotransmission onto a subgroup of identified serotoninergic neurons of the rat dorsal raphe
Hmaied, Cyrine ULiege; Koulchitsky, Stanislav; Seutin, Vincent ULiege

Poster (2019, October 20)

It has been shown repeatedly that the old drug ketamine is able to induce a rapid (within hours to days) antidepressant effect in otherwise treatment-resistant depressive patients. Despite many ... [more ▼]

It has been shown repeatedly that the old drug ketamine is able to induce a rapid (within hours to days) antidepressant effect in otherwise treatment-resistant depressive patients. Despite many preclinical studies, the exact mechanism and precise site of action of ketamine is a matter of debate. Because an hypoactivity of brain dorsal raphe nucleus (DRN) serotonergic neurons has been strongly associated with the pathophysiology of depressive disorders, we tested the hypothesis that ketamine may rapidly enhance the activity of these neurons in a brain slice model. In a first step, we examined whether the drug and one of its possibly important metabolites, hydroxynorketamine (HNK) may alter the excitatory synaptic drive onto these neurons. [less ▲]

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See detailL’expérimentation animale : toujours une nécessité pour la santé animale et humaine
Balthazart, Jacques ULiege; Blanpain, Cédric; Bureau, Fabrice ULiege et al

Article for general public (2019)

Le 1 juillet 2019, « Le Soir » publiait un article relatant la découverte par les chercheurs de l'UCLouvain d'une bactérie pouvant potentiellement contribuer à limiter les risques cardiovasculaires , l ... [more ▼]

Le 1 juillet 2019, « Le Soir » publiait un article relatant la découverte par les chercheurs de l'UCLouvain d'une bactérie pouvant potentiellement contribuer à limiter les risques cardiovasculaires , l'une des premières causes de décès en Belgique. Cet article soulignait l'importance de la recherche fondamentales et du passage nécessaire par l'expérimentation préclinique (animale) pour développer une application chez l’humain. En réaction, Solange T'Kint, administratrice de l'ASBL S.E.A. - Suppression des Expériences sur l'Animal-, publiait le 2 juillet dans « La Libre » un nouveau pamphlet contre l'expérimentation animale. Mme T Kint avait déjà lancé en aout 2018 une pétition attaquant la découverte3 d'un chercheur de l'ULB sur la dépendance aux drogues réalisée chez la souris , démontrant par là à quel point toute avancée médicale imputable à l'expérimentation animale lui est insupportable. Ici se trouve la réponse de Scientifiques qui pensent indispensable d’informer chacun-e- de manière rigoureuse et de ne jamais laisser diffuser de « fake news » sans réagir. [less ▲]

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See detailSubsaturation of the NMDAR glycine site allows the regulation of bursting activity in juvenile rat nigral dopamine neurons
Destreel, Geoffrey ULiege; Seutin, Vincent ULiege; Engel, Dominique ULiege

in European Journal of Neuroscience (2019), 50(9), 3454-3471

The activation of N-methyl-D-aspartate receptors (NMDARs) in substantia nigra pars compacta (SNc) dopamine (DA) cells is central to generate the bursting activity, a phasic signal linked to DA related ... [more ▼]

The activation of N-methyl-D-aspartate receptors (NMDARs) in substantia nigra pars compacta (SNc) dopamine (DA) cells is central to generate the bursting activity, a phasic signal linked to DA related behaviors via the change in postsynaptic DA release. NMDARs are recruited during excitatory synaptic transmission by glutamate release but the glycine site level of occupancy of these receptors during basal action potential-dependent activity is not known for SNc DA neurons. We explored NMDARdependent signals during exogenous applications of co-agonists in midbrain slices from juvenile rats. We found that both glycine and D-serine strengthened the NMDAR-dependent component of excitatory postsynaptic currents (EPSCs) in a concentration-dependent manner. EPSCs were also increased by endogenous glycine via the blockade of the glycine transport. The glycine site of NMDARs contributing to synaptic transmission is therefore subsaturated. The behaviorally relevant burst firing was more sensitive to exogenous D-serine and endogenous glycine than to exogenous glycine. The mechanisms regulating the availability of the co-agonists exert consequently a critical influence on the excitability of DA neurons via NMDARs. The modulation of the phasic firing in DA neurons by ambient NMDAR co-agonists may be important for nigral information processing and downstream motor-related behavior. [less ▲]

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See detailEFFECT OF KETAMINE ON THE EXCITABILITY OF DORSAL RAPHE NEURONS
Hmaied, Cyrine ULiege; Koulchitsky, Stanislav; Seutin, Vincent ULiege

Scientific conference (2019, May 10)

The non-competitive NMDA antagonist ketamine is an old drug that traditionally has been used as an anesthetic with unique properties dissociative anesthesia. More recently, it has been repeatedly shown ... [more ▼]

The non-competitive NMDA antagonist ketamine is an old drug that traditionally has been used as an anesthetic with unique properties dissociative anesthesia. More recently, it has been repeatedly shown that a single dose of ketamine is able to quickly relieve major depressive symptoms (including suicidal thoughts) in severely affected patients. This effect appears to be transient (the effect lasts less than one week), robust and reproducible, although several questions on its clinical use remain to be addressed. We therefore propose to test the hypothesis that ketamine and/or its metabolites acutely enhance serotoninergic (5HT) transmission by either modulating afferent synaptic transmission onto serotonin neurons of the dorsal raphe or changing their intrinsic excitability. We set out to directly test this hypothesis using whole-cell patch clamp recordings in brainstem slices from juvenile (P21-P30) rats. We used a conventional bicarbonate-based Ringer and a KCl-based intrapipette solution. This allowed us to discriminate presumed 5HT from non-5HT neurons. 5HT neurons were identified as cells generating an outward current > 30 pA in voltage clamp at -60 mV during superfusion of 100 nM of the 5HT1A agonist 8-OH-DPAT (calculated EK was = -93 mV). We first tested Ketamine’s effect on sEPSCs by using 10µM gabazine and 1 µM CGP55845. We found that 10 µM racemic ketamine increase the AMPA EPSCs in terms of amplitude and frequency in the half of 5HT recorded neurons (N total = 18).This effect was not observed in the case of non-5HT recorded neurons (N = 6). The same effect was observed by the racemate of its metabolite 2,6 hydroxynorketamine (HNK). In current clamp recordings, both ketamine and HNK increased the firing of 5HT neurons in whole-cell recordings when AMPA, NMDA, GABAA and GABAB receptors were blocked. In conclusion, ketamine and its metabolite HNK robustly enhance AMPA EPSCs onto a subgroup of pharmacologically identified 5HT neurons. It remains to be determined whether this subgroup projects to specific targets, given that subpopulations of DR 5HT neurons have been shown to have specific and non-overlapping projections (Ren et al., Cell 175, 472-487, 2018). [less ▲]

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See detailInvestigating the reciprocal relationships between locomotor sensitization to ethanol and PTSD-like clusters in DBA/2J mice.
Matonda Ma Nzuzi, ULiege; Didone, Vincent ULiege; Seutin, Vincent ULiege et al

in Behavioural Brain Research (2019)

BACKGROUND: Post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) are two conditions that co-occur frequently. The mechanistic explanations of this co-morbidity are still unclear. The goal ... [more ▼]

BACKGROUND: Post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) are two conditions that co-occur frequently. The mechanistic explanations of this co-morbidity are still unclear. The goal of this study was twofold. First to investigate whether PTSD reduces the threshold for the acquisition of ethanol sensitization in an animal model of PTSD. Then to investigate whether ethanol sensitization modulates the expression of PTSD. METHODS: 152 female inbred DBA/2 J mice were submitted to an inescapable footshock paradigm to induce a PTSD-like condition (PTSDLC) and to a paradigm of locomotor sensitization to ethanol. In a first experiment, mice were submitted to the PTSDLC and then repeatedly injected with either saline, 1 g/kg ethanol or 2 g/kg ethanol. Their sensitization to the locomotor stimulant effects of ethanol was then tested in an open field. In a second experiment, mice were first sensitized to the locomotor stimulant effects of ethanol and then tested for their behavioral response to PTSDLC. RESULTS: In the first experiment, PTSDLC failed to induce a significant locomotor sensitization at the subthreshold dose of 1 g/kg ethanol. However, with 2 g/kg ethanol, a stronger ethanol sensitization was observed in mice submitted to the footshock relative to the control group. In the second experiment, ethanol sensitization increased only some of the behavioral clusters of PTSDLC, namely the fear generalization in a new context. CONCLUSION: PTSDLC did not reduce the dose threshold for the acquisition of ethanol sensitization but strengthened the development of ethanol sensitization with effective doses. This suggests that PTSD might interact with one of the mechanisms underlying the development of alcohol sensitization. When the relationship between ethanol sensitization and PTSDLC is tested in the reverse direction, the present study only shows a significant effect of ethanol administration on the "sensitized fear" PTSD cluster. [less ▲]

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See detailEffect of Amphetamine on Ventral Tegmental Area Neurons in awake Rats
Delairesse, Charlotte ULiege; Koulchitsky, Stanislav ULiege; Seutin, Vincent ULiege

Poster (2018, December 18)

Amphetamine (AMPH) is an addictive psychostimulant targeting the dopamine system. But its effect on the neurons of this system is still unclear. Here, we studied the effects of amphetamine on the firing ... [more ▼]

Amphetamine (AMPH) is an addictive psychostimulant targeting the dopamine system. But its effect on the neurons of this system is still unclear. Here, we studied the effects of amphetamine on the firing rate of dopamine (DA) and non-dopamine neurons of the ventral tegmental area, a key structure in the reward circuit, of awake rats. Using wireless neural probes to investigate the electrical activity of the neurons in freely moving rats, we observed that acute injection of AMPH is followed by a decrease of firing rate of most of registered DA units. The remaining population of DA units either increased or did not significantly change their activity. At the same time, AMPH stimulated the locomotor activity and induced a stereotypic behavior. (FR) L'amphétamine (AMPH) est un psychostimulant addictif visant le système dopaminergique. Cependant, ses effets sur les neurones de ce système sont nébuleux. Nous étudions les effets de l'AMPH sur la fréquence de décharge des neurones dopaminergiques et non dopaminergique de l'aire tegmentale ventrale, une structure clef du circuit de la récompense, de rats éveillés. En utilisant un système d'électrodes sans fil pour étudier l'activité électrique des neurones de rats libres de leurs mouvements, nous avons observer que l'injection aiguë d'AMPH est suivie d'une diminution de la fréquence de décharge de la majorité des neurones dopaminergiques enregistrés. Le reste des neurones dopaminergique présentaient une activité augmentée ou qui ne subissait pas de changement significatif. En même temps, l'AMPh stimule l'activité locomotrice et induit un comportement stéréotypé. [less ▲]

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See detailExpérimentation animale: la recette d'une polémique scientifique
Muraille, Eric; de kerchove, Alban; Muylkens, Benoit et al

Article for general public (2018)

La majorité du grand public accepte l’expérimentation animale à condition que celle-ci contribue à l’amélioration de la santé humaine et qu’aucune autre alternative n’existe. En face, les opposants ... [more ▼]

La majorité du grand public accepte l’expérimentation animale à condition que celle-ci contribue à l’amélioration de la santé humaine et qu’aucune autre alternative n’existe. En face, les opposants décrédibilisent la recherche et stigmatise une profession à des fins idéologiques. Relevé de leurs arguments. [less ▲]

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See detailLa souris, le patient, et le faux expert. Décryptage d'une mystification.
Bakker, Julie ULiege; Balthazart, Jacques ULiege; Baron, Frédéric ULiege et al

Article for general public (2018)

La recherche sur animaux est actuellement encadrée de façon stricte en Wallonie comme dans toute l'Union Européenne (voir l'article de Marc Vandenheede publié dans le Vif). Cette législation et les ... [more ▼]

La recherche sur animaux est actuellement encadrée de façon stricte en Wallonie comme dans toute l'Union Européenne (voir l'article de Marc Vandenheede publié dans le Vif). Cette législation et les contrôles qui y sont associés induisent de nombreuses contraintes pratiques, des charges administratives et des coûts financiers importants que les chercheurs seraient certainement heureux d'éviter s'il existait une alternative à l'expérimentation animale. [less ▲]

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See detailL'expérimentation animale ne se fait pas en dehors de tout contrôle (OPINION)
Muraille, Eric; de Kerchove d'Exaerde, Alban; Blanpain, Cedric et al

Article for general public (2018)

Proposer de réduire l'expérimentation animale pour raisons morales est louable. Mais ce choix de société ne doit pas être vendu au citoyen en lui laissant croire que la recherche conserverait la même ... [more ▼]

Proposer de réduire l'expérimentation animale pour raisons morales est louable. Mais ce choix de société ne doit pas être vendu au citoyen en lui laissant croire que la recherche conserverait la même qualité ou en serait améliorée. [less ▲]

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See detailAnalyse détaillée de la seconde version de l’avant-projet de Code du bien-être animal wallon. Lecture commentée au 21/03/2018 du Chapitre 8 (Expérimentation animale)
Drion, Pierre ULiege; Corhay, Albert ULiege; Haubruge, Eric ULiege et al

Report (2018)

La compétence « bien-être animal », auparavant fédérale, a été régionalisée en juillet 2014. Ce projet de code vise à remplacer les dispositions légales en vigueur (la Loi de 1984 telle que modifiée par ... [more ▼]

La compétence « bien-être animal », auparavant fédérale, a été régionalisée en juillet 2014. Ce projet de code vise à remplacer les dispositions légales en vigueur (la Loi de 1984 telle que modifiée par les décrets du Gouvernement wallon). Certains éléments sont repris tels quels de la Directive 2010/63. Cela est nécessaire car la Directive européenne en tant que telle n’a pas de force obligatoire en Belgique. Elle doit être transcrite par un instrument législatif (avant, la Loi de 1984 et ses modifications, aujourd’hui, le projet de code pour la Région wallonne). Certains aspects semblent flous, mais renvoient à des dispositions que le Gouvernement doit encore prendre (au travers d’arrêtés du Gouvernement wallon, comme le faisaient avant les nombreux arrêtés royaux et du gouvernement qui réglementent la matière). Les arrêtés d’exécution devront obligatoirement tenir compte de la Directive européenne et s’inspirer de dispositions actuellement en vigueur. [less ▲]

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See detailL’expérimentation animale reste indispensable (OPINION)
Amorim, Christiani; Andris, Fabienne; Arckens, Lut et al

Article for general public (2017)

Trop fréquemment, l’expérimentation animale est présentée comme une pratique archaïque. Elle a bien changé. Et 100 % des patients traités le sont grâce aux concepts et techniques développés grâce à elle.

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See detailModulation of NMDA receptor mediated excitatory synaptic currents in dopamine neurons of the substantia nigra.
Destreel, Geoffrey ULiege; Seutin, Vincent ULiege; Engel, Dominique ULiege

Poster (2017, November 08)

Dopamine (DA) neurons of the substantia nigra pars compacta (SNc) exhibit two main firing modes, spontaneous single action potential (AP) firing and bursting. The amount of DA released by these neurons in ... [more ▼]

Dopamine (DA) neurons of the substantia nigra pars compacta (SNc) exhibit two main firing modes, spontaneous single action potential (AP) firing and bursting. The amount of DA released by these neurons in target areas depends on the presynaptic AP firing pattern and is essential to modulate several aspects of behavior such as the control of movement. Bursting activity is mediated by excitatory afferents and specifically by the activation of NMDA receptors (NMDARs). However, the level of activation of NMDARs at these synapses during spontaneous synaptic activity is unknown. We assessed the occupancy of the glycine binding sites of the NMDAR by testing the effects of coagonists and by blocking the uptake of glycine on spontaneous excitatory postsynaptic currents (sEPSCs) in DA neurons of the SNc. [less ▲]

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See detailAvant-projet de décret relatif au Code wallon du Bien-être des animaux Lecture commentée au 04 juillet 2017 des chap. 4, 8, 11
Drion, Pierre ULiege; Seutin, Vincent ULiege; Balthazart, Jacques ULiege et al

Report (2017)

La compétence « bien-être animal », auparavant fédérale, a été régionalisée en juillet 2014. Ce projet de code vise à remplacer les dispositions légales en vigueur (la Loi de 1984 telle que modifiée par ... [more ▼]

La compétence « bien-être animal », auparavant fédérale, a été régionalisée en juillet 2014. Ce projet de code vise à remplacer les dispositions légales en vigueur (la Loi de 1984 telle que modifiée par les décrets du Gouvernement wallon). Certains éléments sont repris tels quels de la Directive 2010/63. Cela est nécessaire car la Directive européenne en tant que telle n’a pas de force obligatoire en Belgique. Elle doit être transcrite par un instrument législatif (avant, la Loi de 1984, aujourd’hui, le projet de code). Certains aspects semblent flous, mais renvoient à des dispositions que le Gouvernement doit encore prendre (au travers d’arrêtés du Gouvernement wallon, comme le faisaient avant les nombreux arrêtés royaux et du gouvernement qui réglementent la matière). Les arrêtés d’exécution devront obligatoirement tenir compte de la directive européenne et s’inspirer de dispositions actuellement en vigueur. [less ▲]

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