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, Évaluation de l'activité à long-terme d'un agoniste du récepteur 5-HT4 chez la souris BALB/cJRj : Après avoir montré que le RS 67333 était pourvu de propriétés prophylactiques, nous avons ensuite cherché à connaître l'activité de cette molécule au long-terme, c'est-à-dire si la réponse anxiolytique que le RS 67333 provoque est durable dans le temps. Pour cela, les souris BALB/cJRj ont été injectées par voie systémique avec une unique dose de RS, vol.67333, p.5

, 45 minutes avant de réaliser le Splash Test. Le lendemain, les souris ont été soumises à l'EPM, sans avoir reçu de nouvelle dose de RS, mg/kg) ou de diazépam (1,5 mg/kg)

, 1531) (Figures 35B-C), après une administration unique. Nous n'avons pas retrouvé les effets anxiolytiques attendus du RS 67333 dans l'EPM (t = 0,4990 ; p=0,6286) (Figures 35D-E), 24 heures après l'injection

, 48 heures après l'injection et a diminué la latence pour se nourrir dans le NSF (t = 2,520 ; p<0,05), sans affecter la consommation de nourriture en environnement familier (t = 0,2203 ; p=0,4151) (Figures 35H-I), 72 heures après l'injection. Le diazépam ne possédant pas d'activité de type antidépresseur, il est donc normal de ne retrouver aucun effet dans le Splash Test. Nous n'avons pas non plus observé d'activité à longterme pour le diazépam. Par conséquent, bien que cette étude devrait être répétée, le RS pourrait avoir des prévenir l'apparition des premiers symptômes de dépression, ainsi qu'une meilleure prise en charge des EDC, d'autant plus que la comorbidité anxieuse favorise la résistance au traitement antidépresseur chez ces patients, 2009.

, La stimulation aiguë, par voie systémique, du récepteur 5-HT4 induit un effet de type anxiolytique rapide chez la souris anxieuse BALB/cJRj mâle

. David, EPM, le NSF et l'OF, l'administration unique par voie systémique de RS 67333 (1,5 mg/kg) induit un effet de type anxiolytique rapide similaire à celui du diazépam (1,5 mg/kg). Sans surprise, la fluoxétine (18 mg/kg) n'a eu aucun effet sur les paramètres mesurés dans ces tests, attestant ainsi du délai d'action thérapeutique des ISRS, qui a précédemment été démontré, En utilisant une souche de souris anxieuse à l'état basale, la souris BALB/cJRj, nous avons d'abord étudié l'effet de type anxiolytique rapide d'un agoniste du récepteur 5-HT4, le RS 67333 (pKi = 8,7), 2007.

, Bien que l'affinité du RS 67333 pour le récepteur 5-HT4 soit élevée, nous avons tout de même vérifié la sélectivité de l'effet anxiolytique, en administrant le RS 67333 en association avec un antagoniste sélectif du récepteur 5-HT4

. Mendez-david, Cependant, en coadministration avec le RS 67333, le GR 125487 bloque les effets de l'agoniste du récepteur 5-HT4, Plusieurs études ont montré qu'administré seul, le GR 125487 n'a pas d'effet direct sur le comportement de type anxieux dans différents tests comportementaux comme le LDT (Costall & Naylor, 1997), l'OF, l'EPM ou encore le NSF, 2014.

. Mendez-david, Costall et Naylor ont montré que les effets anxiolytiques du diazépam dans le LDT étaient inhibés par une administration unique d'antagonistes du récepteur 5-HT4 comme le GR 113808 ou le SB 204070. Nos résultats font état d'observations similaires concernant le diazépam puisque la réponse anxiolytique qu'il, En outre, l'activation de ce récepteur n'est pas seulement nécessaire à l'activité anxiolytique du RS 67333, elle l'est aussi à l'activité anxiolytique et antidépressive de la fluoxétine, et à l'activité anxiolytique du diazépam, 2012.

, utilisé pour endormir les rats, avec les récepteurs GABAergiques

, De même, une lésion spécifique des neurones sérotoninergiques du NRD chez le rat

. Thiebot, Toutefois, il a été rapporté que l'administration de diazépam diminue le métabolisme de la sérotonine. C'est le cas chez le rat Lister hooded, où une injection intrapéritonéale de diazépam (2,5 mg/kg) réduit significativement l'augmentation extracellulaire de 5-HT dans l'HPCv, induite par une exposition à l'EPM (Wright et al., 1992). C'est également le cas chez le rat Sprague-Dawley, où une injection de diazépam (20 mg/kg), 10 minutes après une injection de sérotonine radiomarquée, Wistar n'altère pas la réponse anxiolytique du diazépam dans un test de punition liée à la prise alimentaire, 1970.

. Olivier, Il est donc certain que les systèmes sérotoninergique et GABAergique interagissent entre eux pour induire une réponse anxiolytique, bien qu'on ne connaisse pas précisément la nature de cette interaction, surtout que la vaste majorité des neurones sérotoninergiques expriment le récepteur GABAA, 2013.

. Vialou, Ces résultats, ainsi que nos données, suggèrent donc que l'activité anxiolytique pourrait être la conséquence directe d'une activation spécifique du CPFm. Seulement, le CPFm pourrait jouer le rôle d'un carrefour secondaire régulé par l'intermédiaire de structures telles que l'amygdale ou l'HPCv. En effet, une inhibition par optogénétique de 40% des terminaisons neuronales glutamatergiques de l'HPCv, dans le CPFm, provoque une augmentation du temps passé dans les BO de l'EPM et diminue la latence pour se nourrir dans le NSF, chez les souris exprimant Arch, Tableau 21). A l'inverse, une stimulation des projections neuronales glutamatergiques de l'aire PrL dans le NAc, 2014.

. Felix-ortiz, Comme attendu, l'inhibition de ces projections produit l'effet inverse, à savoir que les souris exprimant NpHR évitent de manière équivoque les BO de l'EPM et le centre de l'OF, synonyme d'un phénotype anxieux, qui plus est associé à une augmentation de la Discussion Au laboratoire, nous avons confirmé les effets prophylactiques de la kétamine dans un troisième modèle de stress, le modèle CORT. Nous avons trouvé qu'une administration unique de kétamine (90 mg/kg) chez la souris C57BL/6NTac mâle prévient l'augmentation de l'immobilité dans le FST, la diminution du temps de toilettage dans le splash test et la réduction de la latence pour se nourrir dans le NSF, des conséquences néfastes induites après un traitement chronique par corticostérone (Tableau 22). L'efficacité de la kétamine à une dose plus élevée que celle administrée dans les deux précédents modèles, Évidemment, d'autres circuits sont responsables de la régulation des comportements anxieux, sans directement incriminer le CPFm. Ainsi, l'activation optogénétique des projections des neurones pyramidaux de la BLA sur l'HPCv promeut les comportements anxieux dans l'EPM et l'OF, alors qu'à l'inverse, une inhibition de ces projections augmente le temps passé dans les BO de l'EPM et dans le centre de l'OF, 2013.

L. Fst, &. Tst, L. Epm, and . Splash, Lorsque la kétamine est administrée à la suite d'un stress, que ce soit après un stress de défaite sociale ou un traitement chronique par corticostérone, nous n'avons pas observé d'amélioration significative des paramètres mesurés dans le

. David, La fluoxétine a été utilisée dans cette étude, comme molécule de référence traditionnellement utilisée pour traiter les troubles de l'humeur. Les effets curatifs de la fluoxétine sont désormais bien connus, 2009.

. Mendez-david, Dans notre étude, nous avons constaté qu'une administration chronique de fluoxétine pendant 3 semaines dans l'eau de boisson, ne protège pas systématiquement, ni de manière robuste, contre le développement d'un phénotype dépressif induit par un stress (Tableau 22). En effet, dans le modèle de défaite sociale, 2014.

, 5 mg/kg/j ; 3 semaines) chez le rat Lewis, une souche hautement sensible au stress, de manière préalable à l'application d'un stress de défaite sociale protège contre l

, Toutefois, ces résultats doivent être interprétés avec précaution puisqu'aucune comparaison n'a été faite entre les rats stressés ayant reçu la solution véhicule et les rats stressés ayant reçu la fluoxétine. De manière intéressante, la fluoxétine a montré en clinique, des effets profitables dans la prévention des récidives liées aux EDC puisque dans une étude randomisée et contrôlée menée Discussion, p.327

. Montgomery, EDC unipolaire et traités par fluoxétine (20 mg/j) ont présenté des périodes de rémission plus longues que les patients assignés au placébo, 1988.

, L'administration chronique par voie systémique de RS67333 prévient l'apparition du phénotype anxio-dépressif induit par un traitement chronique par corticostérone

, Pour tester le potentiel protecteur lié à la stimulation du récepteur 5-HT4, le RS, vol.67333, issue.1, p.5

, mg/kg ; mini-pompes) a été administré de manière chronique et par voie systémique pendant 3

, Tout comme la kétamine, nous avons montré que le RS 67333 possède un pouvoir protecteur, mais à l'instar de la kétamine, le RS 67333 est capable de protéger contre le développement d'un phénotype dépressif, mais aussi anxieux. En effet, nous avons observé que le RS 67333, administré pendant 3 semaines, par diffusion osmotique continue grâce des mini-pompes implantées en sous-cutanée chez la souris C57BL/6NTac, augmente le temps passé dans les BO de l'EPM et le temps de toilettage dans le splash test, et diminue la latence pour se nourrir dans le NSF

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