S 47445 counteracts the behavioral manifestations and hippocampal neuroplasticity changes in bulbectomized mice

S 47445 is a positive allosteric modulator of glutamate AMPA-type receptors that possesses procognitive, neurotrophic and enhancing synaptic plasticity properties. Its chronic administration promotes antidepressant- and anxiolytic-like effects in different rodent models of depression. We have evaluated the behavioral effects of S 47445 in the bilateral olfactory bulbectomy mice model (OB) and the adaptive changes in those proteins associated to brain neuroplasticity (BDNF and mTOR pathway). Following OB surgery, adult C57BL/6J male mice were chronically administered S 47445 (1, 3 and 10?mg/kg/day; i.p.) and fluoxetine (18?mg/kg/day; i.p.), and then behaviorally tested in the open field test. Afterwards, the expression levels of BDNF, mTOR, phospho-mTOR, 4EBP1 and phospho-4EBP1 were evaluated in hippocampus and prefrontal cortex. Both drugs reduced the OB-induced locomotor activity, a predictive outcome of antidepressant efficacy, with a similar temporal pattern of action. S 47445, but not fluoxetine, showed an anxiolytic effect as reflected by an increased central activity. Chronic administration of S 47445 reversed OB-induced changes in BDNF and phopho-mTOR expression in hippocampus but not in prefrontal cortex. The chronic administration of S 47445 induced antidepressant- and anxiolytic-like effects at low-medium doses (1 and 3?mg/kg/day, i.p.) associated with the reversal of OB-induced changes in hippocampal BDNF and mTOR signaling pathways.Funding: This work was supported by the Institut de Recherches Internationales Servier and the Spanish Ministry of Economy and Competitiveness (MINECO/FEDER) (grant number SAF2015-67457-R)

Blockade of stress-induced increase of glutamate release in the rat prefrontal/frontal cortex by agomelatine involves synergy between melatonergic and 5-HT2C receptor-dependent pathways

<p>Abstract</p> <p>Background</p> <p>Agomelatine is a melatonergic receptor agonist and a 5HT_2Creceptor antagonist that has shown antidepressant efficacy. In order to analyze separately the effect of the two receptorial components, rats were chronically treated with agomelatine, melatonin (endogenous melatonergic agonist), or S32006 (5-HT_2Cantagonist), and then subjected to acute footshock-stress.</p> <p>Results</p> <p>Only chronic agomelatine, but not melatonin or S32006, completely prevented the stress-induced increase of glutamate release in the rat prefrontal/frontal cortex.</p> <p>Conclusions</p> <p>These results suggest a potential synergy between melatonergic and serotonergic pathways in the action of agomelatine.</p

S 38093, a histamine H3 antagonist/inverse agonist, promotes hippocampal neurogenesis and improves context discrimination task in aged mice

Strategies designed to increase adult hippocampal neurogenesis (AHN) may have therapeutic potential for reversing memory impairments. H3 receptor antagonists/inverse agonists also may be useful for treating cognitive deficits. However, it remains unclear whether these ligands have effects on AHN. The present study aimed to investigate the effects of a 28-day treatment with S 38093, a novel brain-penetrant antagonist/inverse agonist of H3 receptors, on AHN (proliferation, maturation and survival) in 3-month-old and in aged 16-month-old mice. In addition, the effects of S 38093 treatment on 7-month-old APPSWE Tg2576 transgenic mice, a model of Alzheimer’s disease, were also assessed. In all tested models, chronic treatment with S 38093 stimulated all steps of AHN. In aged animals, S 38093 induced a reversal of age-dependent effects on hippocampal brain-derived neurotrophic factor (BDNF) BDNF-IX, BDNF-IV and BDNF-I transcripts and increased vascular endothelial growth factor (VEGF) expression. Finally, the effects of chronic administration of S 38093 were assessed on a neurogenesis-dependent “context discrimination (CS) test” in aged mice. While ageing altered mouse CS, chronic S 38093 treatment significantly improved CS. Taken together, these results provide evidence that chronic S 38093 treatment increases adult hippocampal neurogenesis and may provide an innovative strategy to improve age-associated cognitive deficits

Isoform-Specific Biased Agonism of Histamine H 3 Receptor Agonists s

ABSTRACT The human histamine H 3 receptor (hH 3 R) is subject to extensive gene splicing that gives rise to a large number of functional and nonfunctional isoforms. Despite the general acceptance that G protein-coupled receptors can adopt different ligand-induced conformations that give rise to biased signaling, this has not been studied for the H 3 R; further, it is unknown whether splice variants of the same receptor engender the same or differential biased signaling. Herein, we profiled the pharmacology of histamine receptor agonists at the two most abundant hH 3 R splice variants (hH 3 R 445 and hH 3 R 365 ) across seven signaling endpoints. Both isoforms engender biased signaling, notably for 4-[3-(benzyloxy)propyl]-1H-imidazole (proxyfan) [e.g., strong bias toward phosphorylation of glycogen synthase kinase 3b (GSK3b) via the full-length receptor] and its congener 3-(1H-imidazol-4-yl)propyl-(4-iodophenyl)-methyl ether (iodoproxyfan), which are strongly consistent with the former&apos;s designation as a &quot;protean&quot; agonist. The 80 amino acid IL3 deleted isoform hH 3 R 365 is more permissive in its signaling than hH 3 R 445 : 2-(1H-imidazol-5-yl)ethyl imidothiocarbamate (imetit), proxyfan, and iodoproxyfan were all markedly biased away from calcium signaling, and principal component analysis of the full data set revealed divergent profiles for all five agonists. However, most interesting was the identification of differential biased signaling between the two isoforms. Strikingly, hH 3 R 365 was completely unable to stimulate GSK3b phosphorylation, an endpoint robustly activated by the full-length receptor. To the best of our knowledge, this is the first quantitative example of differential biased signaling via isoforms of the same G proteincoupled receptor that are simultaneously expressed in vivo and gives rise to the possibility of selective pharmacological targeting of individual receptor splice variants

The social construction of coastal risks in two different cultural contexts: A study of marine erosion and flooding in France and Canada

With an increasing number of coastal issues associated with human pressure and exacerbated by climate change, this study examines how residents of coastal communities perceive their living environment and how they perceive risks in this environment and more particularly coastal risks (marine erosion and flooding). An international (Canada-France) questionnaire study was conducted among 190 people, approximately half of whom lived on New Brunswick’s Acadian Coast and half on France’s west coast. The results highlight, on the one hand, the residents’ strong relationship with their coastal living environment and, on the other, a representation of coastal risks as an important area of concern for them. That said, the worry concerning these risks varied among the participants. The local and cultural context (media coverage of this issue and the country-specific risk management strategies) may explain the differences in attitude between the two countries

Chronic treatment with a melatonin agonist in old hamsters facilitates resynchronization of the circadian clock after abrupt shifts in the light-dark circle

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A melatonin agonist facilitates circadian resynchronization in old hamsters after abrupt shifts in the light-dark cycle

Age-related changes in the mammalian circadian system may be associated with a decline in circulating melatonin levels. Using 'jet lag' paradigms involving abrupt shifts in the light-dark cycle, we showed that a melatonin agonist, S-20098, accelerated by ~25% resynchronization of the circadian activity rhythm in old hamsters to the new light-dark cycle. It suggests the usefulness of melatonin-related compounds to treat circadian disorders associated with aging. Copyright (C) 2000 Elsevier Science B.V.SCOPUS: sh.jinfo:eu-repo/semantics/publishe

Dépression et neuroplasticité : implication des systèmes sérotoninergiques

L'analyse des effets des antidépresseurs sur la neuroplasticité, et plus particulièrement sur la formation de nouveaux neurones dans le cerveau adulte, constitue aujourd'hui un thème de recherche novateur compte tenu de l'implication d'une modification de la connectivité neuronale dans la physiopathologie des troubles de l'humeur. Les modèles animaux de stress chronique ont permis de révéler des altérations structurales au niveau de l'hippocampe notamment, qui sont réversibles avec le temps et les traitements antidépresseurs. Chez des patients atteints de dépression majeure, on observe aussi une diminution du volume hippocampique qui a été associée à des déficits cognitifs. Dans ce contexte, la sérotonine (5-HT) apparaît jouer un rôle clé, par ses effets notables dans la réponse au stress et le traitement de la dépression, comme dans son implication dans les processus de la neuroplasticité et sa faculté de stimuler la neurogenèse secondaire. D'autres antidépresseurs, comme l'agomélatine ayant des propriétés à la fois sérotoninergique et mélatoninergique, entraînent aussi une augmentation de ce processus, et bien que ces observations ne permettent pas pour l'instant de proposer un mécanisme sous-jacent commun à l'ensemble de ces effets, leurs conséquences pourraient avoir une implication importante dans le traitement des troubles de l'humeur

Pharmacological or genetic blockade of the dopamine D3 receptor increases cell proliferation in the hippocampus of adult mice

Dopamine plays an important role in cellular processes controlling the functional and structural plasticity of neurons, as well as their generation and proliferation, both in the developing and the adult brain. The precise roles of individual dopamine receptors subtypes in adult neurogenesis remain poorly defined, although D3 receptors are known to be involved in neurogenesis in the subventricular zone. By contrast, very few studies have addressed the influence of dopamine and D3 receptors upon neurogenesis in the subgranular zone of the hippocampus, an issue addressed herein employing constitutive D3 receptor knockout mice, or chronic exposure to the preferential D3 receptor antagonist, S33138. D3 receptor knockout mice revealed increased baseline levels of cell proliferation and ongoing neurogenesis, as measured both using Ki-67 and doublecortin, whereas there was no difference in cell survival as measured by BrdU (5-bromo-2'-deoxyuridine). Chronic administration of S33138 was shown to be functionally active in enhancing levels of the plasticity-related molecule, delta-FosB, in the D3 receptor-rich nucleus accumbens. In accordance with the stimulated neurogenesis seen in D3 receptor knockout mice, S33138 increased proliferation in wild-type mice. These observations suggest that D3 receptors exert a tonic, constitutive inhibitory influence upon adult hippocampal neurogenesis.</p

In a diurnal rodent, adaptation of circadian rhythmicity to a shift in the light dark cycle can be accelerated by a melatonin-agonist

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