16 research outputs found

    The dopamine D2/D3 receptor agonist quinpirole increases checking-like behaviour in an operant observing response task with uncertain reinforcement: a novel possible model of OCD.

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    Excessive checking is a common, debilitating symptom of obsessive-compulsive disorder (OCD). In an established rodent model of OCD checking behaviour, quinpirole (dopamine D2/3-receptor agonist) increased checking in open-field tests, indicating dopaminergic modulation of checking-like behaviours. We designed a novel operant paradigm for rats (observing response task (ORT)) to further examine cognitive processes underpinning checking behaviour and clarify how and why checking develops. We investigated i) how quinpirole increases checking, ii) dependence of these effects on D2/3 receptor function (following treatment with D2/3 receptor antagonist sulpiride) and iii) effects of reward uncertainty. In the ORT, rats pressed an 'observing' lever for information about the location of an 'active' lever that provided food reinforcement. High- and low-checkers (defined from baseline observing) received quinpirole (0.5mg/kg, 10 treatments) or vehicle. Parametric task manipulations assessed observing/checking under increasing task demands relating to reinforcement uncertainty (variable response requirement and active-lever location switching). Treatment with sulpiride further probed the pharmacological basis of long-term behavioural changes. Quinpirole selectively increased checking, both functional observing lever presses (OLPs) and non-functional extra OLPs (EOLPs). The increase in OLPs and EOLPs was long-lasting, without further quinpirole administration. Quinpirole did not affect the immediate ability to use information from checking. Vehicle and quinpirole-treated rats (VEH and QNP respectively) were selectively sensitive to different forms of uncertainty. Sulpiride reduced non-functional EOLPs in QNP rats but had no effect on functional OLPs. These data have implications for treatment of compulsive checking in OCD, particularly for serotonin-reuptake-inhibitor treatment-refractory cases, where supplementation with dopamine receptor antagonists may be beneficial

    Evasion of anti-growth signaling: a key step in tumorigenesis and potential target for treatment and prophylaxis by natural compounds

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    The evasion of anti-growth signaling is an important characteristic of cancer cells. In order to continue to proliferate, cancer cells must somehow uncouple themselves from the many signals that exist to slow down cell growth. Here, we define the anti-growth signaling process, and review several important pathways involved in growth signaling: p53, phosphatase and tensin homolog (PTEN), retinoblastoma protein (Rb), Hippo, growth differentiation factor 15 (GDF15), AT-rich interactive domain 1A (ARID1A), Notch, insulin-like growth factor (IGF), and Krüppel-like factor 5 (KLF5) pathways. Aberrations in these processes in cancer cells involve mutations and thus the suppression of genes that prevent growth, as well as mutation and activation of genes involved in driving cell growth. Using these pathways as examples, we prioritize molecular targets that might be leveraged to promote anti-growth signaling in cancer cells. Interestingly, naturally-occurring phytochemicals found in human diets (either singly or as mixtures) may promote anti-growth signaling, and do so without the potentially adverse effects associated with synthetic chemicals. We review examples of naturally-occurring phytochemicals that may be applied to prevent cancer by antagonizing growth signaling, and propose one phytochemical for each pathway. These are: epigallocatechin-3-gallate (EGCG) for the Rb pathway, luteolin for p53, curcumin for PTEN, porphyrins for Hippo, genistein for GDF15, resveratrol for ARID1A, withaferin A for Notch and diguelin for the IGF1-receptor pathway. The coordination of anti-growth signaling and natural compound studies will provide insight into the future application of these compounds in the clinical setting

    Images de la contestation du pouvoir dans le monde normand (xe-xviiie siècle)

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    Ce colloque, organisé au centre international de Cerisy-la-Salle par l’Office Universitaire d’Études Normandes de l’université de Caen Basse-Normandie, s’est penché pendant cinq jours sur la question de la contestation dans le monde normand. Selon la définition des dictionnaires, contester c’est « dénier », « récuser » ou encore « refuser ». Autant de termes qui s’appliquent parfaitement à une Normandie qui, de ses origines au XVIIIe siècle, a connu, voire subi, différents pouvoirs : celui des ducs jusqu’en 1204, puis celui de la Couronne de France, sans oublier celui de la Couronne d’Angleterre. De plus, l’extension européenne de cette province, en Angleterre et en Italie, n’a pu que susciter des contestations du pouvoir ou plutôt des pouvoirs, ceux auxquels les Normands étaient soumis ou ceux qu’ils ont exercés. Les organisatrices du colloque ont donc souhaité examiner les différents épisodes contestataires liés à ces grandes phases de l’histoire de la Normandie en choisissant toutefois de s’arrêter à la veille de la Révolution française qui constitue une nouvelle étape, qui affecte la France tout entière. Une étude sur le long terme a paru être à même de dégager une éventuelle spécificité de la contestation normande. Sur ce point, signalons que les dictionnaires donnent également comme synonyme de contester le verbe chicaner. Ne dit-on pas justement que le Normand est chicanier ? La fameuse devise « C’est mon droit et j’y tiens », que l’on attribue traditionnellement au Normand, n’est-elle pas révélatrice d’une mentalité contestataire bien affirmée
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