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Ingallinesi M.,French Institute of Health and Medical Research | Le Bouil L.,French Institute of Health and Medical Research | Faucon Biguet N.,French Institute of Health and Medical Research | Do Thi A.,French Institute of Health and Medical Research | And 6 more authors.
Molecular Psychiatry | Year: 2014

Gpr88, an orphan G-protein-coupled receptor, is highly and almost exclusively expressed in the medium spiny projection neurons of the striatum, and may thus participate in the control of motor functions and cognitive processing that are impaired in neuropsychiatric disorders such as Parkinson's disease or schizophrenia (SZ). This study investigated the relevance of Gpr88 to SZ-associated behavior by knocking down Gpr88 gene expression in the ventral striatum (nucleus accumbens) in a neurodevelopmental rat model of SZ, generated by neonatal treatment with phencyclidine (PCP). In this model, we compared the effects of the local inactivation in the adult animal of the expression of Gpr88 and of Drd2, a gene strongly implicated in the etiology of SZ and coding for the dopamine receptor type 2 (D2). To inactivate specifically Gpr88 and D2 expression, we used the lentiviral vector-mediated microRNA silencing strategy. The neonatal PCP treatment induced in the adult rat hyperlocomotion in response to amphetamine (Amph) and social novelty discrimination (SND) deficits. The inactivation of D2 did not modify the locomotor response to Amph or the cognitive deficits induced by PCP, whereas the silencing of Gpr88 inhibited the Amph-induced hyperlocomotion and reduced the impairment of SND elicited by neonatal exposure to PCP. These observations suggest a role for Gpr88 in the regulation of cognitive and motor functions, and support its relevance to the pathophysiology and treatment of SZ and other disorders involving dysfunction of the accumbens-striatal complex.Molecular Psychiatry advance online publication, 26 August 2014; doi:10.1038/mp.2014.92.


PubMed | Institute Of Recherches Servier Idrs, University of California at San Francisco and French Institute of Health and Medical Research
Type: Journal Article | Journal: Molecular psychiatry | Year: 2015

Gpr88, an orphan G-protein-coupled receptor, is highly and almost exclusively expressed in the medium spiny projection neurons of the striatum, and may thus participate in the control of motor functions and cognitive processing that are impaired in neuropsychiatric disorders such as Parkinsons disease or schizophrenia (SZ). This study investigated the relevance of Gpr88 to SZ-associated behavior by knocking down Gpr88 gene expression in the ventral striatum (nucleus accumbens) in a neurodevelopmental rat model of SZ, generated by neonatal treatment with phencyclidine (PCP). In this model, we compared the effects of the local inactivation in the adult animal of the expression of Gpr88 and of Drd2, a gene strongly implicated in the etiology of SZ and coding for the dopamine receptor type 2 (D2). To inactivate specifically Gpr88 and D2 expression, we used the lentiviral vector-mediated microRNA silencing strategy. The neonatal PCP treatment induced in the adult rat hyperlocomotion in response to amphetamine (Amph) and social novelty discrimination (SND) deficits. The inactivation of D2 did not modify the locomotor response to Amph or the cognitive deficits induced by PCP, whereas the silencing of Gpr88 inhibited the Amph-induced hyperlocomotion and reduced the impairment of SND elicited by neonatal exposure to PCP. These observations suggest a role for Gpr88 in the regulation of cognitive and motor functions, and support its relevance to the pathophysiology and treatment of SZ and other disorders involving dysfunction of the accumbens-striatal complex.


Vandesquille M.,French National Center for Scientific Research | Vandesquille M.,Institute Of Recherches Servier Idrs | Baudonnat M.,French National Center for Scientific Research | Decorte L.,French National Center for Scientific Research | And 3 more authors.
Neurobiology of Aging | Year: 2013

The present study investigates in aged mice the working memory (WM) enhancing potential of the selective α4β2* nicotinic receptor agonist S 38232 as compared with the cholinesterase inhibitor donepezil, and their effect on cAMP response element binding protein (CREB) phosphorylation (pCREB) as a marker of neuronal activity. We first showed that aged mice exhibit a WM deficit and an increase of pCREB in the prelimbic cortex (PL) as compared with young mice, whereas no modification appears in the CA1. Further, we showed that systemic administration of S 38232 restored WM in aged mice and alleviated PL CREB overphosphorylation. Donepezil alleviated age-related memory deficits, however, by increasing pCREB in the CA1, while pCREB in PL remained unaffected. Finally, whereas neuronal inhibition by lidocaine infusion in the PL appeared deleterious in young mice, the infusion of Rp-cAMPS (a compound known to inhibit CREB phosphorylation) or S 38232 rescued WM in aged animals. Thus, by targeting the α4β2*-nicotinic receptor of the PL, S 38232 alleviates PL CREB overphosphorylation and restores WM in aged mice, which opens new pharmacologic perspectives of therapeutic strategy. © 2013 Elsevier Inc.


Scott F.F.,University of Manchester | Belle M.D.C.,University of Manchester | Delagrange P.,Institute Of Recherches Servier Idrs | Piggins H.D.,University of Manchester
Journal of Neuroendocrinology | Year: 2010

The master circadian pacemaker in the suprachiasmatic nuclei (SCN) regulates the nocturnal secretion of the pineal hormone melatonin. Melatonin, in turn, has feedback effects on SCN neuronal activity rhythms via high affinity G protein-coupled receptors (MT1 and MT2). However, the precise effects of melatonin on the electrical properties of individual SCN neurones are unclear. In the present study, we investigated the acute effects of exogenous melatonin on SCN neurones using whole-cell patch-clamp recordings in brain slices prepared from Per1::d2EGFP-expressing transgenic mice. In current-clamp mode, bath applied melatonin, at near-physiological concentrations (1 nm), hyperpolarised the majority (63.7%) of SCN neurones tested at all times of the projected light/dark cycle. In addition, melatonin depolarised a small proportion of cells (11.0%). No differences were observed for the effects of melatonin between Per1::GFP or non-Per1::GFP SCN neurones. Melatonin-induced effects were blocked by the MT1/MT2 antagonist, luzindole (1 μm) and the proportion of SCN neurones responsive to melatonin was greatly reduced in the presence of either tetrodotoxin (200 or 500 nm) or gabazine (20 μm). In voltage-clamp recordings, 1 nm melatonin increased the frequency of GABA-mediated currents. These findings indicate, for the first time, that exogenous melatonin can alter neuronal excitability in the majority of SCN neurones, regardless of whether or not they overtly express the core clock gene Per1. The results also suggest that melatonin acts mainly by modulating inhibitory GABAergic transmission within the SCN. This may explain why exogenous application of melatonin has heterogenous effects on individual SCN neurones. © 2010 The Authors. Journal of Neuroendocrinology © 2010 Blackwell Publishing Ltd.


Zhang H.,Institut Universitaire de France | Zhang H.,French National Center for Scientific Research | Etherington L.-A.,University of Dundee | Hafner A.-S.,Institut Universitaire de France | And 12 more authors.
Molecular Psychiatry | Year: 2013

The plasticity of excitatory synapses is an essential brain process involved in cognitive functions, and dysfunctions of such adaptations have been linked to psychiatric disorders such as depression. Although the intracellular cascades that are altered in models of depression and stress-related disorders have been under considerable scrutiny, the molecular interplay between antidepressants and glutamatergic signaling remains elusive. Using a combination of electrophysiological and single nanoparticle tracking approaches, we here report that the cognitive enhancer and antidepressant tianeptine (S 1574, 3-chloro-6-methyl-5,5-dioxo-6,11-dihydro-(c,f)-dibenzo-(1,2-thiazepine)-11-yl) amino-7 heptanoic acid, sodium salt) favors synaptic plasticity in hippocampal neurons both under basal conditions and after acute stress. Strikingly, tianeptine rapidly reduces the surface diffusion of AMPA receptor (AMPAR) through a Ca 2+ /calmodulin-dependent protein kinase II (CaMKII)-dependent mechanism that enhances the binding of AMPAR auxiliary subunit stargazin with PSD-95. This prevents corticosterone-induced AMPAR surface dispersal and restores long-term potentiation of acutely stressed mice. Collectively, these data provide the first evidence that a therapeutically used drug targets the surface diffusion of AMPAR through a CaMKII-stargazin-PSD-95 pathway, to promote long-term synaptic plasticity. © 2013 Macmillan Publishers Limited.


Canet E.,Institute Of Recherches Internationales Servier Iris | Lerebours G.,Institute Of Recherches Internationales Servier Iris | Vilaine J.-P.,Institute Of Recherches Servier Idrs
Annals of the New York Academy of Sciences | Year: 2011

The link between elevated heart rate and cardiovascular events is established in healthy individuals and in patients with cardiovascular disease. The new agent, ivabradine, specifically and selectively inhibits the I f current, with the sole action of heart rate reduction, with no impact on any other cardiac parameters. The benefits of "pure" heart rate reduction with ivabradine have been the focus of one of the largest clinical development programs ever performed, involving >20,000 individuals. Ivabradine has anti-ischemic and antianginal efficacy in monotherapy, as well as in combination with other antianginals, such as beta-blockers, and is safe and well tolerated. Two major morbidity-mortality trials, BEAUTIFUL and SHIFT, showed that heart rate reduction with ivabradine dramatically improves prognosis in patients with coronary artery disease and left ventricular dysfunction, symptomatic angina, or chronic heart failure. The development of ivabradine represents a clear innovation in the management of cardiovascular disease. © 2011 New York Academy of Sciences.


Petit L.,Ecole Polytechnique - Palaiseau | Botez I.,Institute Of Recherches Servier Idrs | Tizot A.,Institute Of Recherches Servier Idrs | Zard S.Z.,Ecole Polytechnique - Palaiseau
Tetrahedron Letters | Year: 2012

Variously substituted novel dihydropyridoazepinones have been prepared by an intermolecular radical addition followed by a radical cyclisation on a pyridine ring. The latter process involved the use of a combination of two different peroxides, an experimental contrivance resulting from a careful product analysis and a better understanding of the cyclisation step. © 2012 Elsevier Ltd. All rights reserved.


Hamon V.,Institute Paoli Calmettes | Bourgeas R.,Institute Paoli Calmettes | Ducrot P.,Institute Of Recherches Servier Idrs | Theret I.,Institute Of Recherches Servier Idrs | And 6 more authors.
Journal of the Royal Society Interface | Year: 2014

Over the last 10 years, protein-protein interactions (PPIs) have shown increasing potential as new therapeutic targets. As a consequence, PPIs are today the most screened target class in high-throughput screening (HTS). The development of broad chemical libraries dedicated to these particular targets is essential; however, the chemical space associated with this 'high-hanging fruit' is still under debate. Here, we analyse the properties of 40 non-redundant small molecules present in the 2P2I database (http://2p2idb.cnrs- mrs.fr/) to define a general profile of orthosteric inhibitors and propose an original protocol to filter general screening libraries using a support vector machine (SVM) with 11 standard DRAGON molecular descriptors. The filtering protocol has been validated using external datasets from PubChem BioAssay and results from in-house screening campaigns. This external blind validation demonstrated the ability of the SVM model to reduce the size of the filtered chemical library by eliminating up to 96% of the compounds as well as enhancing the proportion of active compounds by up to a factor of 8.We believe that the resulting chemical space identified in this paper will provide the scientific community with a concrete support to search for PPI inhibitors during HTS campaigns. © 2013 The Author(s) Published by the Royal Society. All rights reserved.


PubMed | Institute Of Recherches Servier Idrs
Type: Journal Article | Journal: Journal of vascular research | Year: 2012

Age and hypertension are two major determinants of arterial stiffness, as well as endothelial dysfunction. The present study was designed to test whether a chronic reduction of endogenous nitric oxide (NO) produces arterial stiffening close to that observed in old spontaneously hypertensive rats (SHR), and also to study the effect of an acute or a chronic decrease in blood pressure (BP) on aortic distensibility.BP, aortic stiffness, endothelial dysfunction and remodelling were measured in male adult (20-week-old) SHR, in adult SHR treated with a nonspecific NO synthase inhibitor L-NAME (SHR/L-NAME) for 2 weeks, in adult SHR/L-NAME cotreated with perindopril (1 mg/kg/day) and in old SHR (55-week-old). Age-matched WKY were used as a normotensive group.Aortic endothelial dysfunction, remodelling and stiffening appeared in old SHR. Reduction of NO production in adult SHR caused similar alterations. Acute decreases in BP in SHR/L-NAME did not improve isobaric aortic distensibility but a chronic reduction of BP prevented endothelial dysfunction, aortic remodelling and aortic wall stiffening.NO reduction in adult SHR induces aortic alterations similar to those observed during aging, which supports the major role of NO in the development of arterial stiffening. These aortic alterations can be prevented by angiotensin-converting enzyme inhibitor treatment.

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