A novel anxiogenic role for the delta opioid receptor expressed in GABAergic forebrain neurons.

BACKGROUND: The delta opioid receptor (DOR) is broadly expressed throughout the nervous system; it regulates chronic pain, emotional responses, motivation, and memory. Neural circuits underlying DOR activities have been poorly explored by genetic approaches. We used conditional mouse mutagenesis to elucidate receptor function in GABAergic neurons of the forebrain. METHODS: We characterized DOR distribution in the brain of Dlx5/6-CreXOprd1(fl/fl) (Dlx-DOR) mice and tested main central DOR functions through behavioral testing. RESULTS: The DOR proteins were strongly deleted in olfactory bulb and striatum and remained intact in cortex and basolateral amygdala. Olfactory perception, circadian activity, and despair-like behaviors were unchanged. In contrast, locomotor stimulant effects of SNC80 (DOR agonist) and SKF81297 (D1 agonist) were abolished and increased, respectively. The Dlx-DOR mice showed lower levels of anxiety in the elevated plus maze, opposing the known high anxiety in constitutive DOR knockout animals. Also, Dlx-DOR mice reached the food more rapidly in a novelty suppressed feeding task, despite their lower motivation for food reward observed in an operant paradigm. Finally, c-fos protein staining after novelty suppressed feeding was strongly reduced in amygdala, concordant with the low anxiety phenotype of Dlx-DOR mice. CONCLUSIONS: We demonstrate that DORs expressed in the forebrain mediate the described locomotor effect of SNC80 and inhibit D1-stimulated hyperactivity. Our data also reveal an unanticipated anxiogenic role for this particular DOR subpopulation, with a potential novel adaptive role. In emotional responses, DORs exert dual anxiolytic and anxiogenic roles, both of which may have implications in the area of anxiety disorders

Non-nociceptive roles of opioids in the CNS: opioids' effects on neurogenesis, learning, memory and affect.

Mortality due to opioid use has grown to the point where, for the first time in history, opioid-related deaths exceed those caused by car accidents in many states in the United States. Changes in the prescribing of opioids for pain and the illicit use of fentanyl (and derivatives) have contributed to the current epidemic. Less known is the impact of opioids on hippocampal neurogenesis, the functional manipulation of which may improve the deleterious effects of opioid use. We provide new insights into how the dysregulation of neurogenesis by opioids can modify learning and affect, mood and emotions, processes that have been well accepted to motivate addictive behaviours

A Genetic Animal Model of Alcoholism for Screening Medications to Treat Addiction

The purpose of this review is to present up-to-date pharmacological, genetic, and behavioral findings from the alcohol-preferring P rat and summarize similar past work. Behaviorally, the focus will be on how the P rat meets criteria put forth for a valid animal model of alcoholism with a highlight on its use as an animal model of polysubstance abuse, including alcohol, nicotine, and psychostimulants. Pharmacologically and genetically, the focus will be on the neurotransmitter and neuropeptide systems that have received the most attention: cholinergic, dopaminergic, GABAergic, glutamatergic, serotonergic, noradrenergic, corticotrophin releasing hormone, opioid, and neuropeptide Y. Herein, we sought to place the P rat's behavioral and neurochemical phenotypes, and to some extent its genotype, in the context of the clinical literature. After reviewing the findings thus far, this chapter discusses future directions for expanding the use of this genetic animal model of alcoholism to identify molecular targets for treating drug addiction in general

Notre-Dame de la Délivrande : exemple d'un sanctuaire mariai bas-normand

Main place of Marian Worship, Notre-Dame de la Délivrande through the renown of the Black Virgin extends over the Lower Normandy and above. Every year the sanctuary draws several hundreds of pilgrims, but today, in addition to these faithful, there are summer-visitors, a recent reality to take into consideration.Haut-lieu du culte mariai, Notre-Dame de la Délivrande, grâce à la renommée de sa Vierge Noire, rayonne en Basse-Normandie et même au-delà. Chaque année, le sanctuaire attire plusieurs centaines de pèlerins, mais aux fidèles viennent désormais s 'ajouter les touristes, une réalité récente à prendre en considération.Charbogne Marie-Bénédicte. Notre-Dame de la Délivrande : exemple d'un sanctuaire mariai bas-normand. In: Norois, n°174, Avril-Juin 1997. pp. 337-342

Récepteurs opioïdes mu et circuits neuronaux de l'addiction : approches génétiques chez la souris

Mu opioid receptors mediate the strong analgesic and addictive properties of morphine and heroin;however mu receptor function at circuit levels is not well understood and has been poorly studied by genetic approaches. These receptors are widely expressed throughout the nervous system, essentially in GABAergic neurons. The first aim of my project was to genetically inactivate the mu receptor gene in GABAergic forebrain neurons and study the behavioral consequences. Our study shows that these mu receptors are not implicated in morphine-induced analgesia and physical dependence, but are essential for locomotor effects of heroin. Moreover, our data show that these receptors inhibit motivation to consume heroin and chocolate, revealing an entirely new role for this particular population of mu receptors (Manuscript 1: Mu opioid receptors in GABAergic forebrain neurons are necessary for heroin hyperlocomotion and reduce motivation for heroin and palatable food). Also, mu receptors expressed in forebrain GABAergic neurons are not responsible for the autistic syndrome described in total mu receptor knockout mice (Manuscript 2: Mu opioid receptors in GABAergic forebrain neurons are not involved in autistic-like symptoms). Finally, we developed a new transgenic model targeting the mu receptor gene in glutamatergic neurons, but receptor deletion was not detectable in conditional mice. We also initiated the creation of a transgenic Cre driver line to knockout genes of interest in the extended amygdala, and this tool will enable us to study mu receptor function within this microcircuit.Le récepteur opioïde mu est responsable des propriétés analgésiques et addictives puissantes de la morphine et de l’héroïne, mais son mode d’action à l’échelle des circuits neuronaux est mal connu et a été peu étudié par des approches génétiques. Le récepteur mu est largement exprimé dans le système nerveux, essentiellement dans des neurones GABAergiques. Le premier objectif de mon projet a été d’inactiver le gène codant pour le récepteur mu dans les neurones GABAergiques du cerveau antérieur et d’en étudier les conséquences comportementales. Notre étude montre que ces récepteurs ne sont pas impliqués dans l’analgésie et la dépendance physique à la morphine, mais qu’ils sont essentiels à l’effet hyperlocomoteur de l’héroïne. De plus, nos résultats indiquent que ces récepteurs limitent la motivation à consommer de l’héroïne et du chocolat, révélant un rôle entièrement nouveau pour cette population particulière de récepteurs (Manuscrit 1 : Mu opioid receptors in GABAergic forebrain neurons are necessary for heroin hyperlocomotion and reduce motivation for heroin and palatable food). Aussi, cette population de récepteurs mu n’est pas responsable du syndrome autistique décrit chez les souris knockout totales (Manuscrit 2 : Mu opioid receptors in GABAergic forebrain neurons are not involved in autistic-like symptoms). Enfin, nous avons développé un nouveau modèle transgénique visant l’inactivation génétique du récepteur mu dans les neurones glutamatergiques, mais qui n’a pas abouti à un knockout conditionnel détectable. Nous avons aussi initié la création d’une lignée transgénique Cre pour l’inactivation de gènes d’intérêt dans l’amygdale étendue, qui permettra notamment d’étudier le rôle du récepteur mu dans ce microcircuit

Les Slums de Bombay : une exclusion au quotidien ?

The Bombay slums : everyday exclusion ? The shortage of housing, a common phenomenon in towns of the Third world, has led Bombay people who are excluded from the official construction channels to occupy public or private open areas. The omnipresent slums have been subjected to contrasting policies, varying from laissez-faire to repression, before being accepted and partially developed.Le manque de logements, phénomène commun dans les villes du Tiers-Monde, a conduit les habitants de Bombay exclus des circuits de construction officiels à occuper les espaces vacants publics ou privés. Les "slums", omniprésents, ont été l'objet de politiques contradictoires, allant du laissez-faire, à la répression, avant d'être acceptés et partiellement développés.Charbogne Marie-Bénédicte. Les Slums de Bombay : une exclusion au quotidien ? . In: Travaux de l'Institut Géographique de Reims, vol. 23-24, n°91-92, 1995. Marginalité et exclusions dans l'espace urbain, sous la direction de Jean Domingo. pp. 111-128

Intérêt du dosage des D-Dimères au cours du traitement anti-coagulant des thromboses veineuses cérébrales

Il a été démontré que les patients atteints de thrombose veineuse cérébrale (TVC) aiguë présentaient initialement un taux plasmatique élevé de D-Dimères. But de l'étude actuelle : évaluer l'intérêt d'un dosage répété des D-Dimères au cours du traitement des TVC. Méthodes : étude prospective d'Avril 1997 à Septembre 2003, incluant des patients atteints de TVC aiguë (symptômes inférieurs à 15 jours) prouvée par imagerie, et ayant bénéficié d'un dosage de D-Dimères par méthode ELISA rapide (Vidas DD, BioMeyrieux, France) à J0 puis au moins tous les deux jours pendant toute la durée du traitement (Héparine non fractionnée au moins 5 jours, TCA à 2 fois le témoin ou activité anti Xa entre 0.4 et 0.8) puis relais AVK. En cas d'aggravation neurologique, un scanner ou une IRM ainsi qu'un dosage de D-Dimères étaient réalisés. Résultats : 18 patients ont été inclus (14 femmes et 4 hommes), âge moyen 33 ans (extrêmes 18-66 ans). Avant mise en place du traitement, le taux de D-Dimères moyen était de 1927 ng/ml (Tous les patients avaient un taux supérieur à 500 ng/ml, seuil de positivité). On a constaté une décroissance régulière des taux de D-Dimères, parallèlement à une amélioration clinique franche chez 14 patients sur 18, au cours du traitement héparinique. Quatre patients ont présenté une aggravation neurologique contemporaine d'une ascension ou d'une stagnation des D-Dimères, alors que dans le même temps, on rapportait une décoagulation insuffisante. Dans un cas sur quatre, l'imagerie a mis en évidence une extension de la thrombose. Après majoration des doses d'héparine (et thrombolyse pour une patiente), l'évolution était favorable pour tous les patients. Conclusion : Le dosage des D-Dimères apparaît utile dans le suivi des TVC puisque leur variation est parallèle à l'évolution clinique et radiologique, leur stagnation ou réascension étant associée à une extension thrombotique et/ou une décoagulation insuffisante.ST ETIENNE-BU Médecine (422182102) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

West Greenland ichthyoplankton and how melting glaciers could allow Arctic cod larvae to survive extreme summer temperatures

International audienceClimate change is rapidly modifying marine fish assemblages in the Arctic. As fish eggs and larvae have a narrower thermal tolerance than nonreproductive adults, their response to increasing temperatures is likely one of the main drivers of these changes. In this study, we described ichthyoplankton assemblages in West Greenland between 62 and 73 °N, during summers 2017–2019, and investigated the relationship between sea surface temperature in the spring and summer and the survival of Arctic cod (Boreogadus saida (Lepechin, 1774)) early life stages over the hatching season. Warm years were associated with partial recruitment failures resulting from thermal stress to the eggs and larvae hatched late in the season. Using past environmental conditions, we forecasted an imminent decline in Arctic cod recruitment in the regions of Uummannaq and Disko Bay. Observations from fjords suggested that glacial meltwater could create a subsurface thermal refuge allowing Arctic cod larvae to survive despite very high summer sea surface temperature (ca. 10 °C). As the Greenland ice sheet is melting at an unprecedented speed, the mechanism underlying the “glacial meltwater summer refuge hypothesis” could curb some of the negative effects of ocean warming on the survival of young Arctic cod in West Greenland and other Arctic fjord systems

Mu opioid receptors in gamma-aminobutyric acidergic forebrain neurons moderate motivation for heroin and palatable food

BACKGROUND: Mu opioid receptors (MORs) are central to pain control, drug reward, and addictive behaviors, but underlying circuit mechanisms have been poorly explored by genetic approaches. Here we investigate the contribution of MORs expressed in gamma-aminobutyric acidergic forebrain neurons to major biological effects of opiates, and also challenge the canonical disinhibition model of opiate reward. METHODS: We used Dlx5/6-mediated recombination to create conditional Oprm1 mice in gamma-aminobutyric acidergic forebrain neurons. We characterized the genetic deletion by histology, electrophysiology, and microdialysis; probed neuronal activation by c-Fos immunohistochemistry and resting-state functional magnetic resonance imaging; and investigated main behavioral responses to opiates, including motivation to obtain heroin and palatable food. RESULTS: Mutant mice showed MOR transcript deletion mainly in the striatum. In the ventral tegmental area, local MOR activity was intact, and reduced activity was only observed at the level of striatonigral afferents. Heroin-induced neuronal activation was modified at both sites, and whole-brain functional networks were altered in live animals. Morphine analgesia was not altered, and neither was physical dependence to chronic morphine. In contrast, locomotor effects of heroin were abolished, and heroin-induced catalepsy was increased. Place preference to heroin was not modified, but remarkably, motivation to obtain heroin and palatable food was enhanced in operant self-administration procedures. CONCLUSIONS: Our study reveals dissociable MOR functions across mesocorticolimbic networks. Thus, beyond a well-established role in reward processing, operating at the level of local ventral tegmental area neurons, MORs also moderate motivation for appetitive stimuli within forebrain circuits that drive motivated behaviors.This work was supported by the Centre National de la Recherche Scientifique (BLK), Institut National de la Santé et de la Recherche Médicale (BK), Université de Strasbourg (BLK), Medical Research Council/Economic and Social Research Council interdisciplinary studentship (to HLK), the British Pharmacological Society (IK), the European Commission (Genaddict Grant No. LSHMCT2004-005166 to BLK), the U.S. National Institutes of Health (National Institute of Drug Addiction, Grant No. 05010 to BLK and National Institute on Alcohol Abuse and Alcoholism, Grant No. 16658 to BLK), the Canada Fund for Innovation, and the Canada Research Chairs (to BLK). Electrophysiological experiments were funded by the Intramural Programs of National Institute on Alcohol Abuse and Alcoholism and National Institute of Neurological Disorders and Stroke (Grant No. ZIA-AA000421 to VAA) and Japan Society for Promotion of Science (to AMats). Self-administration studies were supported by the Intramural Programs of National Institute on Alcohol Abuse and Alcoholism and National Institute of Neurological Disorders and Stroke (Grant No. ZIA-AA000421 to RM), the Directorate-General for Research of the European Commission Framework Programme 7 (Grant No. HEALTH-2013-602891 to RM), the Spanish Redes Temáticas de Investigación Cooperativa en Salud-Instituto de Salud Carlos III (Grant No. RD12/0028/0023 to RM), the Spanish Ministerio de Economia y Competitividad (Grant No. SAF-2014-59648P to RM), the Plan Nacional Sobre Drogas (Grant No. PNSD-2013-5068 to RM), and the Catalan Government Agència de Gestió d'Ajuts Universitaris i de Recerca (Grant No. 2014-SGR-1547 to RM) and Institució Catalana de Recerca i Estudis Avançats-Acadèmia (Grant No. 2015 to RM). Part of the work was supported by German Research Foundation Excellence Cluster EXC-1086 BrainLinks-BrainTools (to JH)