Realising the therapeutic potential of neuroactive steroid modulators of the GABA_A receptor

In the 1980s particular endogenous metabolites of progesterone and of deoxycorticosterone were revealed to be potent, efficacious, positive allosteric modulators (PAMs) of the GABAA receptor (GABAAR). These reports were followed by the discovery that such steroids may be synthesised not only in peripheral endocrine glands, but locally in the central nervous system (CNS), to potentially act as paracrine, or autocrine "neurosteroid" messengers, thereby fine tuning neuronal inhibition. These discoveries triggered enthusiasm to elucidate the physiological role of such neurosteroids and explore whether their levels may be perturbed in particular psychiatric and neurological disorders. In preclinical studies the GABAAR-active steroids were shown to exhibit anxiolytic, anticonvulsant, analgesic and sedative properties and at relatively high doses to induce a state of general anaesthesia. Collectively, these findings encouraged efforts to investigate the therapeutic potential of neurosteroids and related synthetic analogues. However, following over 30 years of investigation, realising their possible medical potential has proved challenging. The recent FDA approval for the natural neurosteroid allopregnanolone (brexanolone) to treat postpartum depression (PPD) should trigger renewed enthusiasm for neurosteroid research. Here we focus on the influence of neuroactive steroids on GABA-ergic signalling and on the challenges faced in developing such steroids as anaesthetics, sedatives, analgesics, anticonvulsants, antidepressants and as treatments for neurodegenerative disorders

Iaroslav Lebedynsky, Ukraine. Une histoire en questions

Divisé en dix chapitres chronologiques, cet ouvrage analyse l’évolution historique de l’Ukraine dans sa complexité éthique par le biais de cent trente-cinq questions qui deviennent au fil de la lecture autant de repères conceptualisants. Les nombreux renvois qui émaillent le texte assurent une heureuse cohérence. Chaque question fait l’objet d’une réponse concise mais complète dans laquelle l’auteur n’hésite pas à comparer les différentes thèses historiosophiques, démêlant ainsi l’écheveau de..

Neurosteroids and GABAA Receptor Interactions: A Focus on Stress

Since the pioneering discovery of the rapid CNS depressant actions of steroids by the “father of stress,” Hans Seyle 70 years ago, brain-derived “neurosteroids” have emerged as powerful endogenous modulators of neuronal excitability. The majority of the intervening research has focused on a class of naturally occurring steroids that are metabolites of progesterone and deoxycorticosterone, which act in a non-genomic manner to selectively augment signals mediated by the main inhibitory receptor in the CNS, the GABAA receptor. Abnormal levels of such neurosteroids associate with a variety of neurological and psychiatric disorders, suggesting that they serve important physiological and pathophysiological roles. A compelling case can be made to implicate neurosteroids in stress-related disturbances. Here we will critically appraise how brain-derived neurosteroids may impact on the stress response to acute and chronic challenges, both pre- and postnatally through to adulthood. The pathological implications of such actions in the development of psychiatric disturbances will be discussed, with an emphasis on the therapeutic potential of neurosteroids for the treatment of stress-associated disorders

Early-life adversity increases morphine tolerance and persistent inflammatory hypersensitivity through upregulation of δ opioid receptors in mice

Supported by a NIAA (BJA/RCoA) grant WKR0-2017-0066 and WKR0-2019-0067 awarded to T. G. Hales. C. Sneddon and A. Bakina were supported by MRC DTP studentships. S. Singleton and T. G. Hales were supported by a UKRI and vs Arthritis Grant: MR/W002566/1.Exposure to severely stressful events during childhood is associated with poor health outcomes in later life, including chronic pain and substance use disorder. However, the mediators and mechanisms are unclear. We investigated the impact of a well-characterized mouse model of early-life adversity, fragmented maternal care (FC) between postnatal day 2 and 9, on nociception, inflammatory hypersensitivity, and responses to morphine. Male and female mice exposed to FC exhibited prolonged basal thermal withdrawal latencies and decreased mechanical sensitivity. In addition, morphine had reduced potency in mice exposed to FC and their development of tolerance to morphine was accelerated. Quantitative PCR analysis in several brain regions and the spinal cords of juvenile and adult mice revealed an impact of FC on the expression of genes encoding opioid peptide precursors and their receptors. These changes included enhanced abundance of δ opioid receptor transcript in the spinal cord. Acute inflammatory hypersensitivity (induced by hind paw administration of complete Freund's adjuvant) was unaffected by exposure to FC. However, after an initial recovery of mechanical hypersensitivity, there was a reappearance in mice exposed to FC by day 15, which was not seen in control mice. Changes in nociception, morphine responses, and hypersensitivity associated with FC were apparent in males and females but were absent from mice lacking δ receptors or β-arrestin2. These findings suggest that exposure to early-life adversity in mice enhances δ receptor expression leading to decreased basal sensitivity to noxious stimuli coupled with accelerated morphine tolerance and enhanced vulnerability to persistent inflammatory hypersensitivity.Publisher PDFPeer reviewe

Isotopic Carbon Abundances in M71

High resolution echelle spectra of the 8005 Angstroms CN bands are presented for five bright giants in the globular cluster M71 (C1951 +186, NGC 6838). An analysis of the (13) CN feature included in this region confirms the results of \cite{briley94a}; that the M71 red giants evince low (12}C/({13)) C ratios and that these ratios are correlated with CN band strengths (CN-strong stars having lower (12}C/({13)) C ratios). This finding is consistent with the theory that the star-to-star CN band strength variations, as well as the oxygen and possibly sodium differences observed in M71, are related to the CN(O)-cycle of hydrogen burning. (One asymptotic giant branch candidate is also included in the present sample, which exhibits both weak-CN band strength and a low (12}C/({13)) C ratio.) Examination of published data on CN band strengths and (12}C/({13)) C ratios among the more metal-poor clusters implies a metallicity dependence in the efficiency of the underlying mechanism responsible for the low (12}C/({13)) C ratios. A likely candidate appears to be the mixing of CN(O)-processed material into the stellar atmospheres, although a primordial source of CN-processing cannot be ruled out

The Observed Trend of Boron and Oxygen in Field Stars of the Disk

Oxygen abundances are derived in a sample of 13 field F and G dwarfs and subgiants with metallicities in the range of -0.75 < [Fe/H] < +0.15. This is the same sample of stars for which boron abundances have been derived earlier from archived spectra obtained with the Hubble Space Telescope. In a log-log comparison of the B versus the O abundances, a slope of m(BO)=1.39 is found, indicating that in the disk, the abundance of B relative to O is intermediate between primary and secondary production (hybrid behavior). This relation of B versus O for disk stars is compared to the same relation for halo stars.Comment: 14 pages, 3 figures, 1 table. In press to The Astronomical Journal (July 2001

Accompanying death, organising the end of life:An ethnography of a geriatric acute care department

HCERES, cat. A, FNEGE, cat. 2, CNRS, cat.3International audienceThis paper studies the organisation of death in a hospital. Beyond ethical issues, we examine the technical, professional, and sociological stakes of the management of end of life situations. Through an ethnographic study we followed geriatricians and their efforts to organise a ‘good’ death. We show that this invisible work aims at organising the passage toward a “natural” and “confortable” death, a death that is not only “peaceful” but also accompanied.Cet article porte sur l’organisation de la mort dans le contexte hospitalier. Au-delà des questions éthiques, les auteurs étudient les enjeux techniques, professionnels et sociologiques de la gestion hospitalière de la fin de vie. Une étude ethnographique leurs a permis d’observer le travail quotidien de gériatres et leurs efforts pour organiser une « bonne » mort. Ils montrent que ce travail, largement invisible, permet d’organiser le passage vers une mort « naturelle » et « confortable », non seulement « apaisée » mais surtout accompagnée

Early life stress influences acute and sensitised responses of adult mice to cocaine by interacting with GABAA α2 receptor expression

Early life stress (ELS) is known to exert long term effects on brain function, with resulting deleterious consequences for several aspects of mental health, including the development of addiction to drugs of abuse. One potential mechanism in humans is suggested by findings that ELS interacts with polymorphisms of the GABRA2 gene, encoding alpha2 subunits of GABAA receptors, to increase risk for both posttraumatic stress disorder, and vulnerability to cocaine addiction. We used a mouse model, in which the amount of material for nest building was reduced during early postnatal life, to study interactions between ELS and expression of alpha2-containing GABAA receptors in influencing cocaine-related behaviour. Breeding of parents heterozygous for deletion of alpha2 resulted in litters containing homozygous knockout (alpha2-/-), heterozygous knockout (alpha2+/-), and wildtype (alpha2+/+) offspring. Following the ELS procedure, the mice were allowed to develop to adulthood before being tested for the acute effect of cocaine on locomotor stimulation, behavioural sensitisation to repeated cocaine, and to cocaine-conditioned activity. Exposure to ELS resulted in increased acute locomotor stimulant effects of cocaine across all genotypes, with the most marked effects in alpha2-/- mice (which also showed increased activity following vehicle). Repeated cocaine administration to non-stressed mice resulted in sensitisation in alpha2+/+ and alpha2+/- mice, but, in keeping with previous findings, not in alpha2-/- mice. Prior exposure to ELS reduced sensitisation in alpha2+/+ mice, albeit not significantly, and abolished sensitisation in alpha2+/- mice. Conditioned activity was elevated following ELS in all animals, independently of genotype. Thus, while the enhanced acute effects of cocaine following ELS being most marked in alpha2-/- mice suggests a function of alpha2-containing GABAA receptors in protecting against stress, the interaction between ELS and genotype in influencing sensitisation may be more in keeping with ELS reducing expression of alpha2-containing GABAA receptors. The ability of ELS to increase cocaine-conditioned locomotor activity appears to be independent of alpha2-containing GABAA receptors

New Lithium Measurements in Metal-Poor Stars

We provide *lambda*6708 Li 1 measurements in 37 metal-poor stars, most of which are poorly-studied or have no previous measurements, from high-resolution and high-S/N spectroscopy obtained with the McDonald Observatory 2.1m and 2.7m telescopes. The typical line strength and abundance uncertainties, confirmed by the thinness of the Spite plateau manifested by our data and by comparison with previous measurements, are <=4 mAng and <=0.07-0.10 dex respectively. Two rare moderately metal-poor solar-Teff dwarfs, HIP 36491 and 40613, with significantly depleted but still detectable Li are identified; future light element determinations in the more heavily depeleted HIP 40613 may provide constraints on the Li depletion mechanism acting in this star. We note two moderately metal-poor and slightly evolved stars, HIP 105888 and G265-39, that appear to be analogs of the low-Li moderately metal-poor subgiant HD 201889. Preliminary abundance analysis of G 265-39 finds no abnormalities that suggest the low Li content is associated with AGB mass-transfer or deep mixing and p-capture. We also detect line doubling in HIP 4754, heretofore classified as SB1.Comment: Accepted for publication in PASP, volume 912 (Feb 2012) 15 pages, 3 figures, 2 table