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Episodic release of GnRH is essential for reproductive function. In vitro studies have established that this episodic release is an endogenous property of GnRH neurons and that GnRH secretory pulses are associated with synchronization of GnRH neuron activity. The cellular mechanisms by which GnRH neurons synchronize remain largely unknown. There is no clear evidence of physical coupling of GnRH neurons through gap junctions to explain episodic synchronization. However, coupling of glial cells through gap junctions has been shown to regulate neuron activity in their microenvironment. The present study investigated whether glial cell communication through gap junctions plays a role in GnRH neuron activity and secretion in the mouse. Our findings show that Glial Fibrillary Acidic Protein-expressing glial cells located in the median eminence in close vicinity to GnRH fibers expressed Gja1encoding connexin-43. To study the impact of glial-gap junction coupling on GnRH neuron activity, an in vitro model of primary cultures from mouse embryo nasal placodes was used. In this model, GnRH neurons possess a glial microenvironment and were able to release GnRH in an episodic manner. Our findings show that in vitro glial cells forming the microenvironment of GnRH neurons expressed connexin-43 and displayed functional gap junctions. Pharmacological blockade of the gap junctions with 50μM 18-α-glycyrrhetinic acid decreased GnRH secretion by reducing pulse frequency and amplitude, suppressed neuronal synchronization and drastically reduced spontaneous electrical activity, all these effects were reversed upon 18-α-glycyrrhetinic acid washout.

En Europe, les règles relatives à la désignation et à la protection des médicaments orphelins sont issues du règlement (CE) No 141/2000 du Parlement Européen et du Conseil en date du 16 décembre 1999, précisé par le règlement (CE) d’application No 847/2000. Ainsi, la désignation de médicament orphelin implique notamment, outre la preuve de la rareté de la maladie à traiter, la démonstration de l’absence de traitement alternatif satisfaisant ou, à défaut, d’un bénéfice notable apporté par le médicament. Dans le même sens, les médicaments similaires à un médicament orphelin initial, mais plus sûrs, plus efficaces ou cliniquement supérieurs sous d’autres aspects, se verront accorder une dérogation à l’exclusivité commerciale de 10 ans – protection spécifique accordée à ces médicaments. Cet article analyse le concept de bénéfice notable ainsi que les éléments devant être fournis par le promoteur pour justifier de ce bénéfice même lorsque l’expérience clinique liée au médicament orphelin en question est faible ou inexistante et ne peut reposer que sur des hypothèses de bénéfice clinique plausibles.

The article focuses on neuro-glial plasticity of neuroendocrine networks which is a mechanism involved in various physiological functions such as parturition, lactation, and preovulatory surge.

La loi Jardé fait suite à la loi de santé publique n° 2004-806 de transposition en droit français de la directive 2001/20/CE relative aux essais cliniques des médicaments, rendue effective par le décret d’application n° 2006-477 du 26 avril 2006. La nouveauté essentielle introduite par la loi Jardé est d’unifier toutes les « recherches organisées et pratiquées sur l’être humain en vue du développement des connaissances biologiques ou médicales» et de faciliter leur bon déroulement sans exclure du champ de la loi les recherches de type soins courants et les recherches non interventionnelles. L’avis favorable du comité de protection des personnes (CPP) sera désormais requis avant le lancement de toute recherche portant sur la personne, après validation du rapport bénéfice/risque de la recherche. Les exigences et procédures – notamment information et consentement – sont adaptées à chaque catégorie de recherche. Des dispositions nouvelles sont prises pour répondre à des situations particulières, jusque-là oubliées. Enfin, librement choisis, les CPP seront demain désignés de façon aléatoire. La loi Jardé modifie donc substantiellement l’encadrement juridique de la recherche clinique en France. Reste à savoir si ces nouvelles dispositions nationales seront compatibles avec celles issues de la révision de la directive « essais cliniques » 2001/20/CE. En tout état de cause, la loi Jardé n’entrera en vigueur de manière effective qu’une fois pris ses textes règlementaires d’application.

En France, l’affaire du Médiator® et le traumatisme qu’elle a créé, sont à l’origine de la loi n° 2011-2012 du 29 décembre 2011 relative au renforcement de la sécurité sanitaire du médicament et des produits de santé, voulue par le ministre du Travail, de l’Emploi et de la Santé, votée par l’Assemblée nationale, et promulguée dans le but de restaurer la confiance et de renforcer la sécurité sanitaire du médicament et des produits de santé. Cette nouvelle loi implique tous les acteurs professionnels de la santé et touche la majorité des points très sensibles de la vie du médicament : autorisation de mise sur le marché (AMM), remboursement, publicité, visite médicale, distribution, prescription, délivrance, vigilance. Elle prévoit aussi des sanctions financières, administratives ou pénales qui se veulent dissuasives. Au-delà du renforcement des contraintes de sécurité sanitaire relative aux produits de santé, cette nouvelle loi préfigure en France un bouleversement des comportements, des mentalités et du paysage dont nul aujourd’hui ne connait exactement le contour.

Xerostomia is a subjective sensation of mouth dryness often occurring as an unwanted effect of psychotropic drugs.

La directive 2001/20 CE relative aux essais cliniques des médicaments a été transposée en droit français en 2004 par une loi de santé publique. Mais cette transposition est devenue réellement effective le 27 Août 2006 par la mise en application du décret n° 2006-477 du 26 avril 2006 qui a été suivi de nombreux arrêtés. La lecture de ces textes réglementaires montre que ces nouvelles dispositions dépassent largement le cadre de la directive puisqu’elles ont été notamment étendues par le législateur français à tous les produits de santé relevant de la compétence de l’Agence de Sécurité Sanitaire des Produits de Santé (Afssaps) ainsi qu’aux autres études n’impliquant pas les produits de santé. De plus, la réalisation de toute recherche est désormais, préalablement et conjointement, soumise à l’avis favorable motivé d’un Comité de Protection des Personnes (CPP) et à l’autorisation de l’Afssaps. Cette nouvelle réglementation de la recherche biomédicale en France modifie et renforce, de façon substantielle, les dispositions antérieures définies par la loi Huriet depuis 1988, aux plans de la sécurité, de la vigilance et de la traçabilité.

The EC 2001/20 directive relating to the clinical trials of medicinal products was transposed into French law in 2004 by means of a public health law. But this transposition actually came into effect on 27 August 2006 by the implementation of decree no. 2006-477 of 26 April 2006 which has been followed subsequently by numerous statutory orders. A reading of these regulatory texts shows that the new provisions go far beyond the framework of the directive as they have been notably extended by the French legislator to encompass all the health products within the competence of the French Agency for Sanitary Safety in Health Products (Afssaps) as well as to other studies that do not involve health products. In addition, all research undertaken is from now subject to the prior, and jointly favourable, reasoned opinion of a CPP (Ethic Committee) and authorisation by Afssaps. These new regulations for biomedical research in France substantially modify and reinforce the previous provisions defined by the Huriet law of 1988, for safety, vigilance and traceability.

Conversely to rodents, the involvement of hypothalamic neuropeptide Y (NPY) neurons in the control of nutrition is poorly understood in ruminants such as sheep. Therefore, the aim of this work was to describe the NPY neurons of the diencephalon in ewes submitted to different diets. In colchicine‐treated animals, large populations of NPY‐immunoreactive (‐ir) neurons were observed in a ventral and a lateral subpopulation of the infundibular nucleus (IN), in the median eminence, the pituitary stalk, and the dorsomedian and dorsocaudal nuclei. No labeled perikaryon was observed in the magnocellular neurons of the hypothalamus, although numerous labeled fibers were noted in the neural part of the pituitary. The pattern of distribution of NPY‐ir neurons in the sheep hypothalamus is similar in many ways to those of rodents, but it presents also many specific characteristics that have not been previously described. In ewes that were fasted for 24 hours, or fed ad libitum, the number of NPY‐ir neurons was the same whatever the hypothalamic structures. In underfed ewes (40% of maintenance for 24 weeks), the lateral subpopulation of the IN presented a higher number of NPY‐ir neurons than observed in the 100% fed ewes. Conversely, in the ventral subpopulation, the animals refed ad libitum (at least 150% of maintenance for 4 days) presented a lower number of NPY‐ir neurons than the other groups. The other NPY neuronal populations of the hypothalamus were not significantly modified by the dietary treatments. For the first time, we demonstrated the presence of two functionally distinct subpopulations of NPY neurons in the sheep IN. The variations of labeled neurons were correlated with plasma nonesterified fatty acid levels but not with leptinemia. J. Comp. Neurol. 444:129–143, 2002. © 2002 Wiley‐Liss, Inc.

The localization of tyrosine hydroxylase was studied in the brain of sheep foetus during early ontogeny using immunohistochemistry. The first immunoreactive neurons appeared very early since they were found on day 30 of pregnancy in the medioventral part of the mesencephalic flexure. The distribution of the different catecholaminergic groups of neurons was similar to the adult's after 75 days of pregnancy. The latest group to appear was the A12 group.

Using immunohistochemistry with specific antiserotonin anti-sera, the ontogeny of serotonergic neurons was studied in the foetal sheep brain. Serotonergic-immunoreactive perikarya first appeared rostrally on day 25 of pregnancy, in the medio-ventral part of the mesencephalic flexure, and caudally, on day 28, in the medio-ventral part of the cervical flexure. The development of this system is very rapid, because on day 40 of gestation, all serotonergic nuclei present in the adult were visible. Compared with other species such as rodents or primates, serotonin appears early in the sheep nervous system, and the development of the serotonergic system is even more rapid.

The distribution of histaminergic neurons in the sheep brain was studied by immunohistochemistry by using antibodies raised against histamine. For the first time in this species, the presence of histamine‐immunoreactive neurons was described in the caudal diencephalon, around the mammillary bodies, and in the tuberomammillary area. The general pattern of distribution of these neurons was similar to that described previously in other species, i.e., rodents and humans. The distribution in the five neuronal groups described in rodents was not easy to demonstrate in sheep, because the boundaries between each group were not clear. The labeled neurons appeared to form a continuous cell system, as in humans. Numerous histamine‐immunoreactive mast cells were found in the habenula and the thalamus. Histamine‐immunoreactive fibers were found in almost all of the structures studied. The highest density of fibers was seen in the tuberomammillary area, from which dense bundles of fibers ran rostrally and dorsally along the third ventricle in a parasagittal plane. Numerous immunostained fibers were found close to the wall of the ventricles; some of them appeared to reach the cerebrospinal fluid through the ependymal cell layer. Some fibers were also observed in the optic tract, and the lowest density was found in the supraoptic and paraventricular nuclei. These results should be useful for developing further physiological studies on the role of histaminergic neuronal systems in sheep. J. Comp. Neurol. 400:317–333, 1998. © 1998 Wiley‐Liss, Inc.

Anterograde tracers, viz. Phaseolus vulgaris leucoagglutinin and fluorescein dextran, were used in conjunction with tyrosine hydroxylase immunohisto-chemistry to study the projections of the A15 dopaminergic cell group towards the median eminence and pituitary in sheep. After injection of the tracers in the retrochiasmatic area, which contains the cell group A15, fibres containing anterograde tracer were observed in the internal zone of the median eminence and in the pars nervosa of the pituitary. Numerous tyrosine hydroxylase immunoreactive fibers were present in the external zone of the median eminence and in the pars intermedia and the pars nervosa of the pituitary, with characteristic patterns of organisation in each area. Most tyrosine hydroxylase-immunoreactive fibres containing fluorescein dextran were located in the pars nervosa, whereas only a few were observed in the internal zone of the median eminence. It was concluded that at least part of the dopaminergic innervation of the pars nervosa originated from the A15 group. These results provide morphological evidence for (1) the role of dopaminergic neurons of the A15 cell group in the seasonal control of prolactin secretion via the release of dopamine in the pars nervosa, and (2) putative physiological interactions between dopamine and the secretion of neurohypophysial hormones in sheep.