[Stigmatisation of patients with mental disorders by medical interns specialising in general practice: A national survey]. / Stigmatisation des patients atteints d'un trouble mental par les internes de médecine générale : une enquête nationale.

OBJECTIVES: The objective was to assess the level of stigmatisation of psychiatric patients by medical interns specialising in general practice (GP), and to assess the influencing factors of stigmatisation. METHODS: A national survey was carried out among interns in general practice (GP) contacted through their local associations from December 10, 2019 to March 9, 2020. An online questionnaire was diffused. The validated French version of the Mental Illness Clinicians' Attitudes (MICA) was used to measure stigmatising attitudes towards psychiatry and persons with psychiatric disorder by the interns. This 16-item scale is designed to measure attitudes of health care professionals towards people with mental illness with scores ranging from 16 to 96 (the most stigmatizing). Several covariates were collected: socio-demographics, personal experiences with mental health, and mental health trainings during medical studies. All questionnaires were strictly anonymized. Comparative analyses of the MICA score by group were performed using Student's tests. RESULTS: A total of 389 interns responded. The majority of respondents were female (n=277; 71%) and the mean age was 27years [standard deviation (SD)±2.39]. The mean MICA rate was 40.64 (SD±8.09) for a neutral score of 56, reflecting low overall stigmatizing attitudes. MICA scores were significantly lower among female interns (40.11 vs. 41.95; P=0.042), those who had benefited from personal psychological or psychiatric support (38.70 vs. 41.61; P=0.001), and those who had completed a psychiatric externship (39.47 vs. 42.16; P=0.001). CONCLUSIONS: GP interns had an attitude that is generally not very stigmatizing even if its improvement should still be sought. This is particularly verified among those who have completed a psychiatric internship during their externship. This suggested association should be supported by other studies. The stakes are high for the future management of patients since stigmatisation by a physician is strongly implied in the worse healthcare management of patients with psychiatric disorders, leading them to a shorter lifespan.

[Patterns of antidepressant dispensing among children and adolescents between 2015 and 2017 in the French region of Midi-Pyrenees]. / Profil de délivrance des antidépresseurs chez l'enfant et l'adolescent en Midi-Pyrénées entre 2015 et 2017.

BACKGROUND: In France, consumption of antidepressant drugs by children and teenagers has been on the rise, even though recommendations for use are limited due to their association with serious adverse reactions. The objective of this study was to describe the patterns of antidepressant drug dispensing among children and adolescents in the French region of Midi-Pyrenees. METHOD: The data regarding the Midi-Pyrenees region were extracted from the French Health Insurance Database (SNDS) using their ATC codes. The reimbursements for antidepressants, benzodiazepines and neuroleptics dispensed to patients from 6 to 17 years old between January 2015 and June 2017 were analyzed, after which data on the antidepressants themselves were selected. The population was divided into sub-groups according to age (children : 6 to 11 years old, teenagers: 12 to 17 years old). RESULTS: During the 30 months analyzed, 12,783 antidepressants were dispensed to 3506 patients. The antidepressants were primarily issued (90%) to teenagers. In terms of prevalence, 24.7% of the teenagers had amitriptyline delivered at least once, while 31.2% of them received sertraline at least once. Regarding total amount of antidepressant issuances, sertraline was first in both the child (26.9%) and the teenage (40.7%) populations. Benzodiazepine with an antidepressant was issued to 35.1% of the children and teenagers. CONCLUSIONS: Amitriptyline was the most widely dispensed antidepressant among children, and sertraline among teenagers. However, fluoxetine is recommended as the first-line treatment for depression affecting this population. A psychotropic drug prescription assistance website such as psychotropes.fr addressed to general practitioners might improve the implementation of recommendations and guidelines.

Body mass index variations in patients with Parkinson's disease treated with levodopa-carbidopa intestinal gel infusion: A case control study versus standard of care and subthalamic nucleus deep brain stimulation.

BACKGROUND: Levodopa-carbidopa intestinal gel (LCIG) is an advanced therapy for patients with Parkinson Disease (PD). Weight loss has been pointed out as an adverse event of LCIG infusion. AIMS OF THE STUDY: To compare weight changes between three groups of PD patients: patients treated with LCIG, patients within the first year of subthalamic deep brain stimulation (STN-DBS) and patients treated exclusively with oral treatment during 1 year of follow up. METHODS: Patients treated with LCIG were retrospectively matched by age, gender, disease duration and Hoehn and Yahr to patients undergoing STN-DBS and to patients both receiving the standard of care treatment and unwilling advanced therapies (SOC). Clinical features and weight were collected at baseline, and 12 months after introducing the treatment (LCIG and STN-DBS groups) or for one year of treatment (SOC). RESULTS: Eighteen patients were included in each group. They had no differences in clinical and demographic features, except for cognitive impairment. There was a mean weight (-5.8kg ±6.8) and BMI (-2.1kg/m2±2.6) reduction in the LCIG group after 12 months, while there was a slight weight loss in the SOC (-1.4kg ±3.1) and a weight increase in the STN-DBS group (5.4kg ±4.7). Differences of weight were statistically different between, LCIG and STN-DBS (P<0.001), LCIG and SOC (P=0.002) and STN-DBS and SOC (P<0.001). CONCLUSIONS: The study shows a significant weight reduction after starting LCIG infusion compared to the other groups. Weight loss should be closely monitored in patients treated with LCIG.

[Management of child and adolescent depression in primary care: A systematic meta-review]. / Prise en charge de la dépression de l'enfant et l'adolescent en soins premiers : une métarevue systématique de la littérature.

OBJECTIVE: To develop a practical guide for the management of child and adolescent depression for general practitioners (GPs), suited to their practice frame, that can be implemented on a website aimed to help GPs to manage the main mental disorders encountered in primary care. METHOD: A systematic meta-review was performed as recommended by the PRISMA statement. Each step, articles' selection, inclusion, methodological assessment and data extraction for the narrative synthesis was independently performed by two researchers. A study protocol was registered on PROSPERO (number CRD42016042710). The databases Pubmed, Cochrane and Web of Science were explored. Each step was performed independently by two researchers following PRISMA. Meta-analyses and systematic reviews (including guidelines based on a systematic review), published between 2002 and 2015, in English or French, dealing with the therapeutic management, in primary care, of patients aged 6 to 18 years old with a major depressive disorder (MDD) were included. Grey literature was explored searching the websites of national and international health agencies, learned societies, and article references. The methodological and report qualities were assessed using the AGREE II, PRISMA checklist and R-AMSTAR grid. A narrative synthesis was performed to produce the practical guide, prioritizing data from the best evaluated articles. An expert group of GPs' and one child psychiatrist validated the guide in its final form. RESULTS: Thirty-eight studies were included: 12 recommendations, 5 systematic reviews and 21 meta-analyses. The best evaluated guideline had an AGREE-II assessment of 81%, and the best evaluated meta-analysis had an assessment of 86% for R-AMSTAR and 96% for PRISMA. The average scores of the R-AMSTAR and PRISMA assessments were 65% and 72% respectively. The average score of the AGREE II grid assessment was 57%. The data were synthesized into a practical guide for the GPs' practice, corresponding to the different consultation times. MDD diagnosis should be done on the DSM or ICD basis. The Childrens' Depression Rating Scale-revised or the Revised Beck Depression Inventory are useful in primary care for MDD appraisal in children and adolescents. For mild MDD a supportive psychotherapy and surveillance for 4 to 6 weeks is preconized in primary care. In the absence of improvement, a specific and structured psychotherapy is recommended, and the patient should be addressed to a child psychiatrist. For moderate to severe MDD, the young patient should be addressed to a specialist in child psychiatry. A psychotherapy, which can be associated with fluoxetine, especially in adolescents, is indicated with a revaluation of the pharmacological treatment between 4 to 8 weeks. A weekly follow-up by the GP is recommended during the first month, especially after the initiation of an antidepressant to assess the suicidal risk. Beyond the first month, a consultation should be scheduled every two weeks. CONCLUSION: A clinical guide was created from the best evidence-based data to help GPs in the management of child and adolescent MDD. A French-language website, aimed to assist GPs in mental disease management and available during their consultation, will be created based on the compilation of this meta-review with other similar meta-reviews.

Cognitive complaint in early Parkinson's disease: A pilot study.

BACKGROUND: Subjective cognitive complaint (SCC) is a criterion recommended by the Movement Disorder Society (MDS) task force for the diagnosis of mild cognitive impairment (MCI). Until now there were few specific tools for detecting SCC in PD. We sought to develop a new tool to assess SCC specifically dedicated for PD. MATERIALS AND METHODS: We set a group of experts in movements disorders and neurocognition to develop an easy-to-use tool based on a visual analogue scale (VAS) for five cognitive domains: memory, executive functions, spatial orientation, attention, and language. We use it to assess SCC twice (at a one-month interval) in PD patients with disease duration of less than 5 years. Comprehensibility of the VAS was assessed. Controls were assessed with the same VAS. Patients with PD also underwent neuropsychological testing. RESULTS: VAS was easily understandable by the 70 patients with PD. We found significant SCC for the patients with PD vs controls in three cognitive domains: executive functions (1.7 ± 1.9 vs 0.8 ± 1.1; P < .001), language (2.3 ± 2.5 vs 1.0 ± 1.3, P < .001), and attention (2.1 ± 2.2 vs 1.2 ± 1.2; P < .01). Reproducibility between the two evaluations of patients with PD was good. There was no relationship between SCC and the results of neuropsychological testing. CONCLUSIONS: SCC seems to appear early in PD, in three cognitive domains (executive functions, language, and attention), and VAS might be a good way to detect SCC in PD, but need to be validated.

[Did the recommendation of the French public health council modify the antipapillomavirus vaccines' prescription level?]. / Impact de la modification d'avis du Haut Conseil de la santé publique (HCSP) sur le taux de prescription des vaccins papillomavirus humains en région Midi-Pyrénées.

BACKGROUND: In France, two vaccines are approved for prevention of papillomavirus infection: Cervarix(®) and Gardasil(®). The 17th of December 2010 the French High Committee of Public Hearth changed its recommendation about Cervarix(®) and decided that no scientific element justified a preference using Gardasil(®). This notification was published the 25th of January 2011. Our study aimed to determine whether this decision changed medical prescriptions. METHODS: An ecological study was performed with reimbursement data for the two vaccines. We performed a Chi(2) test for qualitative variables and Student's t test for quantitative variables. RESULTS: A significant difference was observed between the prescription of Cervarix(®) before and after the 25th January 2011. The difference favored increased prescription, compared to Gardasil(®) (P ≤ 0.05). CONCLUSION: This variation can be explained by the impact of recommendations for medical decisions. The strong involvement of pharmaceutical firms in medical education may explain why prescribers reacted so rapidly after the publication of the new recommendations.

Steroid hormones modulate H19 gene expression in both mammary gland and uterus.

H19 is an imprinted and developmentally regulated gene whose product remains apparently untranslated. In a previous study on breast adenocarcinomas, we reported that overexpression of the H19 gene was significantly correlated with the presence of steroid receptors, suggesting the putative role of hormones in H19 transcription. To determine the mode of steroid action, we have detected levels of H19 RNA synthesis during mammary gland development by in situ hybridization (ISH): two peaks of H19 transcription occur during puberty and pregnancy. Furthermore, we demonstrated by ISH that in the uterus H19 RNA synthesis is high during estrus and metestrus phases. To test steroid control of H19 transcription, ovariectomized and adrenalectomized mice were supplemented, 1 week after surgery, with 17-beta-estradiol (E2, 20 microg/kg/day), progesterone (P, 1 mg/kg/day) or corticosterone (B, 0.3 mg/ kg/day) for 2 weeks. According to ISH data, E2 and to a lesser extent B stimulated H19 transcription in the uterus, whereas P inhibited it. To confirm the in vivo results, in vitro experiments were performed using cultures of MCF-7 cells (a hormone-sensitive mammary cell line). E2 stimulated the endogenous H19 gene of this cell line and tamoxifen inhibited this effect. Furthermore, we performed transient cotransfections in MCF-7, in HBL-100 (another hormone-sensitive mammary cell line) and in BT-20 (a hormone-insensitive mammary cell line) with various constructs of ERalpha (WT or mutated) and PR-A, in presence or absence of steroid hormones. We demonstrated that ERalpha up-regulated the H19 promoter in MCF-7 and in HBL-100, whereas PR-A did not have any effect per se. Moreover, in MCF-7, PR-A antagonized clearly the ERalpha-mediated promoter enhancement, but in HBL-100 this counteracting effect on the ERalpha up-regulation was not found. Interestingly, the same experiments performed in BT-20 cell line provided very similar results as those obtained in MCF-7 cells, with a clear down-regulation mediated by PR-A on the H19 promoter. All these in vitro data are in agreement with in vivo results. In addition, data obtained with ERalpha mutants indicate that H19 promoter activation is both ligand-dependent and ligand-independent. We have thus demonstrated that H19 gene expression is controlled by steroid hormones; furthermore, this gene is highly expressed in hormone-sensitive organs when the hormonal stimulation is accompanied with a morphological repair.

Maternal undernutrition during late gestation induces fetal overexposure to glucocorticoids and intrauterine growth retardation, and disturbs the hypothalamo-pituitary adrenal axis in the newborn rat.

As fetal overexposure to glucocorticoids has been postulated to induce intrauterine growth retardation (IUGR) in humans, we investigated the effects of maternal 50% food restriction (FR50) in rats during the last week of gestation on the hypothalamo-pituitary adrenal (HPA) axis activity in both mothers and their fetuses. In mothers, FR50 increased both the plasma corticosterone (B) level from embryonic days 19-21 and the relative adrenal weight at term. FR50 decreased at term both the maternal plasma corticosteroid-binding globulin level and placental 11beta-hydroxysteroid dehydrogenase type 2 expression. In newborns, maternal FR50 reduced body and adrenal weights, glucocorticoid and mineralocorticoid receptor expressions in the hippocampus, corticoliberin expression in the hypothalamic paraventricular nucleus, and plasma ACTH. In FR50 newborns, the plasma B level was increased at birth and decreased 2 h later. When maternal circulating B was maintained at the basal level by adrenalectomy and B supply, FR50 induced IUGR in pups and decreased placental 11beta- hydroxysteroid dehydrogenase type 2 expression at term, but did not disturb the offspring's HPA axis. These results suggest that maternal undernutrition during late gestation induces both IUGR and an overexposure of fetuses to maternal B, which disturb the development of the HPA axis.

Developmental patterns of somatostatin-receptors and somatostatin-immunoreactivity during early neurogenesis in the rat.

The temporal pattern of distribution of somatostatin receptor was investigated using the somatostatin analogue [125I]Tyr0-DTrp8-somatostatin14 as a ligand and compared with that of somatostatin immunoreactivity during early developmental stages in the spinal cord and the sensory derivatives in rat fetuses. Qualitative and quantitative analysis showed that somatostatin receptors were detected in a transient manner. In the neural tube, they were clearly associated with immature premigratory cells and with the developing white matter. During the time-period examined (from day 10.5 to 16.5), the disappearance of somatostatin receptors followed a ventro to dorsal gradient probably linked to the regression of the ventricular zone. In sensory derivatives, they were expressed in the forming ganglia and their central and peripheral nerves from embryonic day 12.5 to 16.5 inclusive, with a peak around day 14.5 and low levels observed at day 16.5. Competition experiments performed at embryonic day 14.5 demonstrated that somatostatin1-14, somatostatin1-28, and Octreotide displaced specific binding with nanomolar affinities while CGP 23996 was only active at micromalar doses. Such displacements are compatible with the SSTR2 and/or SSTR4 pharmacology. During the time period examined, some transient somatostatin immunoreactive cell bodies and fibers were detected in the neural tube and in the sensory derivatives. These results demonstrate the existence, in neuronal derivatives, of a complex temporal and anatomical pattern of expression of somatostatin receptors, from the SSTR2/SSTR4 subtype(s), and somatostatin immunoreactivity. It appears that the transient expression of somatostatin receptors and/or somatostatin immunoreactivity characterizes critical episodes in the development of a cohort of neurons; a fact that unequivocally reinforces the notion that somatostatin plays a fundamental role during neurogenesis in vertebrates.

Responses of rat fetal adrenals to synthetic adrenocorticotrophic hormone and alpha-melanocyte-stimulating hormone in-vivo and in-vitro studies.

The response of the adrenals from rat fetuses at 16, 18 and 20 days of gestation to 1-24 ACTH and alpha-melanocyte-stimulating hormone (alpha-MSH) was studied in vitro. The response to 1-24 ACTH increased as gestation progressed. By the end of fetal life, corticosterone release induced by ACTH from whole adrenals was greater than that observed with adrenal tissue from non-pregnant adult female rats. High doses of alpha-MSH also stimulated adrenal activity but the response to ACTH was always higher than that to alpha-MSH. The effect of 1-24 ACTH and alpha-MSH on fetal adrenal growth was also compared in vivo. The adrenal atrophy induced by fetal hypophysectomy on day 17 of gestation could be prevented by i.m. administration of 10 microgram 1-24 ACTH or alpha-MSH. However, the adrenal growth was greater in ACTH-treated fetuses than in alpha-MSH treated ones. Later in gestation, between days 19 and 20, 1-24 ACTH but not alpha-MSH was able to prevent atrophy induced by fetal hypophysectomy. These findings are discussed in relation to the literature on levels of ACTH and alpha-MSH in the plasma and pituitary glands of the rat throughout the last third of gestation. High levels of ACTH in the fetal circulation contrast sharply with very weak or undetectable concentrations of alpha-MSH. Since the present data suggest that both trophic and steroidogenic activities of ACTH were greater than those of alpha-MSH, it may be concluded that ACTH but not alpha-MSH plays a major physiological role during gestation in the regulation of both fetal adrenal growth and function in the rat.

Adrenocorticotrophic hormone in the anterior and neurointermediate lobes of the fetal rat pituitary gland.

The concentration of ACTH in the pars distalis and pars intermedia of the fetal rat hypophysis from days 17-21 of pregnancy was measured with a specific radioimmunoassay and a bioassay using isolated adrenal cells from adult rats. In both lobes of the pituitary gland, a significant correlation was observed between immunoreactive and bioreactive values, expressed as pg equivalents synthetic human 1-39 ACTH per microgram protein. In the pars distalis, ACTH concentrations increased steadily from days 17-20 and then remained unchanged to term. At this time they were tenfold higher than on day 17. In the neurointermediate lobe, ACTH was detected only from day 18; the concentration of ACTH increasing between days 18 and 19. At each of the stages of pregnancy examined, the concentration of ACTH in the pars distalis was greater than that in the pars intermedia. These data have demonstrated that ACTH is present in both anterior and neurointermediate lobes of the fetal rat hypophysis, that the functional differentiation of the pars distalis takes place earlier than that of the pars intermedia, and that the concentrations of corticotrophin in the pars distalis and in the pars intermedia have different patterns of development as gestation progresses.

In-vitro effects of corticosterone, synthetic ovine corticotrophin releasing factor and arginine vasopressin on the release of adrenocorticotrophin by fetal rat pituitary glands.

The in-vitro release of ACTH by fetal rat pituitary glands on days 17, 19 and 21 of pregnancy was measured using radioimmunoassay. The spontaneous release of ACTH, expressed in pg ACTH/gland per h, increased with fetal age, in correlation with the sharp rise in pituitary ACTH content. However, since pituitary ACTH content was nearly sevenfold higher at term than on day 17, while basal release of ACTH was only threefold higher, one can speculate that the spontaneous release of ACTH was proportionally greater on day 17 than on day 21 of gestation. As corticosterone, at a physiological concentration (865 nmol/l), reduced ACTH release, it was concluded that the pituitary gland was one site of the negative feedback action of the corticosteroids during fetal life. Quantities of synthetic ovine corticotrophin releasing factor (CRF) which gave concentrations of 0.3-30 nmol/l in the incubation medium induced a sharp rise in ACTH release which was log-dose dependent between 0.3 and 3 nmolCRF /1 on day 17 and between 0.3 and 30 nmolCRF /1 on days 19 and 21. The response to CRF increased with fetal age. Quantities of arginine vasopressin (AVP) which gave concentrations of 2-200 nmol/l stimulated ACTH release at all stages of gestation investigated. However, the response to AVP was much lower than that to CRF. Potentiation of CRF-induced ACTH release was not observed when whole pituitary glands from 21-day-old fetuses were incubated with AVP (20 nmol/1) + CRF ( 3nmol /1). Such results were correlated with the ontogenesis of immunoreactive vasopressin- and CRF-containing fibres in the median eminence of the rat fetus, as well as with the CRF-like immunoreactivity present in adult rat pituitary portal plasma and the AVP content of the fetal rat hypophysis.

ACTH secretion from isolated hypophysial anterior lobes of male and female newborn rats: effects of corticotrophin-releasing factor, arginine vasopressin and oxytocin alone or in combination.

ACTH release by the anterior pituitary lobes of 8-day-old newborn rats (males and females) in the presence of rat corticotrophin-releasing factor (rCRF), arginine vasopressin (AVP) and oxytocin, given alone or in association, was measured in vitro. Rat CRF and AVP induced a dose-dependent release of ACTH in both sexes, while oxytocin was unable to stimulate ACTH secretion except at the highest dose tested. No sex-related difference was noted for any of the responses. Oxytocin (1 nmol/l) potentiated the response to rCRF (0.20 nmol/l) by the anterior pituitary lobes of females but not by those of males. This oxytocin potentiation was abolished when female newborn rats were injected at birth with testosterone (1 mg). AVP (1 nmol/l) alone stimulated ACTH release from the anterior pituitary lobes of the newborn rats of both sexes and markedly potentiated the ACTH response to rCRF. Although no difference between the sexes was noted for basal levels of AVP and oxytocin in the hypothalamus, the neurointermediate lobe and the peripheral plasma, the present data on the sex-related effect of oxytocin on the newborn adenohypophysis could, in part, explain why ACTH release in response to ether stress was previously reported to be more lasting in females than in males on day 8 postpartum.

Maternal and foetal corticosterone levels during late pregnancy in rats.

Adrenal and plasma corticosterone levels were determined in rat foetuses and in intact or adrenalectomized mothers during late pregnancy. Foetal adrenal and plasma corticosterone concentrations reached a peak on day 19 of pregnancy, while maternal plasma corticosterone increased on day 18 and remained high until parturition. From day 18, mothers adrenalectomized on day 14 had corticosterone levels similar to those of intact pregnant rats. At every stage of gestation (except day 21) plasma corticosterone levels were higher in the foetuses than in the mothers. The corticosterone concentration in the maternal plasma correlated with the number of live foetuses during the last 3 days of gestation. These results suggest that corticosterone can cross the placenta from foetus to mother as early as day 18 and that the foetus contributes to the maternal corticosterone pool after day 18.

Ontogeny of ACTH(1-24) receptors in rat adrenal glands during the perinatal period.

Binding of ACTH to receptors was studied on crude adrenal membranes from fetal and newborn rats. 125I-Labelled ACTH(1-24) was used as the radioligand, the steroidogenic potency of which was 100-fold lower than that of unlabelled ACTH(1-24). Binding was specific, rapidly equilibrated and temperature dependent. Scatchard analysis of the binding data revealed a single class of binding sites with a dissociation constant of about 100 nmol/l at all stages of development studied. The concentration of ACTH receptors expressed per mg membrane proteins decreased in fetuses between days 17 and 21 of gestation and remained stable in newborn rats from weeks 1 to 4. The number of ACTH receptors expressed per adrenal increased regularly in fetal and newborn rats. The perinatal evolution of these concentrations of ACTH receptors is related to the increase in the size of the adrenals and the changes in cytoplasmic structures of the adrenocortical cells. When the number of ACTH-binding sites was expressed per microgram DNA, maximum values occurred in fetuses on day 19 of gestation, and minimum values in newborn rats, 1 week after birth. There was an excellent correlation between the plasma levels of immunoreactive ACTH and corticosterone and the number of ACTH receptors per microgram DNA during the perinatal period. Other results suggest that ACTH is able to up-regulate the number of its own receptors.

Corticotrophin-releasing factor immunoreactivity in the hypothalamus of the rat during the perinatal period.

Corticotrophin-releasing factor-41 (CRF-41) immunoreactivity has been measured in hypothalamic extracts of fetal (on days 17, 19 and 21 of gestation), neonatal (1, 2, 3 and 4 weeks of age) and adult rats with a specific radioimmunoassay developed for synthetic rat CRF-41. The hypothalamic content (fmol) and concentration (fmol/mg protein) of immunoreactive CRF-41 gradually increased with age. Chromatography of hypothalamic extracts on Sephadex G-50 Fine showed one single peak of immunoreactive CRF-41 which co-eluted with synthetic rat CRF-41. The retention time of hypothalamic CRF-41 during high-performance liquid chromatography was identical to that of synthetic rat CRF-41 at all stages investigated. These results are consistent with the development of neurones containing CRF-41-like molecules in both the hypothalamus and the median eminence of the fetus, as well as with the hypothalamic control of the cortico-stimulating function of the pituitary gland as early as day 19 of gestation.

Development of adenylate cyclase activity in rat adrenal glands during the perinatal period.

Adenylate cyclase activity was studied in crude adrenal membranes from fetal and newborn rats. Basal adenylate cyclase activity was higher in fetal than in newborn rats. ACTH(1-24) (1 mumol/l), guanosine (beta,gamma-imido diphosphate) (Gpp(NH)p) (10 mumols/l) and forskolin (100 mumols/l) stimulated the activity of the enzyme at all stages studied. The sensitivity of the enzyme to ACTH was maximal on days 17 and 19 of gestation. When Gpp(NH)p was added to ACTH(1-24), the response was significantly higher than that induced by Gpp(NH)p alone. Forskolin and Gpp(NH)p alone increased the adenylate cyclase activity and the sensitivity of the enzyme to these compounds was higher in newborn rats than in fetuses. Treatment of 21-day-old rat fetuses with ACTH increased the response of adenylate cyclase to Gpp(NH)p alone or to forskolin whereas treatment with dexamethasone did not modify the response of the enzyme to either Gpp(NH)p alone or forskolin. Our results show that the change in the responsiveness of adenylate cyclase takes place immediately after birth during the first week and ACTH is able to induce a maturation of the fetal adrenal adenylate cyclase system.

Maternal undernutrition during late gestation-induced intrauterine growth restriction in the rat is associated with impaired placental GLUT3 expression, but does not correlate with endogenous corticosterone levels.

Fetal intrauterine growth restriction (IUGR) is a frequently occurring and serious complication of pregnancy. Infants exposed to IUGR are at risk for numerous perinatal morbidities, including hypoglycemia in the neonatal period, as well as increased risk of later physical and/or mental impairments, cardiovascular disease and non-insulin-dependent diabetes mellitus. Fetal growth restriction most often results from uteroplacental dysfunction during the later stage of pregnancy. As glucose, which is the most abundant nutrient crossing the placenta, fulfills a large portion of the fetal energy requirements during gestational development, and since impaired placental glucose transport is thought to result in growth restriction, we investigated the effects of maternal 50% food restriction (FR50) during the last week of gestation on rat placental expression of glucose transporters, GLUT1, GLUT3 and GLUT4, and on plasma glucose content in both maternal and fetal compartments. Moreover, as maternal FR50 induces fetal overexposure to glucocorticoids and since these hormones are potent regulators of placental glucose transporter expression, we investigated whether putative alterations in placental GLUT expression correlate with changes in maternal and/or fetal corticosterone levels. At term (day 21 of pregnancy), plasma glucose content was significantly reduced (P<0.05) in mothers subjected to FR50, but was not affected in fetuses. Food restriction reduced maternal body weight (P<0.001) but did not affect placental weight. Plasma corticosterone concentration, at term, was increased (P<0.05) in FR50 mothers. Fetuses from FR50 mothers showed reduced body weight (P<0.001) but higher plasma corticosterone levels (P<0.05). Adrenalectomy (ADX) followed by corticosterone supplementation of the mother prevented the FR50-induced rise in maternal plasma corticosterone at term. Food restriction performed on either sham-ADX or ADX mothers induced a similar reduction in the body weight of the pups at term (P<0.01). Moreover, plasma corticosterone levels were increased in pups from sham-ADX FR50 mothers (P<0.01) and in pups from ADX control mothers (P<0.01). Western blot analysis of placental GLUT proteins showed that maternal FR50 decreased placental GLUT3 protein levels in all experimental groups at term (P<0.05 and P<0.01), but did not affect either GLUT1 or GLUT4 protein levels. Northern blot analysis of placental GLUT expression showed that both GLUT1 and GLUT3 mRNA were not affected by the maternal feeding regimen or surgery. We concluded that prolonged maternal malnutrition during late gestation decreases maternal plasma glucose content and placental GLUT3 glucose transporter expression, but does not obviously affect fetal plasma glucose concentration. Moreover, the present results are not compatible with a role of maternal corticosterone in the development of growth-restricted rat fetuses.

Morphine-induced stimulation of pituitary-adrenocortical activity is mediated by activation of nitric oxide in the early stages of postnatal life in the rat.

OBJECTIVE: The first aim of the present study was to determine if morphine, a prototypic mu-opioid agonist drug, affects pituitary-adrenocortical activity in developing rat pups (first and second weeks of postnatal life). The second aim of this study was to explore, in vivo, if nitric oxide (NO) could be involved in the neurohormonal response to morphine in the early stages of postnatal life. METHODS: Plasma ACTH and corticosterone concentrations were determined by RIA in rat pups (n=5-14 rats/experimental group) after they had been killed by decapitation. In a first experiment, 1-day and 1- and 2-week-old rats were treated s.c. with morphine (20 mg/kg) or with vehicle (0.9% NaCl) and killed 5-90 min later. In a second experiment, 2-week-old pups were pretreated s.c. with naltrexone (NAL; 0.4 mg/kg or 10 mg/kg), and injected 1 h later with either morphine (20 mg/kg) or vehicle, and killed 30 min later. Some pups injected with only NAL were killed 60 or 90 min later. On the other hand, pups injected with NAL (10 mg/kg) or NAL and morphine were killed 30 min later. In a third experiment, 2-week-old pups were pretreated s.c. with N-omega-nitro l arginine methyl-ester (L-NAME; 30 mg/kg or 100 mg/kg), and injected 1 h later with either morphine (20 mg/kg) or vehicle, and killed 30 min later. Moreover, some pups injected with L-NAME (100 mg/kg) or L-NAME with morphine were killed 30 min later. In a final experiment, pups were injected s.c. with either S-nitroso-N-acetylpenicillamine (SNAP; 5 mg/kg) or vehicle, and killed 60 or 90 min later. RESULTS: Morphine administered to rat pups elicited marked rises in both ACTH and corticosterone secretion. Moreover, these responses increased with advancing postnatal age. In 2-week-old rat pups, NAL, a competitive antagonist at mu-opioid receptors, administered alone increased both plasma ACTH and corticosterone concentrations 30 min later. L-NAME, a specific NO synthase inhibitor, did not affect plasma ACTH and corticosterone concentrations 30 min later when administered alone. NAL, when concomitantly administered with morphine, was unable to block morphine responses. In contrast, morphine responses were blocked by pretreatment (60 min before) with NAL or with L-NAME. Acute injection of SNAP increased both ACTH and corticosterone release. CONCLUSION: Our results suggest that opioids have controversial effects on pituitary-adrenocortical activity in the early postnatal period in the rat, and that endogenous NO is one of the major factors in the response of the pituitary-adrenocortical axis to morphine.

Metyrapone-induced glucocorticoid depletion modulates tyrosine hydroxylase and phenylethanolamine N-methyltransferase gene expression in the rat adrenal gland by a noncholinergic transsynaptic activation.

The hypothalamic corticotropin-releasing hormone system and the sympathetic nervous system are anatomically and functionally interconnected and hormones of the hypothalamic-pituitary-adrenocortical axis contribute to the regulation of catecholaminergic systems. To investigate the role of glucocorticoids on activity of the adrenal gland, we analysed plasma and adrenal catecholamines, tyrosine hydroxylase (TH) and phenylethanolamine N-methyltransferase (PNMT) mRNA expression in rats injected with metyrapone or dexamethasone. Metyrapone-treated rats had significantly lower epinephrine and higher norepinephrine production than control rats. Metyrapone increased TH protein synthesis and TH mRNA expression whereas its administration did not affect PNMT mRNA expression. Dexamethasone restored plasma and adrenal epinephrine concentrations and increased PNMT mRNA levels, which is consistent with an absolute requirement of glucocorticoids for PNMT expression. Adrenal denervation completely abolished the metyrapone-induced TH mRNA expression. Blockage of cholinergic neurotransmission by nicotinic or muscarinic receptor antagonists did not prevent the metyrapone-induced rise in TH mRNA. Finally, pituitary adenylate cyclase activating polypeptide (PACAP) adrenal content was not affected by metyrapone. These results provide evidence that metyrapone-induced corticosterone depletion elicits transsynaptic TH activation, implying noncholinergic neurotransmission. This may involve neuropeptides other than PACAP.