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      Effects of Neonatal Handling on Central Noradrenergic and Nitric Oxidergic Systems and Reproductive Parameters in Female Rats

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          Abstract

          Early-life environmental events that disrupt the mother-pup relationship may induce profound long-lasting changes on several behavioral and neuroendocrine systems. The neonatal handling procedure, which involves repeated brief maternal separations followed by experimental manipulations, reduces sexual behavior and induces anovulatory estrous cycles in female rats. On the afternoon of proestrus, neonatally handled females show a reduced surge of luteinizing hormone (LH) and an increased content of gonadotropin-releasing hormone in the medial preoptic area (MPOA). In order to detect the possible causes for the reduced ovulation and sexual behavior, the present study aimed to analyze the effects of neonatal handling on noradrenaline (NA) and nitric oxide (NO) levels in the MPOA on the afternoon of proestrus. Neonatal handling reduced MHPG (NA metabolite) levels and MHPG/NA ratio in the MPOA, indicating decreased NAergic activity. Additionally, neonatal handling decreased NO levels, as measured by the metabolites (NO<sub>x</sub>), nitrite and nitrate in the same period. We may conclude that the neonatal handling procedure decreased activity of the NAergic and NOergic systems in the MPOA during proestrus, which is involved in the control of LH and FSH secretion, and this may possibly explain the anovulatory estrous cycles and reduced sexual behavior of the neonatally handled female rats.

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          Most cited references 38

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          Early, postnatal experience alters hypothalamic corticotropin-releasing factor (CRF) mRNA, median eminence CRF content and stress-induced release in adult rats

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            Developmental determinants of sensitivity and resistance to stress.

            The purpose of this paper is two fold. First, to revisit the issue of the definition of stress and to highlight the difficulties with the contemporary definitions and, second, to review the literature on the influence of early experiences on the endocrine stress responses and behavior in rodents, sub-human primates and humans. Early experiences, usually involving some manipulation that results in disruption of the mother-infant relationship, have been shown to have long-term influences on the behavioral and endocrine responses to stress. In the rodent, brief periods of separation result in an attenuated adrenal response to stress (reduced secretion of corticosterone). In contrast, longer periods of separation result in an exaggerated response and several behavioral anomalies i.e. increased alcohol consumption, increased startle response etc. However, the effects of disruptions of the mother-infant relationships in primates reveal a pattern of behavioral disturbance but little influence on the endocrine response. Brief maternal separations result in a blunted cortisol response in juvenile squirrel monkeys. The long-term effects of early experiences in humans are very difficult to interpret. It is not possible to determine the length and severity of the experiences, and when in development the experiences were imposed on the child. Despite these limitations, there is a general consensus that adverse early experiences contribute to adult psychopathology.
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              The role of corticotropin-releasing factor--norepinephrine systems in mediating the effects of early experience on the development of behavioral and endocrine responses to stress.

              Naturally occurring variations in maternal care in early postnatal life are associated with the development of individual differences in behavioral and hypothalamic-pituitary-adrenal responses to stress in the rat. These effects appear to be mediated by the influence of maternal licking and grooming on the development of central corticotropin-releasing factor (CRF) systems, which regulate the expression of behavioral, endocrine, and autonomic responses to stress through activation of forebrain noradrenergic systems. These findings provide a neurobiologic basis for the observed relationship between early life events and health in adulthood. In more recent studies, we explored the behavioral transmission of individual differences in stress reactivity, and thus, vulnerability to stress-induced illness, across generations.
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                Author and article information

                Journal
                NEN
                Neuroendocrinology
                10.1159/issn.0028-3835
                Neuroendocrinology
                S. Karger AG
                0028-3835
                1423-0194
                2008
                April 2008
                06 December 2007
                : 87
                : 3
                : 151-159
                Affiliations
                aLaboratório de Neuroendocrinologia do Comportamento, and bLaboratório de Fisiologia Cardiovascular, Departamento de Fisiologia, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, cDepartamento de Fisiologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, and dLaboratório de Neuroendocrinologia, Departamento de Morfologia Estomatologia e Fisiologia, Faculdade de Odontologia de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil
                Article
                112230 Neuroendocrinology 2008;87:151–159
                10.1159/000112230
                18057864
                © 2007 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 5, References: 58, Pages: 9
                Categories
                GnRH, Gonadotropins, Gonadal Steroids and Reproduction

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