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      Nitric Oxide Synthase Inhibitor Attenuates the Effects of Repeated Restraint Stress on Synaptic Transmission in the Paraventricular Nucleus of the Rat Hypothalamus

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          Corticotropin-releasing hormone (CRH)-synthesizing parvocellular neuroendocrine cells (PNCs) of the hypothalamic paraventricular nucleus (PVN) play a key role in the activation of the hypothalamic-pituitary-adrenocortical (HPA) axis. Several studies have demonstrated that synaptic inputs to these cells may undergo stress-related enhancement but, on the other hand, it has been reported that exposition to the same stressor for prolonged time periods may induce a progressive reduction in the response of the HPA axis to homotypic stressors. In the present study rats were subjected to 10 min restraint sessions, repeated twice daily for 3 or 7 days. Miniature excitatory and inhibitory postsynaptic currents (mEPSCs and mIPSCs) were then recorded from PNCs in ex vivo hypothalamic slice preparations obtained 24 h after the last restraint. Restraint stress repeated over 3 days resulted in increased mean frequency and decreased rise time and decay time constant of mEPSCs, accompanied by a decrease in the excitability of PNCs, however, no such changes were evident in slices obtained from rats subjected to restraint over 7 days. There were no changes in mIPSCs after repeated restraint. Administration of the unspecific nitric oxide synthase (NOS) blocker Nω-Nitro-L-arginine (L-NNA) before each restraint, repeated over 3 days, prevented the occurrence of an increase in mEPSC frequency. However, animals receiving L-NNA and subjected to repeated restraint had similar changes in PNCs membrane excitability and mEPSC kinetics as stressed rats not receiving L-NNA. Comparison of the effects of a single 10 min restraint session followed by either an immediate or delayed (24 h) decapitation revealed an increase in the mean mEPSC frequency and a decrease in the mean mIPSC frequency in slices prepared immediately after restraint, with no apparent effects when slice preparation was delayed by 24 h. These results demonstrate that restraint, lasting 10 min and repeated twice daily for 3 days, induces a selective and long-lasting enhancement of excitatory synaptic input onto PNCs, partially by a NOS-dependent mechanism, and reduces PNC excitability, whereas prolongation of repeated stress for up to 7 days results in an adaptation.

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          Most cited references 35

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          Nongenomic glucocorticoid inhibition via endocannabinoid release in the hypothalamus: a fast feedback mechanism.

          Glucocorticoid negative feedback in the brain controls stress, feeding, and neural-immune interactions by regulating the hypothalamic-pituitary-adrenal axis, but the mechanisms of inhibition of hypothalamic neurosecretory cells have never been elucidated. Using whole-cell patch-clamp recordings in an acute hypothalamic slice preparation, we demonstrate a rapid suppression of excitatory glutamatergic synaptic inputs to parvocellular neurosecretory neurons of the hypothalamic paraventricular nucleus (PVN) by the glucocorticoids dexamethasone and corticosterone. The effect was maintained with dexamethasone conjugated to bovine serum albumin and was not seen with direct intracellular glucocorticoid perfusion via the patch pipette, suggesting actions at a membrane receptor. The presynaptic inhibition of glutamate release by glucocorticoids was blocked by postsynaptic inhibition of G-protein activity with intracellular GDP-beta-S application, implicating a postsynaptic G-protein-coupled receptor and the release of a retrograde messenger. The glucocorticoid effect was not blocked by the nitric oxide synthesis antagonist N(G)-nitro-L-arginine methyl ester hydrochloride or by hemoglobin but was blocked completely by the CB1 cannabinoid receptor antagonists AM251 [N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide] and AM281 [1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-4-morpholinyl-1H-pyrazole-3-carboxamide] and mimicked and occluded by the cannabinoid receptor agonist WIN55,212-2 [(beta)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate], indicating that it was mediated by retrograde endocannabinoid release. Several peptidergic subtypes of parvocellular neuron, identified by single-cell reverse transcripton-PCR analysis, were subject to rapid inhibitory glucocorticoid regulation, including corticotropin-releasing hormone-, thyrotropin-releasing hormone-, vasopressin-, and oxytocin-expressing neurons. Therefore, our findings reveal a mechanism of rapid glucocorticoid feedback inhibition of hypothalamic hormone secretion via endocannabinoid release in the PVN and provide a link between the actions of glucocorticoids and cannabinoids in the hypothalamus that regulate stress and energy homeostasis.
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                Author and article information

                Front Cell Neurosci
                Front Cell Neurosci
                Front. Cell. Neurosci.
                Frontiers in Cellular Neuroscience
                Frontiers Media S.A.
                03 May 2017
                : 11
                1Department of Physiology, Institute of Pharmacology, Polish Academy of Sciences Kraków, Poland
                2Institute of Zoology and Biomedical Research, Jagiellonian University Kraków, Poland
                3Department of Neurobiology, Institute of Pharmacology, Polish Academy of Sciences Kraków, Poland
                Author notes

                Edited by: Andrea Barberis, Fondazione Istituto Italiano di Technologia, Italy

                Reviewed by: Amiel Rosenkranz, Rosalind Franklin University of Medicine and Science, USA; Annalisa Scimemi, University at Albany, SUNY, USA

                *Correspondence: Krzysztof Tokarski ktok@
                Copyright © 2017 Kusek, Tokarska, Siwiec, Gadek-Michalska, Szewczyk, Hess and Tokarski.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 6, Tables: 1, Equations: 0, References: 37, Pages: 10, Words: 7752
                Funded by: Narodowe Centrum Nauki 10.13039/501100004281
                Award ID: 2012/07/N/NZ4/02687
                Original Research


                stress, mipsc, hpa, pvn, corticosterone, glutamatergic, gabaergic, mepsc


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