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dc.contributor.authorHarvey, B.H.
dc.contributor.authorOosthuizen, F.
dc.contributor.authorBrand, L.
dc.contributor.authorWegener, G.
dc.contributor.authorStein, D.J.
dc.identifier.citationHarvey BH, Oosthuizen F, Brand L, Wegener G, Stein DJ. Stress-restress evokes sustained iNOS activity and altered GABA levels and NMDA receptors in rat hippocampus. Psychopharmacologiaen_US
dc.description.abstractRationale: Stress-related glucocorticoid and glutamate release have been implicated in hippocampal atrophy evident in patients with post-traumatic stress disorder (PTSD). Glutamatergic mechanisms activate nitric oxide synthase (NOS), while gamma-amino-butyric acid (GABA) may inhibit both glutamatergic and nitrergic transmission. Animal studies support a role for NOS in stress. Objectives: We have studied the role of NOS and glucocorticoids, as well as inhibitory and excitatory transmitters, in a putative animal model of PTSD that emphasizes repeated trauma. Methods: Hippocampal NOS activity, N-methyl-D-aspartate (NMDA) receptor binding characteristics and GABA levels were studied in Sprague-Dawley rats 21 days after exposure to a stress-restress paradigm, using radiometric analysis, radioligand studies and high-performance liquid chromatography (HPLC) analysis with electrochemical detection, respectively. The NOS isoform involved, and the role of stress-mediated corticosterone release in NOS activation, was verified with the administration of selective iNOS and nNOS inhibitors, aminoguanidine (50 mg/kg/day i.p.) and 7-nitroindazole (12.5 mg/kg/day i.p.), and the steroid synthesis inhibitor, ketoconazole (24 mg/kg/day i.p.), administered for 21 days prior to and during the stress procedure. Results: Stress evoked a sustained increase in NOS activity, but reduced NMDA receptor density and total GABA levels. Aminoguanidine or ketoconazole, but not 7-nitroindazole or saline, blocked stress-induced NOS activation. Conclusions: Stress-restress-mediated glucocorticoid release activates iNOS, followed by a reactive downregulation of hippocampal NMDA receptors and dysregulation of inhibitory GABA pathways. The role of NO in neuronal toxicity, and its regulation by glutamate and GABA has important implications in stress-related hippocampal degeneration.en_US
dc.description.sponsorshipThe authors thank the National Research Foundation (grant number 2053203; B.H.H.), the South African Medical Research Council (B.H.H., L.B. and D.J.S.) and the Danish Medical Research Council (G.W.) for financial assistance. The authors also acknowledge the contribution to this work by Dr. Francois van der Westhuizen, Cor Bester and Antoinette Fick.en_US
dc.relation.url .en_US
dc.rightsAttribution 3.0 United States*
dc.subjectPharmacology drugsen_US
dc.subjectBiological and medical sciencesen_US
dc.subjectAnxiety disorderen_US
dc.subjectPosttraumatic syndromeen_US
dc.subjectNMDA receptoren_US
dc.titleStress-restress evokes sustained iNOS activity and altered GABA levels and NMDA receptors in rat hippocampusen_US
dc.contributor.departmentMRC Unit on Anxiety and Stress Disorders, Department of Psychiatry, University of Stellenbosch, Tygerberg, South Africa.en_US
dc.research.unitClosed Unitsen_US

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Attribution 3.0 United States
Except where otherwise noted, this item's license is described as Attribution 3.0 United States