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This Article Accepted manuscript (PDF) All Versions of this Article: JOE-08-0509v1 202/1/87    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Adzic, M. Articles by Krstic-Demonacos, M. Search for Related Content PubMed PubMed Citation Articles by Adzic, M. Articles by Krstic-Demonacos, M.

M Adzic, Laboratory of Molecular Biology and Endocrinology, VINCA Institute of Nuclear Sciences, Belgrade, Serbia
J Djordjevic, Laboratory of Molecular Biology and Endocrinology, VINCA Institute of Nuclear Sciences, Belgrade, Serbia
A Djordjevic, Belgrade, Serbia
A Niciforovic, Belgrade, Serbia
C Demonacos, School of Pharmacy, The University of Manchester, Manchester, United Kingdom
M Radojcic, Belgrade, Serbia
M Krstic-Demonacos, Faculty of Life Sciences, The University of Manchester, Manchester, M13 9PT, United Kingdom

Correspondence: Marija Krstic-Demonacos, Email: m.k.demonacos{at}manchester.ac.uk

Chronic stress and impaired glucocorticoid receptor (GR) feedback are important factors for the compromised hypothalamic-pituitary-adrenal (HPA) axis activity. We investigated the effects of chronic 21 day isolation of Wistar rats on the extrinsic negative feedback part of HPA axis: hippocampus (HIPPO) and prefrontal cortex (PFC). In addition to serum corticosterone (CORT), we followed GR subcellular localisation, GR phosphorylation at serine 232 and serine 246, expression of GR regulated genes: GR, CRF and BDNF, and activity of JNK and Cdk5 kinases that phosphorylate GR. These parameters were also determined in animals subjected to acute 30 min immobilization which was taken as ‘normal’ adaptive response to stress. In isolated animals we found decreased CORT, whereas in animals exposed to acute immobilization CORT was markedly increased. Even though the GR was predominantly localised in the nucleus of HIPPO and PFC in acute, but not in chronic stress, the expression of GR, CRF and BDNF genes was similarly regulated under both acute and chronic stresses. Thus, the transcriptional activity of GR under chronic isolation did not seem to be exclusively dependent on high serum CORT levels nor on the subcellular location of the GR protein. Rather, it resulted from the increased Cdk5 activation and phosphorylation of the nuclear GR at serine 232 and the decreased JNK activity reflected in decreased phosphorylation of the nuclear GR at serine 246. Our study suggests that this nuclear isoform of hippocampal and cortical GR may be related to hypocorticism i.e. HPA axis hypoactivity under chronic isolation stress.