title: Temporal variability of glucocorticoid receptor activity is functionally important for the therapeutic action of fluoxetine in the hippocampus.
abstract: Previous studies have shown inconsistent results regarding the actions of antidepressants on glucocorticoid receptor (GR) signalling. To resolve these inconsistencies, we used a lentiviral-based reporter system to directly monitor rat hippocampal GR activity during stress adaptation. Temporal GR activation was induced significantly by acute stress, as demonstrated by an increase in the intra-individual variability of the acute stress group compared with the variability of the non-stress group. However, the increased intra-individual variability was dampened by exposure to chronic stress, which was partly restored by fluoxetine treatment without affecting glucocorticoid secretion. Immobility in the forced-swim test was negatively correlated with the intra-individual variability, but was not correlated with the quantitative GR activity during fluoxetine therapy; this highlights the temporal variability in the neurobiological links between GR signalling and the therapeutic action of fluoxetine. Furthermore, we demonstrated sequential phosphorylation between GR (S224) and (S232) following fluoxetine treatment, showing a molecular basis for hormone-independent nuclear translocation and transcriptional enhancement. Collectively, these results suggest a neurobiological mechanism by which fluoxetine treatment confers resilience to the chronic stress-mediated attenuation of hypothalamic-pituitary-adrenal axis activity.
authors.affiliation: Bio-Imaging Centre, Korea Basic Science Institute, Chuncheon, South Korea.
authors.forename: M-S
authors.initials: MS
authors.lastname: Lee
authors.affiliation: Bio-Imaging Centre, Korea Basic Science Institute, Chuncheon, South Korea.
authors.forename: Y-H
authors.initials: YH
authors.lastname: Kim
authors.affiliation: Bio-Imaging Centre, Korea Basic Science Institute, Chuncheon, South Korea.
authors.forename: W-S
authors.initials: WS
authors.lastname: Park
authors.affiliation: Bio-Imaging Centre, Korea Basic Science Institute, Chuncheon, South Korea.
authors.forename: O-K
authors.initials: OK
authors.lastname: Park
authors.affiliation: Bio-Imaging Centre, Korea Basic Science Institute, Chuncheon, South Korea.
authors.forename: S-H
authors.initials: SH
authors.lastname: Kwon
authors.affiliation: Division of MR Research, Korea Basic Science Institute, Cheongwon, South Korea.
authors.forename: K S
authors.initials: KS
authors.lastname: Hong
authors.affiliation: Neuroscience Centre, Korea Institute of Science and Technology, Seoul, South Korea.
authors.forename: H
authors.initials: H
authors.lastname: Rhim
authors.affiliation: Acupuncture and Meridian Science Research Centre, Kyung Hee University, Seoul, South Korea.
authors.forename: I
authors.initials: I
authors.lastname: Shim
authors.affiliation: Department of Nursing, Shikoku University, School of Health Sciences, Tokushima, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Morita
authors.affiliation: Department of Psychiatry, Harvard Medical School and Laboratory of Molecular and Developmental Neurobiology, McLean Hospital, Belmont, MA, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Wong
authors.affiliation: Department of Psychiatry, Molecular and Behavioral Neuroscience Institute, University of Michigan Medical Centre, Ann Arbor, MI, USA.
authors.forename: P D
authors.initials: PD
authors.lastname: Patel
authors.affiliation: Departments of Psychiatry, Stanford University Medical Centre, Stanford, CA, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Lyons
authors.affiliation: Departments of Psychiatry, Stanford University Medical Centre, Stanford, CA, USA.
authors.forename: A F
authors.initials: AF
authors.lastname: Schatzberg
authors.affiliation: Bio-Imaging Centre, Korea Basic Science Institute, Chuncheon, South Korea.
authors.forename: S
authors.initials: S
authors.lastname: Her
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology; D003345:Corticosterone / Q000494:pharmacology; D005473:Fluoxetine / Q000494:pharmacology*; D006624:Hippocampus / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism; D008297:Male; D010766:Phosphorylation; D010913:Pituitary-Adrenal System / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013315:Stress, Psychological
chemical_list: D000928:Antidepressive Agents; D018687:Antidepressive Agents, Second-Generation; D011965:Receptors, Glucocorticoid; D005473:Fluoxetine; D003345:Corticosterone