Neurochemical and Behavioral Alterations in Glucocorticoid Receptor-Impaired Transgenic Mice after Chronic Mild Stress
Open Access
- 17 March 2004
- journal article
- Published by Society for Neuroscience in Journal of Neuroscience
- Vol. 24 (11), 2787-2796
- https://doi.org/10.1523/jneurosci.4132-03.2004
Abstract
Mice (GR-i) bearing a transgene encoding a glucocorticoid receptor (GR) antisense RNA under the control of a neuron-specific neurofilament promoter were used to investigate the effects of a 4 week chronic mild stress (CMS) on the hypothalamo–pituitary–adrenocortical (HPA) axis and the serotoninergic system in a transgenic model of vulnerability to affective disorders. GR-i mice showed a decrease in both GR-specific binding (hippocampus and cerebral cortex) and GR mRNA levels [hippocampus, cerebral cortex, and dorsal raphe nucleus (DRN)] as well as a deficit in HPA axis feedback control (dexamethasone test) compared with paired wild-type (WT) mice. In the latter animals, CMS exposure caused a significant decrease in both GR mRNA levels and the density of cytosolic GR binding sites in the hippocampus, whereas, in the DRN, GR mRNA levels tended to increase. In contrast, in stressed GR-i mice, both GR mRNA levels and the density of GR binding sites were significantly increased in the hippocampus, cerebral cortex, and DRN. Electrophysiological recordings in brainstem slices and [γ-35S]GTP-S binding measurements to assess 5-HT1A receptor functioning showed that CMS exposure produced a desensitization of DRN 5-HT1A autoreceptors in WT, but not in GR-i, mice. In addition, CMS was found to facilitate choice behavior of WT, but not GR-i, mice in a decision-making task derived from an alternation paradigm. These results demonstrate that impaired GR functioning affects normal adaptive responses of the HPA axis and 5-HT system to CMS and alters stress-related consequences on decision-making behaviors.Keywords
This publication has 44 references indexed in Scilit:
- Regional specificity of brain glucocorticoid receptor mRNA alterations in subjects with schizophrenia and mood disordersMolecular Psychiatry, 2002
- Serotonin 1A Receptors, Serotonin Transporter Binding and Serotonin Transporter mRNA Expression in the Brainstem of Depressed Suicide VictimsNeuropsychopharmacology, 2001
- Serotonin, stress and corticoidsJournal of Psychopharmacology, 2000
- Dexamethasone nonsuppression in transgenic mice expressing antisense RNA to the glucocorticoid receptorJournal of Psychiatric Research, 1994
- Antidepressant treatment prevents chronic unpredictable mild stress-induced anhedonia as assessed by ventral tegmentum self-stimulation behavior in ratsEuropean Neuropsychopharmacology, 1992
- Impaired type II glucocorticoid-receptor function in mice bearing antisense RNA transgeneNature, 1992
- Chronic immobilization stress: evidence for decreases of 5-hydroxy-tryptamine immunoreactivity and for increases of glucocorticoid receptor immunoreactivity in various brain regions of the male ratJournal of Neural Transmission, 1989
- Glucocorticoid Negative Feedback and Glucocorticoid Receptors After Hippocampectomy in RatsHormone and Metabolic Research, 1987
- Analysis of radioligand binding experimentsJournal of Pharmacological Methods, 1985
- Genetic and environmental factors in major depressionJournal of Affective Disorders, 1985