title: Neurochemical and behavioral alterations in glucocorticoid receptor-impaired transgenic mice after chronic mild stress.
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 [gamma-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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U288-Neuropsychopharmacologie Cellulaire et Fonctionnelle, Faculté de Médecine Pitié-Salpêtrière, Centre Hospitalier Universitaire Pitié-Salpêtrière, 75013 Paris, France. nifroger@ext.jussieu.fr
authors.forename: Nicolas
authors.initials: N
authors.lastname: Froger
authors.forename: Enza
authors.initials: E
authors.lastname: Palazzo
authors.forename: Claudette
authors.initials: C
authors.lastname: Boni
authors.forename: Naïma
authors.initials: N
authors.lastname: Hanoun
authors.forename: Françoise
authors.initials: F
authors.lastname: Saurini
authors.forename: Chantal
authors.initials: C
authors.lastname: Joubert
authors.forename: Isabelle
authors.initials: I
authors.lastname: Dutriez-Casteloot
authors.forename: Michaela
authors.initials: M
authors.lastname: Enache
authors.forename: Stefania
authors.initials: S
authors.lastname: Maccari
authors.forename: Nicholas
authors.initials: N
authors.lastname: Barden
authors.forename: Charles
authors.initials: C
authors.lastname: Cohen-Salmon
authors.forename: Michel
authors.initials: M
authors.lastname: Hamon
authors.forename: Laurence
authors.initials: L
authors.lastname: Lanfumey
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000502:physiology; D001933:Brain Stem / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D002755:Choice Behavior / Q000502:physiology; D002908:Chronic Disease; D020022:Genetic Predisposition to Disease; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism / Q000493:pharmacokinetics; D006624:Hippocampus / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D019964:Mood Disorders / Q000235:genetics*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000503:physiopathology; D016372:RNA, Antisense / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000378:metabolism; D011903:Raphe Nuclei / Q000378:metabolism; D051381:Rats; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D058825:Serotonin 5-HT1 Receptor Agonists; D013312:Stress, Physiological / Q000378:metabolism / Q000503:physiopathology*
chemical_list: D016372:RNA, Antisense; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D058825:Serotonin 5-HT1 Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; D016244:Guanosine 5'-O-(3-Thiotriphosphate)