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The Journal of Neuroscience, March 17, 2004, 24(11):2787-2796; doi:10.1523/JNEUROSCI.4132-03.2004

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Behavioral/Systems/Cognitive
Neurochemical and Behavioral Alterations in Glucocorticoid Receptor-Impaired Transgenic Mice after Chronic Mild Stress

Nicolas Froger,¹ Enza Palazzo,¹ Claudette Boni,¹ Naïma Hanoun,¹ Françoise Saurini,¹ Chantal Joubert,² Isabelle Dutriez-Casteloot,³ Michaela Enache,³ Stefania Maccari,⁴ Nicholas Barden,⁵ Charles Cohen-Salmon,² Michel Hamon,¹ and Laurence Lanfumey¹

¹ Institut National de la Santé et de la Recherche Médicale U288–Neuropsychopharmacologie and ² Unité Mixte de Recherche 7593–Centre National de la Recherche Scientifique–Personnalités et Conduites Adaptatives, Institut Fédératif de Recherche 70 des Neurosciences, Centre Hospitalier Universitaire Pitié-Salpêtrière, 75013 Paris, France, ³Neuroendocrinologie du Développement, UPRES-EA 2701, and ⁴Stress Périnatal, UPRES-JE 2395, Université de Lille 1, 59655 Villeneuve d'Ascq, France, and ⁵Laval University Hospital Research Centre and Department of Anatomy and Physiology, University Laval, Ste Foy, Quebec G1V 4G2, Canada

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 [-³⁵S]GTP-S binding measurements to assess 5-HT_1A receptor functioning showed that CMS exposure produced a desensitization of DRN 5-HT_1A 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.

Key words: 5-HT_1A receptors; glucocorticoid receptors; dorsal raphe nucleus; transgenic mice; chronic mild stress; major depressive disorders

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Received Sep 8, 2003; revised December 29, 2003; accepted January 17, 2004.

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