title: Glucocorticoid receptor gene inactivation in dopamine-innervated areas selectively decreases behavioral responses to amphetamine.
abstract: The meso-cortico-limbic system, via dopamine release, encodes the rewarding and reinforcing properties of natural rewards. It is also activated in response to abused substances and is believed to support drug-related behaviors. Dysfunctions of this system lead to several psychiatric conditions including feeding disorders and drug addiction. These disorders are also largely influenced by environmental factors and in particular stress exposure. Stressors activate the corticotrope axis ultimately leading to glucocorticoid hormone (GCs) release. GCs bind the glucocorticoid receptor (GR) a transcription factor ubiquitously expressed including within the meso-cortico-limbic tract. While GR within dopamine-innervated areas drives cocaine's behavioral responses, its implication in responses to other psychostimulants such as amphetamine has never been clearly established. Moreover, while extensive work has been made to uncover the role of this receptor in addicted behaviors, its contribution to the rewarding and reinforcing properties of food has yet to be investigated. Using mouse models carrying GR gene inactivation in either dopamine neurons or in dopamine-innervated areas, we found that GR in dopamine responsive neurons is essential to properly build amphetamine-induced conditioned place preference and locomotor sensitization. c-Fos quantification in the nucleus accumbens further confirmed defective neuronal activation following amphetamine injection. These diminished neuronal and behavioral responses to amphetamine may involve alterations in glutamate transmission as suggested by the decreased MK801-elicited hyperlocomotion and by the hyporeactivity to glutamate of a subpopulation of medium spiny neurons. In contrast, GR inactivation did not affect rewarding and reinforcing properties of food suggesting that responding for natural reward under basal conditions is preserved in these mice.
authors.affiliation: UMR 7224 CNRS, Physiopathologie des Maladies du Système Nerveux Central, "Gene Regulation and Adaptive Behaviors" Group Paris, France ; INSERM, UMRs 952, Physiopathologie des Maladies du Système Nerveux Central Paris, France ; Université Pierre et Marie Curie, Physiopathologie des Maladies du Système Nerveux Central Paris, France ; Department of Psychiatry, Columbia University New York, NY, USA.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Parnaudeau
authors.affiliation: UMR 7224 CNRS, Physiopathologie des Maladies du Système Nerveux Central, "Gene Regulation and Adaptive Behaviors" Group Paris, France ; INSERM, UMRs 952, Physiopathologie des Maladies du Système Nerveux Central Paris, France ; Université Pierre et Marie Curie, Physiopathologie des Maladies du Système Nerveux Central Paris, France.
authors.forename: Marie-Louise
authors.initials: ML
authors.lastname: Dongelmans
authors.affiliation: UMR 7224 CNRS, Physiopathologie des Maladies du Système Nerveux Central, "Gene Regulation and Adaptive Behaviors" Group Paris, France ; INSERM, UMRs 952, Physiopathologie des Maladies du Système Nerveux Central Paris, France ; Université Pierre et Marie Curie, Physiopathologie des Maladies du Système Nerveux Central Paris, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Turiault
authors.affiliation: Pathophysiology of Addiction, Institut National de la Santé et de la Recherche Médicale, U862, NeuroCentre Magendie Bordeaux Cedex, France ; Department of Neurology, Center for Integrative Neuroscience and the Ernest Gallo Clinic and Research Center, University of California at San Francisco San Francisco, CA, USA.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Ambroggi
authors.affiliation: Unité de Biologie Fonctionnelle et Adaptative, Sorbonne Paris Cité, UMR 8251 CNRS, Université Paris Diderot Paris, France.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Delbes
authors.affiliation: Unité de Biologie Fonctionnelle et Adaptative, Sorbonne Paris Cité, UMR 8251 CNRS, Université Paris Diderot Paris, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Cansell
authors.affiliation: Unité de Biologie Fonctionnelle et Adaptative, Sorbonne Paris Cité, UMR 8251 CNRS, Université Paris Diderot Paris, France.
authors.forename: Serge
authors.initials: S
authors.lastname: Luquet
authors.affiliation: Pathophysiology of Addiction, Institut National de la Santé et de la Recherche Médicale, U862, NeuroCentre Magendie Bordeaux Cedex, France.
authors.forename: Pier-Vincenzo
authors.initials: PV
authors.lastname: Piazza
authors.affiliation: UMR 7224 CNRS, Physiopathologie des Maladies du Système Nerveux Central, "Gene Regulation and Adaptive Behaviors" Group Paris, France ; INSERM, UMRs 952, Physiopathologie des Maladies du Système Nerveux Central Paris, France ; Université Pierre et Marie Curie, Physiopathologie des Maladies du Système Nerveux Central Paris, France.
authors.forename: François
authors.initials: F
authors.lastname: Tronche
authors.affiliation: UMR 7224 CNRS, Physiopathologie des Maladies du Système Nerveux Central, "Gene Regulation and Adaptive Behaviors" Group Paris, France ; INSERM, UMRs 952, Physiopathologie des Maladies du Système Nerveux Central Paris, France ; Université Pierre et Marie Curie, Physiopathologie des Maladies du Système Nerveux Central Paris, France ; Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275 Valbonne, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Barik
keywords: amphetamine; dopamine pathway; food reward; glucocorticoid receptor; glutamate; motivation