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Gene Expression Is Altered in the Lateral Hypothalamus upon Activation of the mu Opioid Receptor

Authors

  • K. Befort,

    1. Institut de Génétique et de Biologie Moléculaire et Cellulaire, Département Neurobiologie et Génétique, Illkirch, France;
      Inserm, Illkirch, France; CNRS, Illkirch, France; Université Louis Pasteur, Strasbourg, France
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  • D. Filliol,

    1. Institut de Génétique et de Biologie Moléculaire et Cellulaire, Département Neurobiologie et Génétique, Illkirch, France;
      Inserm, Illkirch, France; CNRS, Illkirch, France; Université Louis Pasteur, Strasbourg, France
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  • E. Darcq,

    1. Institut de Génétique et de Biologie Moléculaire et Cellulaire, Département Neurobiologie et Génétique, Illkirch, France;
      Inserm, Illkirch, France; CNRS, Illkirch, France; Université Louis Pasteur, Strasbourg, France
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  • A. Ghate,

    1. Institut de Génétique et de Biologie Moléculaire et Cellulaire, Département Neurobiologie et Génétique, Illkirch, France;
      Inserm, Illkirch, France; CNRS, Illkirch, France; Université Louis Pasteur, Strasbourg, France
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  • A. Matifas,

    1. Institut de Génétique et de Biologie Moléculaire et Cellulaire, Département Neurobiologie et Génétique, Illkirch, France;
      Inserm, Illkirch, France; CNRS, Illkirch, France; Université Louis Pasteur, Strasbourg, France
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  • A. Lardenois,

    1. Institut de Génétique et de Biologie Moléculaire et Cellulaire, Laboratoire de Bioinformatique et de Génomique Intégratives
    2. Groupe d'étude de la reproduction chez l'homme et les Mammifères, Institut Fédératif de Recherche 140, Université de Rennes-1, Rennes, France
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  • J. Muller,

    1. Institut de Génétique et de Biologie Moléculaire et Cellulaire, Laboratoire de Bioinformatique et de Génomique Intégratives
    2. Laboratoire de Biologie Moléculaire, d'Analyse Génique et de Modélisation, Centre de Recherche Public-Santé, Luxembourg
    3. Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
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  • C. Thibault,

    1. Institut de Génétique et de Biologie Moléculaire et Cellulaire, Microarray Plateform
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  • D. Dembele,

    1. Institut de Génétique et de Biologie Moléculaire et Cellulaire, Microarray Plateform
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  • O. Poch,

    1. Institut de Génétique et de Biologie Moléculaire et Cellulaire, Laboratoire de Bioinformatique et de Génomique Intégratives
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  • B.L. Kieffer

    1. Institut de Génétique et de Biologie Moléculaire et Cellulaire, Département Neurobiologie et Génétique, Illkirch, France;
      Inserm, Illkirch, France; CNRS, Illkirch, France; Université Louis Pasteur, Strasbourg, France
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Address for correspondence: Katia Befort, IGBMC, Département de Neurobiologie et Génétique, 1 rue Laurent Fries, 67400 Illkirch, France. Voice: +33-(0)3-88-65-56-94; fax: +33-(0)3-88-65-56-04.
 befort@igbmc.u-strasbg.fr

Abstract

The lateral hypothalamus (LH) is a brain structure that controls hedonic properties of both natural rewards and drugs of abuse. Mu opioid receptors are known to mediate drug reward, but whether overstimulation of these receptors impacts on LH function has not been studied. Here we have used a genome-wide microarray approach to identify LH responses to chronic mu opioid receptor activation at the transcriptional level. We have subjected wild-type and mu opioid receptor knockout mice to an escalating morphine regimen, which produces severe physical dependence in wild-type but not mutant animals. We have analyzed gene profiles in LH samples using the 430A.2 Affymetrix array and identified a set of 25 genes whose expression is altered by morphine in wild-type mice only. The regulation was confirmed for a subset of these genes using real-time quantitative PCR on samples from independent treatments. Altered expression of aquaporin 4, apolipoprotein D, and prostaglandin synthase is indicative of modified LH physiology. The regulation of two signaling genes (the serum glucocorticoid kinase and the regulator of G protein signaling 4) suggests that neurotransmission is altered in LH circuitry. Finally, the downregulation of apelin may indicate a potential role for this neuropeptide in opioid signaling and hedonic homeostasis. Altogether, our study shows that chronic mu opioid receptor stimulation induces gene expression plasticity in the LH and provides a unique collection of mu opioid receptor-dependent genes that potentially contribute to alter reward processes in addictive diseases.

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