Nature Medicine
11, 35 - 42 (2004)
Published online: 19 December 2004; | doi:10.1038/nm1163
There is an Erratum (February 2005) associated with this Article.
The clock gene Per2 influences the glutamatergic system and modulates alcohol consumptionRainer Spanagel1, Gurudutt Pendyala2, Carolina Abarca1, 3, Tarek Zghoul1, Carles Sanchis-Segura1, Maria Chiara Magnone2, Jesús Lascorz1, Martin Depner1, David Holzberg4, Michael Soyka5, Stefan Schreiber6, Fumihiko Matsuda7, Mark Lathrop7, Gunter Schumann1
& Urs Albrecht2, 41
Departments of Psychopharmacology and Psychiatry, Central Institute of Mental Health, J5, 68159 Mannheim, Germany. 2
Department of Medicine, Division of Biochemistry, University of Fribourg, 1700 Fribourg, Switzerland. 3
Department of Pharmaceutical Chemistry, Experimental Neuropharmacology, Vrije Universiteit Brussel, 1090 Brussels, Belgium. 4
Max-Planck-Institute for Experimental Endocrinology, 30625 Hannover, Germany. 5
Department of Psychiatry and Psychotherapy, University of Munich, 80336 Munich, Germany. 6
Institute for Clinical Molecular Biology, Christian-Albrechts-University, UKSH Kiel, 24098 Kiel, Germany. 7
Centre National de Génotypage, 91057 Evry, France.
Correspondence should be addressed to Rainer Spanagel spanagel@zi-mannheim.de or Urs Albrecht urs.albrecht@unifr.chPeriod (Per) genes are involved in regulation of the circadian clock and are thought to modulate several brain functions. We demonstrate that Per2Brdm1 mutant mice, which have a deletion in the PAS domain of the Per2 protein, show alterations in the glutamatergic system. Lowered expression of the glutamate transporter Eaat1 is observed in these animals, leading to reduced uptake of glutamate by astrocytes. As a consequence, glutamate levels increase in the extracellular space of Per2Brdm1 mutant mouse brains. This is accompanied by increased alcohol intake in these animals. In humans, variations of the PER2 gene are associated with regulation of alcohol consumption. Acamprosate, a drug used to prevent craving and relapse in alcoholic patients is thought to act by dampening a hyper-glutamatergic state. This drug reduced augmented glutamate levels and normalized increased alcohol consumption in Per2Brdm1 mutant mice. Collectively, these data establish glutamate as a link between dysfunction of the circadian clock gene Per2 and enhanced alcohol intake.
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