TY - JOUR
T1 - The clock gene Per2 influences the glutamatergic system and modulates alcohol consumption
AU - Spanagel, Rainer
AU - Pendyala, Gurudutt
AU - Abarca, Carolina
AU - Zghoul, Tarek
AU - Sanchis-Segura, Carles
AU - Magnone, Maria Chiara
AU - Lascorz, Jesús
AU - Depner, Martin
AU - Holzberg, David
AU - Soyka, Michael
AU - Schreiber, Stefan
AU - Matsuda, Fumihiko
AU - Lathrop, Mark
AU - Schumann, Gunter
AU - Albrecht, Urs
N1 - Funding Information:
This study was supported by two Bundeministerium für Bildung und Forschung grants: FKZ 01GS0475/NGFN to R.S. and G.S., and FKZ 01 EB 0410 to R.S. and GS (MWK-BW Projekt 12a), the Swiss National Science Foundation (SNF 31-63653.00) to U.A., the State of Fribourg, and two EC grants: TARGALC QLG3-CT-2002-01048 to R.S., and Braintime QLG3-CT-2002-01829 to U.A.
PY - 2005/1
Y1 - 2005/1
N2 - Period (Per) genes are involved in regulation of the circadian clock and are thought to modulate several brain functions. We demonstrate that Per2 Brdm1 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.
AB - Period (Per) genes are involved in regulation of the circadian clock and are thought to modulate several brain functions. We demonstrate that Per2 Brdm1 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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U2 - 10.1038/nm1163
DO - 10.1038/nm1163
M3 - Article
C2 - 15608650
AN - SCOPUS:13444254068
VL - 11
SP - 35
EP - 42
JO - Nature Medicine
JF - Nature Medicine
SN - 1078-8956
IS - 1
ER -