title: The clock gene Per2 influences the glutamatergic system and modulates alcohol consumption.
abstract: 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 Per2(Brdm1) 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 Per2(Brdm1) mutant mice. Collectively, these data establish glutamate as a link between dysfunction of the circadian clock gene Per2 and enhanced alcohol intake.
authors.affiliation: Department of Psychopharmacology, Central Institute of Mental Health, J5, 68159 Mannheim, Germany. spanagel@zi-mannheim.de
authors.forename: Rainer
authors.initials: R
authors.lastname: Spanagel
authors.forename: Gurudutt
authors.initials: G
authors.lastname: Pendyala
authors.forename: Carolina
authors.initials: C
authors.lastname: Abarca
authors.forename: Tarek
authors.initials: T
authors.lastname: Zghoul
authors.forename: Carles
authors.initials: C
authors.lastname: Sanchis-Segura
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Magnone
authors.forename: Jesús
authors.initials: J
authors.lastname: Lascorz
authors.forename: Martin
authors.initials: M
authors.lastname: Depner
authors.forename: David
authors.initials: D
authors.lastname: Holzberg
authors.forename: Michael
authors.initials: M
authors.lastname: Soyka
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Matsuda
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.forename: Gunter
authors.initials: G
authors.lastname: Schumann
authors.forename: Urs
authors.initials: U
authors.lastname: Albrecht
mesh_terms: D000077443:Acamprosate; D000427:Alcohol Deterrents / Q000494:pharmacology; D000428:Alcohol Drinking / Q000235:genetics* / Q000378:metabolism; D000437:Alcoholism / Q000235:genetics / Q000378:metabolism; D027322:Amino Acid Transport System X-AG / Q000378:metabolism; D000818:Animals; D001683:Biological Clocks / Q000235:genetics / Q000502:physiology; D018797:Cell Cycle Proteins; D003042:Cocaine / Q000378:metabolism; D019970:Cocaine-Related Disorders / Q000235:genetics / Q000378:metabolism; D018698:Glutamic Acid / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D056950:Period Circadian Proteins; D013654:Taurine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013997:Time Factors; D014157:Transcription Factors
chemical_list: D000427:Alcohol Deterrents; D027322:Amino Acid Transport System X-AG; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; C421902:PER2 protein, human; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D014157:Transcription Factors; D013654:Taurine; D018698:Glutamic Acid; D003042:Cocaine; D000077443:Acamprosate