The clock gene Per2 influences the glutamatergic system and modulates alcohol consumption.
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.
Spanagel
Rainer
R
Department of Psychopharmacology, Central Institute of Mental Health, J5, 68159 Mannheim, Germany. spanagel@zi-mannheim.de
Pendyala
Gurudutt
G
Abarca
Carolina
C
Zghoul
Tarek
T
Sanchis-Segura
Carles
C
Magnone
Maria Chiara
MC
Lascorz
Jesús
J
Depner
Martin
M
Holzberg
David
D
Soyka
Michael
M
Schreiber
Stefan
S
Matsuda
Fumihiko
F
Lathrop
Mark
M
Schumann
Gunter
G
Albrecht
Urs
U
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
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