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.
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A Per2 polymorphism was associated with more alcohol use in patients with AUDs.
“A Per2 polymorphism was associated with more alcohol use in patients with AUDs (Spanagel et al., 2005)”
From Sleep and circadian contributions to adolescent alcohol use disorder (2015) · cites this paper as Spanagel et al., 2005
Circadian gene mutants often demonstrate altered reward behavior, such as increased preference for alcohol or hypersensitization to cocaine.
“Furthermore, circadian gene mutants often demonstrate altered reward behavior, such as increased preference for alcohol or hypersensitization to cocaine (McClung et al., 2005; Spanagel et al., 2005).”
From Sleep and circadian contributions to adolescent alcohol use disorder (2015) · cites this paper as Spanagel et al., 2005
Additional studies have found associations between members of the molecular clock and other psychiatric disorders such as schizophrenia and alcoholism.
“additional studies have found associations between members of the molecular clock and other psychiatric disorders such as schizophrenia and alcoholism”
From Circadian genes, rhythms and the biology of mood disorders (2007) · cites this paper as Spanagel et al., 2005
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- Authors
- Spanagel, R., Pendyala, G., Abarca, C., Zghoul, T., Sanchis-Segura, C., Magnone, M. C., Lascorz, J., Depner, M., Holzberg, D., Soyka, M., Schreiber, S., Matsuda, F., Lathrop, M., Schumann, G., & Albrecht, U.
- Affiliations
- Central Institute of Mental Health (DE)
- University of Fribourg (CH)
- Vrije Universiteit Brussel (BE)
- Max Planck Society (DE)
- Ludwig-Maximilians-Universität München (DE)
- Christian-Albrechts-Universität zu Kiel (DE)
- Corresponding author
- Spanagel, Rainer
- Albrecht, Urs
- ORCID
- Venue
- Nature Medicine
- Published
- 2004-12-19
- Volume
- 11
- Issue
- 1
- Pages
- 35-42
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2140395780
- Cited by
- 594
- References
- 50
- Citations by year
- 2026: 10 · 2025: 13 · 2024: 12 · 2023: 15 · 2022: 21 · 2021: 32 · 2020: 33 · 2019: 16 · 2018: 34 · 2017: 22 · 2016: 19 · 2015: 30 · 2014: 32 · 2013: 37 · 2012: 29
- FWCI
- 9.96
- Type
- journal article
- Language
- en
- Update notices
- erratum (2005-02-01)
- Open access
- closed
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- reroDoc Digital Library (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- VUBIR (Vrije Universiteit Brussel) (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- Per2, clock genes, glutamatergic system, alcohol consumption, astrocytes, extracellular glutamate, acamprosate, alcohol craving
- MeSH terms
- Acamprosate, Alcohol Deterrents, Alcohol Drinking, Alcoholism, Animals, Biological Clocks, Cocaine, Humans, Nuclear Proteins, Taurine, Time Factors, Transcription Factors, Glutamic Acid, Cell Cycle Proteins, Cocaine-Related Disorders, Amino Acid Transport System X-AG, Mice, Period Circadian Proteins
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