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The clock gene Per2 influences the glutamatergic system and modulates alcohol consumption

An Erratum to this article was published on 01 February 2005

Abstract

Period (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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Figure 1: Expression of the glutamate transporter Eaat1 in brain tissue.
Figure 2: Protein levels of mGluRs1, 2, 3, 5 and Eaat2.
Figure 3: Glutamate levels in brain tissue and glutamate uptake by astrocytes.
Figure 4: Intake and preference of different alcohol solutions at increasing concentrations of Per2Brdm1 mutant mice and wild-type (wt) littermate mice.
Figure 5: Operant ethanol self-administration and progressive ratio measurements in Per2Brdm1 mutant mice and wild-type littermates.
Figure 6: Effects of acamprosate on extracellular glutamate levels and alcohol consumption in Per2Brdm1 mutant mice and wild-type littermates.

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Acknowledgements

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.

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Correspondence to Rainer Spanagel or Urs Albrecht.

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Supplementary information

Supplementary Table 1

Distribution of genotypes and results of association tests of alcohol dependent patients with high (≥300 g/d) and low (≤300 g/d) alcohol intake. (PDF 17 kb)

Supplementary Table 2

Results of haplotype analysis (PDF 15 kb)

Supplementary Methods (PDF 70 kb)

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Spanagel, R., Pendyala, G., Abarca, C. et al. The clock gene Per2 influences the glutamatergic system and modulates alcohol consumption. Nat Med 11, 35–42 (2005). https://doi.org/10.1038/nm1163

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