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

Abstract

NM A22834 (Albrecht) 3 Across a spectrum of living organisms, ranging from cyanobacteria to humans, it has been observed that biological functions follow a pattern of circadian rhythmicity.These endogenous rhythms display a periodicity close to 24 hours in the absence of environmental cues, thus reflecting the existence of an intrinsic biological clock. In mammals, circadian rhythms in different tissues are coordinated by a master clock located in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus 1 . This circadian clock is thought to be advantageous in synchronising physiological and biochemical pathways, allowing the organism to anticipate daily changes, thus ensuring better adaptation to the environment 2 .The oscillatory mechanism of the circadian clock has been unraveled by means of genetic analysis in Drosophila and mammals [3][4][5] . In the latter, the heterodimeric complex of two transcriptional activators, CLOCK and BMAL1 (MOP3), induce the expression of several genes by interacting with the enhancer elements, termed E-boxes, of their promoters. Amongst these genes are Per1, Per2, Cry1 and Cry2, whose protein products, upon entering the nucleus, inhibit the activity of the CLOCK/BMAL1 complex, and thereby generating an inhibitory feedback loop driving recurrent rhythms in mRNA and protein levels of their own genes. This molecular mechanism seems to be present in the local clocks of most tissues and brain regions. Furthermore, these different clocks may then be synchronized by the SCN via neural and endocrine outputs 6 . Transporter 1, also known as Glast) is found to be reduced in these mice. Excess glutamate is cleared from the synaptic cleft by glutamate transporters 10 , located on astroglial cells and transported back to the neuron via the glutamine-glutamate cycle.A deficit in the removal of glutamate from the synaptic cleft, results in a hyperglutamatergic state and is suggested to produce alterations at the behavioral level 10,11 .Importantly, a hyper-glutamatergic state has been implicated in the aetiology of alcohol dependence [12][13][14] . We observe that in Per2 Brdm1 mutant mice voluntary alcohol consumption is enhanced. In humans we find an association between alcoholic patients and genetic variations in the human PER2 gene. Acamprosate, a medication thought to dampen a hyper-glutamatergic state in the alcohol dependent human brain 15-17 reduces augmented glutamate levels and normalizes enhanced alcohol consumption in Per2 Brdm1 mutant mice. These findings support the view that a hyperglutamatergic state can be involved in several aspects of alcohol dependence [12][13][14][18][19][20] . RESULTS Glutamate transporters in Per2 Brdm1 miceWild type and Per2 Brdm1 mutant mice differ in their behavioral response to a light pulse administered at zeitgeber time (ZT) 14 9 (ZT0 corresponds to lights on and ZT12 to lights off). Therefore, we set out to search for a difference in gene expression between wild type and Per2 Brdm1 mutant mice at ZT15. This time point has been chosen beca...

PRECLINICAL STUDY: Circadian regulation of central ethanol sensitivity by the mPer2 gene

“…Our key finding is that this phenomenon is mediated by the CNS and the clock gene mPer2, and not by circadian variations in ethanol metabolism. These findings might well be translated to the human level, as we could repeatedly demonstrate in previous studies that variations in the human Per2 gene are associated with high alcohol consumption (Spanagel 2009)--an observation, which is in accordance with enhanced alcohol consumption in Per2 Brdm1 mutant mice (Spanagel et al 2005a). High doses of ethanol induce LORR.…”

“…Recently, we were able to demonstrate that mutations in Per1 and Per2 genes can modulate the effects of drugs of abuse in a different manner (Abarca, Albrecht & Spanagel 2002;Spanagel et al 2005aSpanagel et al , 2005bZghoul et al 2007;Perreau-Lenz & Spanagel 2008;Spanagel 2009). In particular, we established that although mice mutant in the Per2 gene (Per2 Brdm1 ) display enhanced alcohol consumption and preference (Spanagel et al 2005a), Per1 Brdm1 mutant mice did not show such an enhancement in alcohol drinking behavior (Zghoul et al 2007). Hence, in order to more closely elucidate the role of the circadian clock in ethanol's effects on brain sensitivity, we therefore examined the diurnal rhythm of CNS sensitivity in the mouse clock mutants Per1 Brdm1 and Per2 Brdm1 .…”

Circadian genes, rhythms and the biology of mood disorders

“…Furthermore, a SNP in BMAL1 and a SNP in the Timeless gene have also been identified that associate with BPD (Mansour et al, 2006). It should be noted that additional studies have found associations between members of the molecular clock and other psychiatric disorders such as schizophrenia and alcoholism, suggesting that these genes are important in a range of psychiatric conditions (Spanagel et al, 2005;Mansour et al, 2006). However, in general, most of these studies only find modest associations, and other studies that have examined SNPs throughout the sequence of some of the central members of the circadian clock have found no associations with these genes and any psychiatric disorders (Shiino et al, 2003;Nievergelt et al, 2005;Mansour et al, 2006;Nievergelt et al, 2006).…”

Acamprosate Produces Its Anti-Relapse Effects Via Calcium

“…This hyperglutamatergic state may then drive alcohol-seeking and relapse behavior (Tsai et al 1995;Spanagel and Kiefer 2008). Acamprosate dampens hyperglutamatergic activity in excessively ethanol drinking mice, thereby reducing alcohol intake (Mann et al 2008;Spanagel et al, 2005). In a recent double-blind, placebo-controlled study, which applied magnetic resonance spectroscopy acamprosate also reduced glutamate levels in the brains of detoxified alcoholdependent patients (Umhau et al, 2010).…”