Effects of the Circadian Rhythm Gene Period 1 (Per1) on Psychosocial Stress-Induced Alcohol Drinking

Department of Psychiatry and Psychotherapy, Universität Regensburg, Ratisbon, Bavaria, Germany
American Journal of Psychiatry (Impact Factor: 12.3). 08/2011; 168(10):1090-8. DOI: 10.1176/appi.ajp.2011.10111579
Source: PubMed


Circadian and stress-response systems mediate environmental changes that affect alcohol drinking. Psychosocial stress is an environmental risk factor for alcohol abuse. Circadian rhythm gene period 1 (Per1) is targeted by stress hormones and is transcriptionally activated in corticotropin releasing factor-expressing cells. The authors hypothesized that Per1 is involved in integrating stress response and circadian rhythmicity and explored its relevance to alcohol drinking.
In mice, the effects of stress on ethanol intake in mPer1-mutant and wild-type mice were assessed. In humans, single nucleotide polymorphisms (SNPs) in hPer1 were tested for association with alcohol drinking behavior in 273 adolescents and an adult case-control sample of 1,006 alcohol-dependent patients and 1,178 comparison subjects. In vitro experiments were conducted to measure genotype-specific expression and transcription factor binding to hPer1.
The mPer1-mutant mice showed enhanced alcohol consumption in response to social defeat stress relative to their wild-type littermates. An association with the frequency of heavy drinking in adolescents with the hPer1 promoter SNP rs3027172 and with psychosocial adversity was found. There was significant interaction between the rs3027172 genotype and psychosocial adversity on this drinking measure. In a confirmatory analysis, association of hPer1 rs3027172 with alcohol dependence was shown. Cortisol-induced transcriptional activation of hPer1 was reduced in human B-lymphoblastoid cells carrying the risk genotype of rs3027172. Binding affinity of the transcription factor Snail1 to the risk allele of the hPer1 SNP rs3027172 was also reduced.
The findings indicate that the hPer1 gene regulates alcohol drinking behavior during stressful conditions and provide evidence for underlying neurobiological mechanisms.

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Available from: Urs Albrecht, Sep 29, 2015
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    • "Forced Swimming Test (FST). This test was performed as previously described (Dong et al., 2011). In a pre-test session, mice were forced to swim individually for 6 min in a glass beaker (basin height: 10 cm, 21°C). "
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    ABSTRACT: It is suggested that striatal cAMP responsive element binding protein (CREB) regulates sensitivity to psychostimulants. To test the cell-specificity of this hypothesis we examined the effects of a dominant-negative CREB protein variant expressed in dopamine receptor D1 (D1R) neurons on cocaine-induced behaviors. A transgenic mouse strain was generated by pronuclear injection of a BAC-derived transgene harboring the A-CREB sequence under the control of the D1R gene promoter. Compared to wild-type, drug-naïve mutants showed moderate alterations in gene expression, especially a reduction in basal levels of activity-regulated transcripts such as Arc and Egr2. The behavioral responses to cocaine were elevated in mutant mice. Locomotor activity after acute treatment, psychomotor sensitization after intermittent drug injections and the conditioned locomotion after saline treatment were increased compared to wild-type littermates. Transgenic mice had significantly higher cocaine conditioned place preference, displayed normal extinction of the conditioned preference, but showed an augmented cocaine-seeking response following priming-induced reinstatement. This enhanced cocaine-seeking response was associated with increased levels of activity-regulated transcripts and prodynorphin. The primary reinforcing effects of cocaine were not altered in the mutant mice as they did not differ from wild-type in cocaine self-administration under a fixed ratio schedule at the training dose. Collectively, our data indicate that expression of a dominant-negative CREB variant exclusively in neurons expressing D1R is sufficient to recapitulate the previously reported behavioral phenotypes associated with virally expressed dominant-negative CREB.
    Frontiers in Behavioral Neuroscience 07/2014; 8:212. DOI:10.3389/fnbeh.2014.00212 · 3.27 Impact Factor
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    • "In Per1 ldcϪ/Ϫ mice, there are no mood phenotypes under baseline conditions. However, there are differences in voluntary alcohol consumption, seen only after social defeat stress, suggesting altered reward processing pathways sensitive to stress (Dong et al., 2011; Zghoul et al., 2007). Mouse studies have revealed a more prominent role for Per2 in mood and reward processing. "
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    ABSTRACT: An association between circadian clock function and mood regulation is well established and has been proposed as a factor in the development of mood disorders. Patients with depression or mania suffer disturbed sleep-wake cycles and altered rhythms in daily activities. Environmentally disrupted circadian rhythms increase the risk of mood disorders in the general population. However, proof that a disturbance of circadian rhythms is causally involved in the development of psychiatric disorders remains elusive. Using clock gene mutants, manipulations of sleep-wake and light-dark cycles, and brain lesions affecting clock function, animal models have been developed to investigate whether circadian rhythm disruptions alter mood. In this review, selected animal models are examined to address the issue of causality between circadian rhythms and affective behavior. (PsycINFO Database Record (c) 2014 APA, all rights reserved).
    Behavioral Neuroscience 03/2014; 128(3). DOI:10.1037/a0036029 · 2.73 Impact Factor
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    • "Although animal models and imaging studies have suggested that some 5-HT receptors (such as HTR1A, HTR1B, and HTR3) might also play roles in the pathogenesis of AUD [16], [17], [18], only a limited number of genetic association studies were performed, yielding mixed results [19], [20]. Similarly, genes from other neurotransmitter systems — such as the neuropeptide Y (NPY) gene of neuropeptide Y system [21]; the neuronal nicotinic acetylcholine receptor beta 2 (CHRNB2) gene of cholinergic system [22]; period circadian clock 1 (PER1); and period circadian clock 2 (PER2) of period family [23] — were also found to be associated with AUD in some studies but failed to be replicated in other research [24]. In Chinese ethnic groups, relatively few studies have focused on the role of neurotransmitter genes in the pathogenesis of alcohol use disorders. "
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