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Treutlein J, Kissling C, Frank J, Wiemann S, Dong L, Depner M et al. Genetic association of the human corticotropin releasing hormone receptor 1 (CRHR1) with binge drinking and alcohol intake patterns in two independent samples. Mol Psychiatry 11: 594-602

Molecular Genetics Laboratory and Department of Addiction Medicine, Central Institute of Mental Health, Mannheim, Germany.
Molecular Psychiatry (Impact Factor: 15.15). 06/2006; 11(6):594-602. DOI: 10.1038/sj.mp.4001813
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ABSTRACT To investigate the role of the corticotropin releasing hormone receptor 1 (CRHR1) in patterns of human alcohol drinking and its potential contribution to alcohol dependence, we analysed two independent samples: a sample of adolescents, which consisted of individuals from the 'Mannheim Study of Risk Children' (MARC), who had little previous exposure to alcohol, and a sample of alcohol-dependent adults, who met DSM-IV criteria of alcohol dependence. Following determination of allelic frequencies of 14 polymorphisms of the CRHR1 gene, two haplotype tagging (ht)SNPs discriminating between haplotypes with a frequency of > or =0.7% were identified. Both samples were genotyped and systematically examined for association with the htSNPs of CRHR1. In the adolescent sample, significant group differences between genotypes were observed in binge drinking, lifetime prevalence of alcohol intake and lifetime prevalence of drunkenness. The sample of adult alcohol-dependent patients showed association of CRHR1 with high amount of drinking. This is the first time that an association of CRHR1 with specific patterns of alcohol consumption has been reported. Our findings support results from animal models, suggesting an importance of CRHR1 in integrating gene-environment effects in alcohol use disorders.

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    • "This group more recently reported that stressful life events occurring between either 12e15 years of age (Blomeyer et al., 2008) or between 15-19 years of age (Schmid et al., 2010) resulted in heavier and earlier initiation of alcohol use in subjects that had either the rs1876831 or rs242938 SNP in the CRHR1 gene. Though it is currently unknown what functional implications the rs242938 SNP has on CRHR1, the rs1876831 SNP has been implicated in elevated transcriptional activation of CRHR1 (Treutlein et al., 2006). It is important to note that experiments using genetically selected rats with a high alcohol preference show increased Crhr1 expression levels in the brain compared to unselected rats with little alcohol preference (Hansson et al., 2006). "
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    ABSTRACT: Interest in adolescence as a crucial stage of neurobehavioral maturation is growing, as is the concern of how stress may perturb this critical period of development. Though it is well recognized that stress-related vulnerabilities increase during adolescence, not all adolescent individuals are uniformly affected by stress nor do stressful experiences inevitability lead to negative outcomes. Indeed, many adolescents show resilience to stress-induced dysfunctions. However, relatively little is known regarding the mechanisms that may mediate resilience to stress in adolescence. The goal of this brief review is to bring together a few separate, yet related lines of research that highlight specific variables that may influence stress resilience during adolescence, including early life programming of the hypothalamic-pituitary-adrenal (HPA) axis, stress inoculation, and genetic predisposition. Though we are far from a clear understanding of the factors that mediate resistance to stress-induced dysfunctions, it is imperative that we identify and delineate these aspects of resilience to help adolescents reach their full potential, even in the face of adversity.
    01/2015; 1(1). DOI:10.1016/j.ynstr.2014.11.001
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    • "The corticotropin–releasing hormone (CRH) is a well-known neuroendocrine mediator of behavioural and immune response to stress. It is released from the hypothalamus upon exposure to stressful signals and binds to the CRHR1 (Bittencourt et al., 2000; Treutlein et al., 2006). CRHR1 is a predominant receptor in pituitary gland, regulates the adrenocorticotropic hormone (ACTH) and the catecholaminergic response to CRH. "
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    ABSTRACT: Corticotrophin releasing hormone receptor1 (CRHR1) is a potent mediator of endocrine, autonomic, behavioural, and immune responses to stress, supposed to play a pivotal role in steroid pathway. The genetic variations of this gene have significant influences in response to corticosteroid therapy in a wide range of disease. Number of genotyping methods has been developed to investigate the genetic variants of this gene. However, classical polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) analysis is still lacking. Therefore, we aimed to develop this straightforward and affordable method to detect the nucleotide variation (rs242941: G>T) of CRHR1gene, can apply in basic research study of complex genetic diseases. The 100 clinically defined asthmatic patients from North India region were recruited for this study and their DNA were extracted. Primer set was designed by Batch primer3 Software. The PCR-RFLP assays were performed by endonuclease (AciI) digestion of PCR-amplified DNA visualized in agarose gel. The allele frequencies for G>T variation were 0.74 (G allele) and 0.25 (TT allele). This work is the first to provide evidence for PCR-RFLP being the method of choice for CRHR1:rs242941 SNP genotyping. This is affordable, specific, reproducible, with sufficiently throughput capacity and particularly appropriate for medium-scale genotyping purposes.
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    • "Further work done in msP rats provided evidence that excessive alcohol drinking and stress vulnerability may be associated with the occurrence of two single nucleotide polymorphisms (SNPs) in the promoter region (position −1836 and −2097) of the gene encoding the CRF1 receptor, an observation that closely correlated with innate upregulation of the CRF1-R transcript (Hansson et al., 2006). Genetic variation at the CRF1-R locus as a susceptibility factor for excessive alcohol drinking might have parallels in humans, where a similar association was reported (Treutlein et al., 2006). It is, however, unclear whether the −1836 and −2097 SNPs are causally related to escalated alcohol consumption. "
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    ABSTRACT: Marchigian Sardinian alcohol-preferring (msP) rats exhibit innate preference for alcohol, are highly sensitive to stress and stress-induced alcohol seeking. Genetic analysis showed that over-expression of the corticotropin-releasing factor (CRF) system of msP rats is correlated with the presence of two single nucleotide polymorphisms (SNPs) occurring in the promoter region (position -1836 and -2097) of the CRF1 receptor (CRF1-R) gene. Here we examined whether these point mutations were associated to the innate alcohol preference, stress-induced drinking and seeking. We have recently re-derived the msP rats to obtain two distinct lines carrying the wild type (GG) and the point mutations (AA), respectively. The phenotypic characteristics of these two lines were compared with those of unselected Wistar rats. Both AA and GG rats showed similar patterns of voluntary alcohol intake and preference. Similarly, the pharmacological stressor yohimbine (0.0, 0.625, 1.25 and 2.5 mg/kg) elicited increased operant alcohol self-administration under fixed and progressive ratio reinforcement schedules in all three lines. Following extinction, yohimbine (0.0, 0.625, 1.25 and 2.5 mg/kg) significantly reinstated alcohol seeking in the three groups. However, at the highest dose this effect was no longer evident in AA rats. Treatment with the CRF1-R antagonist antalarmin (0, 5, 10 and 20 mg/kg) significantly reduced alcohol-reinforced lever pressing in the AA line (10 and 20 mg/kg) while a weaker or no effect was observed in the Wistar and the GG group, respectively. Finally, antalarmin significantly reduced yohimbine-induced increase in alcohol drinking in all three groups. In conclusion, these specific SNPs in the CRF1-R gene do not seem to play a primary role in the expression of the msP excessive-drinking phenotype or stress-induced drinking but may be associated with a decreased threshold for stress-induced alcohol seeking and an increased sensitivity to the effects of pharmacolo
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