Article

Genetic association of the human corticotropin releasing hormone receptor 1 (CRHR1) with binge drinking and alcohol intake patterns in two independent samples

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
Source: PubMed

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.

Full-text

Available from: Ulrich W Preuss, Mar 18, 2014
0 Followers
 · 
112 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Twin and family studies indicate that smoking addiction is highly influenced by genetic factors. Variants in the corticotropin-releasing hormone receptor 1 (CRHR1) gene have been associated with alcoholism and depression. In this study, we tested five single nucleotide polymorphisms (SNPs) in CRHR1 for their association with ND, which was assessed by smoking quantity (SQ), the Heaviness of Smoking Index (HSI), and the Fagerström test for ND (FTND) in 2,037 subjects from 602 families of either European American (EA) or African American (AA) ancestry. Association analysis of the five SNPs revealed a significant association of rs171440 with SQ in the AA sample and with SQ and FTND in the pooled AA and EA samples. Haplotype-based association analysis indicated significant association of haplotypes C-C (56.9%) and T-C (38.9%), formed by SNPs rs171440 and rs1396862, with SQ in the AA sample, C-C-G (47.6%) with SQ, and T-C-G (42.3%), formed by SNPs rs171440, rs1396862, and rs878886, with SQ and FTND in the pooled AA and EA samples. However, none of these associations remained significant after correction for multiple testing. Together, our results provide suggestive evidence for the involvement of CRHR1 in ND, which warrants further investigation using larger independent samples.
    01/2015; 2015:263864. DOI:10.1155/2015/263864
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 'Omics'-techniques are widely used to identify novel mechanism underlying brain function and pathology. Here we applied a novel metabolomics approach to further ascertain the role of fronto-striatal brain regions for the expression of addiction-like behaviors in rat models of alcoholism. Rats were made dependent via chronic intermittent alcohol vapor exposure. Following a three-week abstinence period rats had continuous access to alcohol in a two-bottle, free-choice paradigm for seven weeks. Non-targeted flow injection time-of-flight mass spectroscopy was used to assess global metabolic profiles of two cortical (prelimbic, infralimbic) and two striatal (accumbens core and shell) brain regions. Alcohol consumption produces pronounced global effects on neurometabolomic profiles leading to a clear separation of metabolic phenotypes between treatment groups, particularly. When further comparing regional tissue levels of various metabolites, most notably dopamine and Met-enkephalin, allow the extrapolation of alcohol consumption history. Finally, a high-drinking metabolic fingerprint was identified indicating a distinct alteration of central energy metabolism in the accumbens shell of excessively drinking rats that could indicate a so far unrecognized pathophysiological mechanism in alcohol addiction. In conclusion, global metabolic profiling from distinct brain regions by mass spectrometry identifies profiles reflective of an animal's drinking history and provides a versatile tool to further investigate pathophysiological mechanisms in alcohol dependence.Neuropsychopharmacology accepted article preview online, 24 November 2014. doi:10.1038/npp.2014.312.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 11/2014; 40(5). DOI:10.1038/npp.2014.312 · 7.83 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The results of many studies support the influence of the corticotropin-releasing factor (CRF) system on ethanol consumption and ethanol-induced neuroadaptations that are critical in the addiction process. This review summarizes the preclinical data in this area after first providing an overview of the components of the CRF system. This complex system involves hypothalamic and extra-hypothalamic mechanisms that play a role in the central and peripheral consequences of stressors, including ethanol and other drugs of abuse. In addition, several endogenous ligands and targets make up this system and show differences in their involvement in ethanol drinking and in the effects of chronic or repeated ethanol treatment. In general, genetic and pharmacological approaches paint a consistent picture of the importance of CRF signaling via type 1 CRF receptors (CRF1) in ethanol-induced neuroadaptations that result in higher levels of intake, encourage alcohol seeking during abstinence, and alter ethanol sensitivity. Furthermore, genetic findings in rodents, non-human primates and humans have provided some evidence of associations of genetic polymorphisms in CRF-related genes with ethanol drinking, though additional data are needed. These results suggest that CRF1 antagonists have potential as pharmacotherapeutics for alcohol use disorders. However, given the broad and important role of these receptors in adaptation to environmental and other challenges, full antagonist effects may be too profound and consideration should be given to treatments with modulatory effects.
    Genes Brain and Behavior 01/2015; 14(1). DOI:10.1111/gbb.12189 · 3.51 Impact Factor