Genetical genomic determinants of alcohol consumption in rats and humans

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Background

We have used a genetical genomic approach, in conjunction with phenotypic analysis of alcohol consumption, to identify candidate genes that predispose to varying levels of alcohol intake by HXB/BXH recombinant inbred rat strains. In addition, in two populations of humans, we assessed genetic polymorphisms associated with alcohol consumption using a custom genotyping array for 1,350 single nucleotide polymorphisms (SNPs). Our goal was to ascertain whether our approach, which relies on statistical and informatics techniques, and non-human animal models of alcohol drinking behavior, could inform interpretation of genetic association studies with human populations.

Results

In the HXB/BXH recombinant inbred (RI) rats, correlation analysis of brain gene expression levels with alcohol consumption in a two-bottle choice paradigm, and filtering based on behavioral and gene expression quantitative trait locus (QTL) analyses, generated a list of candidate genes. A literature-based, functional analysis of the interactions of the products of these candidate genes defined pathways linked to presynaptic GABA release, activation of dopamine neurons, and postsynaptic GABA receptor trafficking, in brain regions including the hypothalamus, ventral tegmentum and amygdala. The analysis also implicated energy metabolism and caloric intake control as potential influences on alcohol consumption by the recombinant inbred rats. In the human populations, polymorphisms in genes associated with GABA synthesis and GABA receptors, as well as genes related to dopaminergic transmission, were associated with alcohol consumption.

Conclusion

Our results emphasize the importance of the signaling pathways identified using the non-human animal models, rather than single gene products, in identifying factors responsible for complex traits such as alcohol consumption. The results suggest cross-species similarities in pathways that influence predisposition to consume alcohol by rats and humans. The importance of a well-defined phenotype is also illustrated. Our results also suggest that different genetic factors predispose alcohol dependence versus the phenotype of alcohol consumption.

Related collections

Most cited references 103

Record: found
Abstract: not found
Article: not found

Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing

Yoav Benjamini, Yosef Hochberg (1995)

0 comments Cited 25149 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Drugs of abuse: anatomy, pharmacology and function of reward pathways.

George F Koob (1992)

Drugs of abuse are very powerful reinforcers, and even in conditions of limited access (where the organism is not dependent) these drugs will motivate high rates of operant responding. This presumed hedonic property and the drugs' neuropharmacological specificity provide a means of studying the neuropharmacology and neuroanatomy of brain reward. Three major brain systems appear to be involved in drug reward--dopamine, opioid and GABA. Evidence suggests a midbrain-forebrain-extrapyramidal circuit with its focus in the nucleus accumbens. Data implicating dopamine and opioid systems in indirect sympathomimetic and opiate reward include critical elements in both the nucleus accumbens and ventral tegmental areas. Ethanol reward appears to depend on an interaction with the GABAA receptor complex but may also involve common elements such as dopamine and opioid peptides in this midbrain-forebrain-extrapyramidal circuit. These results suggest that brain reward systems have a multidetermined neuropharmacological basis that may involve some common neuroanatomical elements.

0 comments Cited 191 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

The rostromedial tegmental nucleus (RMTg), a GABAergic afferent to midbrain dopamine neurons, encodes aversive stimuli and inhibits motor responses.

Thomas Jhou, Howard L. Fields, Mark G. Baxter … (2009)

Separate studies have implicated the lateral habenula (LHb) or amygdala-related regions in processing aversive stimuli, but their relationships to each other and to appetitive motivational systems are poorly understood. We show that neurons in the recently identified GABAergic rostromedial tegmental nucleus (RMTg), which receive a major LHb input, project heavily to midbrain dopamine neurons, and show phasic activations and/or Fos induction after aversive stimuli (footshocks, shock-predictive cues, food deprivation, or reward omission) and inhibitions after rewards or reward-predictive stimuli. RMTg lesions markedly reduce passive fear behaviors (freezing, open-arm avoidance) dependent on the extended amygdala, periaqueductal gray, or septum, all regions that project directly to the RMTg. In contrast, RMTg lesions spare or enhance active fear responses (treading, escape) in these same paradigms. These findings suggest that aversive inputs from widespread brain regions and stimulus modalities converge onto the RMTg, which opposes reward and motor-activating functions of midbrain dopamine neurons.

0 comments Cited 190 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Journal

Journal ID (nlm-ta): BMC Biol

Title: BMC Biology

Publisher: BioMed Central

ISSN (Electronic): 1741-7007

Publication date Collection: 2009

Publication date (Electronic): 27 October 2009

Volume: 7

Page: 70

Affiliations

[1 ]Department of Pharmacology, University of Colorado, Denver, Aurora, CO, USA

[2 ]Department of Pharmacology, University of California San Diego, La Jolla, CA, USA

[3 ]Department of Pediatrics, University of California Irvine, Irvine, CA, USA

[4 ]Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA

[5 ]Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA, USA

[6 ]Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Denver, Aurora, CO, USA

[7 ]Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN, USA

[8 ]Max Delbrück Center for Molecular Medicine, Berlin, Germany

[9 ]Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic

[10 ]MRC Clinical Sciences Centre, London, UK

[11 ]Department of Psychiatry, McGill University, Montreal, Quebec, Canada

[12 ]Drug Health Services, Royal Prince Alfred Hospital, Sydney Medical School, University of Sydney, New South Wales, Australia

[13 ]Queensland Institute of Medical Research, Queensland, Australia

[14 ]School of Medicine, University of Queensland, Brisbane, Queensland, Australia

[15 ]Division of Epidemiology, National Institute on Alcohol Abuse and Alcoholism, Rockville, MD, USA

[16 ]Department Psychology-Neuroscience, University of Massachusetts Amherst, Amherst, MA, USA

[17 ]Applied Biosystems, Lingley House, 120 Birchwood Blvd., Warrington, Cheshire, WA3 7QH, UK

Article

Publisher ID: 1741-7007-7-70

DOI: 10.1186/1741-7007-7-70

PMC ID: 2777866

PubMed ID: 19874574

SO-VID: 607849dc-91af-4c46-ab39-af02c78b1bb6

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 29 September 2009

Date accepted : 27 October 2009

Comments

Comment on this article

scite_

Cited by 40

See all cited by

Genetical genomic determinants of alcohol consumption in rats and humans

Read this article at

Abstract

Background

Results

Conclusion

Related collections

When did Helicobacter first colonise humans?

Most cited references 103

Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing

Drugs of abuse: anatomy, pharmacology and function of reward pathways.

The rostromedial tegmental nucleus (RMTg), a GABAergic afferent to midbrain dopamine neurons, encodes aversive stimuli and inhibits motor responses.

Author and article information

Journal

Affiliations

Article

History

Categories

Comments

Comment on this article

Similar content 71

Cited by 40