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Alcohol Consumption: A Study of Genetic and Environmental Correlates with Focus on the Stress System
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. (Neuropsychopharmacology)
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Early life stress (ELS) is associated with risk of excessive alcohol drinking. However, the genetic mechanisms underlying the susceptibility to excessive alcohol drinking are not well understood. DNA methylation may mediate the influence of ELS on gene function and thereby contribute to alcohol misuse. Furthermore, susceptible genotypes of polymorphisms in interaction with early environment may influence alcohol related behaviors in adulthood.

The present thesis comprised of a study of rodents and a study of humans. The former aimed to investigate the effects of ELS, alcohol drinking and housing on the expression of stress and DNA methylation regulatory genes in the hypothalamus and pituitary, and the expression of the Fkbp5 in the mesocorticolimbic system and dorsal striatum. The effects of ELS, alcohol, and housing on the DNA methylation of the promoters of genes of interest and blood corticosterone levels were also examined.

Hypothalamic Adra2a expression was lower in alcohol drinking rats exposed to ELS, whereas ELS and ethanol drinking exerted independent effects on the expression of other genes in the hypothalamus and pituitary, however in a manner that depended on the control group used. Single housing associated with differential gene expression suggesting single housing as a confounding factor. Water and ethanol drinking in rats exposed to ELS was associated with higher and lower blood corticosterone, respectively. Brain region-dependent interaction effects between alcohol and ELS were observed on Fkbp5 expression in mesolimbic regions. These results indicate a counter-balancing effect of alcohol drinking to ELS.

The study of humans investigated whether environment in interaction with single nucleotide polymorphisms of stress-related genes associate with alcohol use problems in young adults. The functional FKBP5 rs1360780 TT genotype in interaction with poor parent-child relationship was associated with problematic drinking behaviour. Regarding CRHR1, aversive and supportive environment in interaction with the rs1876831 AA genotype were associated with higher and lower alcohol drinking problems, respectively.

Altogether, the present thesis deepens the knowledge of underlying genetic mechanisms for ELS-mediated propensity to drink alcohol and presents the novel insight into genetic susceptibility of FKBP5 and CRHR1 to early environment in relation to alcohol drinking problems.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. , 58 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1214
Keyword [en]
Alcohol, ELS, maternal separation, gene-environment
National Category
Medical and Health Sciences
Research subject
Neuroscience
Identifiers
URN: urn:nbn:se:uu:diva-283065ISBN: 978-91-554-9554-1 (print)OAI: oai:DiVA.org:uu-283065DiVA: diva2:918191
Public defence
2016-06-01, B21, Biomedical center, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2016-05-09 Created: 2016-04-10 Last updated: 2016-05-09
List of papers
1. Alpha 2a-Adrenoceptor Gene Expression and Early Life Stress-Mediated Propensity to Alcohol Drinking in Outbred Rats
Open this publication in new window or tab >>Alpha 2a-Adrenoceptor Gene Expression and Early Life Stress-Mediated Propensity to Alcohol Drinking in Outbred Rats
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2015 (English)In: International Journal of Environmental Research and Public Health, ISSN 1661-7827, E-ISSN 1660-4601, Vol. 12, no 7, 7154-7171 p.Article in journal (Refereed) Published
Abstract [en]

Stressful events early in life, later high alcohol consumption and vulnerability to alcohol use disorder (AUD) are tightly linked. Norepinephrine is highly involved in the stress response and the alpha 2A-adrenoceptor, which is an important regulator of norepinephrine signalling, is a putative target in pharmacotherapy of AUD. The aim of the present study was to investigate the effects of early-life stress and adult voluntary alcohol drinking on the alpha 2A-adrenoceptor. The relative expression and promoter DNA methylation of the Adra2a gene were measured in the hypothalamus, a key brain region in stress regulation. A well-characterized animal model of early-life stress was used in combination with an episodic voluntary drinking in adulthood. Alcohol drinking rats with a history of early-life stress had lower Adra2a expression than drinking rats not exposed to stress. Alcohol intake and Adra2a gene expression were negatively correlated in high-drinking animals, which were predominantly rats subjected to early-life stress. The results provide support for a link between early-life stress, susceptibility for high alcohol consumption, and low Adra2a expression in the hypothalamus. These findings can increase our understanding of the neurobiological basis for vulnerability to initiate risk alcohol consumption and individual differences in the response to 2A-adrenoceptor agonists.

Keyword
alpha 2A-adrenoceptor, alcohol, brain, gene expression, rat, maternal separation, stress
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:uu:diva-261997 (URN)10.3390/ijerph120707154 (DOI)000359342300004 ()26121187 (PubMedID)
Funder
Swedish Research Council, K2012-61X-22090-01-3The Swedish Brain Foundation, PS2013-0052
Available from: 2015-09-07 Created: 2015-09-07 Last updated: 2017-12-04Bibliographically approved
2. HPA Axis Gene Expression and DNA Methylation Profiles in Rats Exposed to Early Life Stress, Adult Voluntary Ethanol Drinking and Single Housing
Open this publication in new window or tab >>HPA Axis Gene Expression and DNA Methylation Profiles in Rats Exposed to Early Life Stress, Adult Voluntary Ethanol Drinking and Single Housing
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2016 (English)In: Frontiers in Molecular Neuroscience, ISSN 1662-5099, Vol. 8, 90Article in journal (Refereed) Published
Abstract [en]

The neurobiological basis of early life stress (ELS) impact on vulnerability to alcohol use disorder is not fully understood. The effect of ELS, adult ethanol consumption and single housing, on expression of stress and DNA methylation regulatory genes as well as blood corticosterone levels was investigated in the hypothalamus and pituitary of adult out-bred Wistar rats subjected to different rearing conditions. A prolonged maternal separation (MS) of 360 min (MS360) was used to study the effect of ELS, and a short MS of 15 min (MS15) was used as a control. Voluntary ethanol drinking was assessed using a two-bottle free choice paradigm to simulate human episodic drinking. The effects of single housing and ethanol were assessed in conventional animal facility rearing (AFR) conditions. Single housing in adulthood was associated with lower Crhr1 and higher Pomc expression in the pituitary, whereas ethanol drinking was associated with higher expression of Crh in the hypothalamus and Crhr1 in the pituitary, accompanied by lower corticosterone levels. As compared to controls with similar early life handling, rats exposed to ELS displayed lower expression of Pomc in the hypothalamus, and higher Dnmt1 expression in the pituitary. Voluntary ethanol drinking resulted in lower Fkbp5 expression in the pituitary and higher Crh expression in the hypothalamus, independently of rearing conditions. In rats exposed to ELS, water and ethanol drinking was associated with higher and lower corticosterone levels, respectively. The use of conventionally reared rats as control group yielded more significant results than the use of rats exposed to short MS. Positive correlations, restricted to the hypothalamus and ELS group, were observed between the expression of the hypothalamus-pituitary-adrenal receptor and the methylation-related genes. Promoter DNA methylation and expression of respective genes did not correlate suggesting that other loci are involved in transcriptional regulation. Concluding, single housing is a confounding factor to be considered in voluntary ethanol drinking paradigms. ELS and ethanol drinking in adulthood exert independent effects on hypothalamic and pituitary related genes, however, in a manner dependent on the control group used.

Keyword
DNA methylation; early life stress; ethanol; gene expression; housing; hypothalamus; pituitary; gland; rat
National Category
Substance Abuse
Identifiers
urn:nbn:se:uu:diva-276525 (URN)10.3389/fnmol.2015.00090 (DOI)000370554700001 ()26858597 (PubMedID)
Funder
Forte, Swedish Research Council for Health, Working Life and Welfare, 2011-0627Lars Hierta Memorial FoundationThe Swedish Brain Foundation, PS2013-0052EU, European Research Council, EA 11 30Swedish Research Council, K2012-61X-22090-01-3The Swedish Brain FoundationForte, Swedish Research Council for Health, Working Life and Welfare
Note

Shared last authorship (Comasco and Nylander)

Available from: 2016-02-15 Created: 2016-02-15 Last updated: 2017-11-30
3. Fkbp5/FKBP5 mediates the influence of parent-offspring relationship on alcohol drinking in young adult rats and humans
Open this publication in new window or tab >>Fkbp5/FKBP5 mediates the influence of parent-offspring relationship on alcohol drinking in young adult rats and humans
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(English)In: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1740-634XArticle in journal (Other academic) Submitted
Keyword
Fkbp5, alcohol, stress
National Category
Medical and Health Sciences
Research subject
Neuroscience
Identifiers
urn:nbn:se:uu:diva-283060 (URN)
Available from: 2016-04-10 Created: 2016-04-10 Last updated: 2017-11-30
4. CRHR1 Genotype Sensitivity to Supportive and Aversive Environmental Influences in Relation to Alcohol Misuse
Open this publication in new window or tab >>CRHR1 Genotype Sensitivity to Supportive and Aversive Environmental Influences in Relation to Alcohol Misuse
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(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-283053 (URN)
Available from: 2016-04-09 Created: 2016-04-09 Last updated: 2016-04-09

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