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.
| Identifer | oai:union.ndltd.org:UPSALLA1/oai:DiVA.org:uu-283065 |
| Date | January 2016 |
| Creators | Todkar, Aniruddha |
| Publisher | Uppsala universitet, Institutionen för neurovetenskap, Uppsala |
| Source Sets | DiVA Archive at Upsalla University |
| Language | English |
| Detected Language | English |
| Type | Doctoral thesis, comprehensive summary, info:eu-repo/semantics/doctoralThesis, text |
| Format | application/pdf |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, 1651-6206 ; 1214 |
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