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Effect of voluntary alcohol consumption on Maoa expression in the mesocorticolimbic brain of adult male rats previously exposed to prolonged maternal separation.: Maoa,ELS and alcohol
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
2015 (English)In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 5, article id e690Article in journal (Refereed) Published
Abstract [en]

Discordant associations between monoamine oxidase A (MAOA) genotype and high alcohol drinking have been reported in human and non-human primates. Environmental influences likely moderate genetic susceptibility. The biological basis for this interplay remains elusive, and inconsistencies call for translational studies in which conditions can be controlled and brain tissue is accessible. The present study investigated whether early life stress and subsequent adult episodic alcohol consumption affect Maoa expression in stress- and reward-related brain regions in the rat. Outbred Wistar rats were exposed to rearing conditions associated with stress (prolonged maternal separation) or no stress during early life, and given free choice between alcohol and/or water in adulthood. Transcript levels of Maoa were assessed in the ventral tegmental area, nucleus accumbens (NAc), medial prefrontal cortex, cingulate cortex, amygdala and dorsal striatum (DS). Blood was collected to assess corticosterone levels. After alcohol consumption, lower blood corticosterone and Maoa expression in the NAc and DS were found in rats exposed to early life stress compared with control rats. An interaction between early life stress and voluntary alcohol intake was found in the NAc. Alcohol intake before death correlated negatively with Maoa expression in DS in high alcohol-drinking rats exposed to early life stress. Maoa expression is sensitive to adulthood voluntary alcohol consumption in the presence of early life stress in outbred rats. These findings add knowledge of the molecular basis of the previously reported associations between early life stress, MAOA and susceptibility to alcohol misuse.

Place, publisher, year, edition, pages
2015. Vol. 5, article id e690
National Category
Medical and Health Sciences Psychiatry
Identifiers
URN: urn:nbn:se:uu:diva-271230DOI: 10.1038/tp.2015.186ISI: 000367666900002PubMedID: 26645625OAI: oai:DiVA.org:uu-271230DiVA, id: diva2:891453
Funder
Swedish Research Council, K2012-61X-22090-01-3Lars Hierta Memorial FoundationAvailable from: 2016-01-07 Created: 2016-01-07 Last updated: 2024-01-17Bibliographically approved
In thesis
1. Predictors of Alcohol Misuse: Role of MAOA Genotype, Methylation, Transcription, and Negative and Positive Environmental factors
Open this publication in new window or tab >>Predictors of Alcohol Misuse: Role of MAOA Genotype, Methylation, Transcription, and Negative and Positive Environmental factors
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Alcohol misuse is a risk factor for alcohol use disorder (AUD). Gene-environment interactions contribute to the risk or resilience for AUD. A functional polymorphism in the promoter of the monoamine oxidase A gene (MAOA-uVNTR), in interaction with negative environment (Eneg), is associated with alcohol misuse and AUD. Men carrying short (MAOA-S), and women carrying long (MAOA-L), MAOA-uVNTR alleles who experienced maltreatment or poor parent-child relationships are at increased susceptibility to alcohol misuse and AUD. This thesis assessed whether the association of MAOAxEneg with the risk of AUD is moderated by MAOA methylation or positive environment and whether MAOA methylation-associated changes in MAOA expression in the stress- and reward-related brain regions is an underlying mechanism.

The thesis reveals that the association of MAOAxEneg with alcohol misuse is moderated by MAOA methylation in men, but not in women. In the clinical sample, men carrying MAOA-S allele who experienced maltreatment and had low MAOA methylation displayed higher alcohol-related problems than those without maltreatment or MAOA-L carriers with and without maltreatment. Furthermore, the quality of the parent–child relationship moderated the association of MAOAxEneg with alcohol misuse in a sex- and AUD stage-dependent manner. In the non-clinical sample of adolescents, girls carrying MAOA-L allele who experienced maltreatment and poor parent–child relationship displayed higher alcohol consumption, whereas those with average or good parent–child relationship had lower alcohol consumption. In the clinical sample of adolescents, however, no such association was observed. These results suggest that a good parent–child relationship protects MAOA susceptibility genotype carriers exposed to maltreatment during the early stages of alcohol use. The preclinical studies revealed that the male rats exposed to Eneg and alcohol had higher CpG-specific Maoa promoter methylation, which was associated with lower Maoa expression in the nucleus accumbens than the control rats. Thus, MAOA methylation-associated changes in MAOA expression in the nucleus accumbens might mediate the effect of environment on alcohol use.

The thesis contributes to the understanding of biological mechanisms underlying MAOAxEnvironment effect and the critical role of MAOA methylation and positive environment in moderating risk and resilience for AUD. Also, the identification of subgroups may benefit from personalised interventions for AUD.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. p. 115
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1602
Keywords
Alcohol, AUD, MAOA, methylation, expression, early-life stress, maltreatment, parent–child relationship, gene–environment interactions.
National Category
Medical and Health Sciences
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-393306 (URN)978-91-513-0769-5 (ISBN)
Public defence
2019-11-27, Aulan, 21, Västmanlands Hospital, Västerås, 13:15 (English)
Opponent
Supervisors
Available from: 2019-11-06 Created: 2019-10-08 Last updated: 2019-11-27

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Bendre, MeghaComasco, ErikaNylander, IngridNilsson, Kent W
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Neuro-psycho-pharmacologyDepartment of Pharmaceutical BiosciencesCentre for Clinical Research, County of Västmanland
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