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. 2018 Jun;59(6):650-658.
doi: 10.1111/jcpp.12843. Epub 2017 Dec 2.

Methylation of OPRL1 Mediates the Effect of Psychosocial Stress on Binge Drinking in Adolescents

Free PMC article

Methylation of OPRL1 Mediates the Effect of Psychosocial Stress on Binge Drinking in Adolescents

Barbara Ruggeri et al. J Child Psychol Psychiatry. .
Free PMC article


Background: Nociceptin is a key regulator linking environmental stress and alcohol drinking. In a genome-wide methylation analysis, we recently identified an association of a methylated region in the OPRL1 gene with alcohol-use disorders.

Methods: Here, we investigate the biological basis of this observation by analysing psychosocial stressors, methylation of the OPRL1 gene, brain response during reward anticipation and alcohol drinking in 660 fourteen-year-old adolescents of the IMAGEN study. We validate our findings in marchigian sardinian (msP) alcohol-preferring rats that are genetically selected for increased alcohol drinking and stress sensitivity.

Results: We found that low methylation levels in intron 1 of OPRL1 are associated with higher psychosocial stress and higher frequency of binge drinking, an effect mediated by OPRL1 methylation. In individuals with low methylation of OPRL1, frequency of binge drinking is associated with stronger BOLD response in the ventral striatum during reward anticipation. In msP rats, we found that stress results in increased alcohol intake and decreased methylation of OPRL1 in the nucleus accumbens.

Conclusions: Our findings describe an epigenetic mechanism that helps to explain how psychosocial stress influences risky alcohol consumption and reward processing, thus contributing to the elucidation of biological mechanisms underlying risk for substance abuse.

Keywords: OPRL1 methylation; adolescence; binge drinking; nucleus accumbens; stressful life events.

Conflict of interest statement

Conflict of interest statement: See acknowledgements for disclosures.

The remaining authors have declared that they have no competing or potential conflicts of interest.


Figure1. Association of OPRL1 methylation with lifetime frequency of binge drinking (N= 609) and stressful life events (N= 626) in adolescents
Negative association of OPRL1 methylation and lifetime frequency of binge drinking (p=2.2×10−04) (panel A). Positive association of stressful life events and lifetime frequency of binge drinking (p=8.7×10−06) in 14-year-old adolescents (panel B). Negative association of lifetime frequency of binge drinking and OPRL1 methylation (p=0.013) (panel C).
Figure2. Association of activation of the ventral striatal activation during Monetary Incentive Delay Task and lifetime binge drinking in adolescents (N=393) and interaction with OPRL1 methylation
Significant interaction between OPRL1 methylation and the left VS activation (p= 0.007, pcorrected=0.014) while the interaction was only a trend in the right VS (p=0.030, pcorrected=0.060). Methylation values in panel A and B are separated into low and high methylation using a median slip. Coronal section shows methylation differences in right and left ventral activation during reward anticipation (xyz: ±9, 11, −2) (panel C and D).
Figure3. Association of early stress and intermittent alcohol intake in the msP rats
One-way ANOVA revealed a significant overall effect of the stress exposure on voluntary alcohol intake in msP rats (p<0.0001). The effect appeared from the third day of alcohol exposure and remained significant on the fourth and fifth day of alcohol exposure as shown by Newman–Keuls tests.* p<0.05.

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