Early Life Stress and Substance Use Disorders: Underlying Neurobiology and Pathways to Adverse Outcomes

AbstractEarly life stress has been linked to increased methylation of the Nuclear Receptor Subfamily 3 Group C Member 1 (NR3C1) gene, which codes for the glucocorticoid receptor. Moreover, early life stress has been associated with substance use initiation at a younger age, a risk factor for developing substance use disorders. However, no studies to date have investigated whether NR3C1 methylation can predict substance use in young individuals. This study included adolescents 13–14 years of age that reported no history of substance use at baseline, (N = 1041; males = 46%). Participants contributed saliva DNA samples and were followed in middle adolescence as part of KUPOL, a prospective cohort study of 7th-grade students in Sweden. Outcome variables were self-reports of (i) recent use, (ii) lifetime use, and (iii) use duration of (a) alcohol, (b) tobacco products, (c) cannabis, or (d) any substance. Outcomes were measured annually for three consecutive years. The predictor variable was DNA methylation at the exon 1 F locus of NR3C1. Risk and rate ratios were calculated as measures of association, with or without adjustment for internalizing symptoms and parental psychiatric disorders. For a subset of individuals (N = 320), there were also morning and afternoon salivary cortisol measurements available that were analyzed in relation to NR3C1 methylation levels. Baseline NR3C1 hypermethylation associated with future self-reports of recent use and use duration of any substance, before and after adjustment for potential confounders. The overall estimates were attenuated when considering lifetime use. Sex-stratified analyses revealed the strongest association for cigarette use in males. Cortisol analyses revealed associations between NR3C1 methylation and morning cortisol levels. Findings from this study suggest that saliva NR3C1 hypermethylation can predict substance use in middle adolescence. Additional longitudinal studies are warranted to confirm these findings.

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Early life stress and development: potential mechanisms for adverse outcomes

Journal of Neurodevelopmental Disorders ◽

10.1186/s11689-020-09337-y ◽

2020 ◽

Vol 12 (1) ◽

Author(s):

Karen E. Smith ◽

Seth D. Pollak

Keyword(s):

Individual Differences ◽

Life Stress ◽

Early Life ◽

Early Life Stress ◽

Adverse Outcomes ◽

Stressful Events ◽

Negative Effects ◽

Extreme Stress ◽

Wide Range ◽

Stress Influences

Abstract Background Chronic and/or extreme stress in early life, often referred to as early adversity, childhood trauma, or early life stress, has been associated with a wide range of adverse effects on development. However, while early life stress has been linked to negative effects on a number of neural systems, the specific mechanisms through which early life stress influences development and individual differences in children’s outcomes are still not well understood. Main text The current paper reviews the existing literature on the neurobiological effects of early life stress and their ties to children’s psychological and behavioral development. Conclusions Early life stress has persistent and pervasive effects on prefrontal–hypothalamic–amygdala and dopaminergic circuits that are at least partially mediated by alterations in hypothalamic–pituitary–adrenal axis function. However, to date, this research has primarily utilized methods of assessment that focus solely on children’s event exposures. Incorporating assessment of factors that influence children’s interpretation of stressors, along with stressful events, has the potential to provide further insight into the mechanisms contributing to individual differences in neurodevelopmental effects of early life stress. This can aid in further elucidating specific mechanisms through which these neurobiological changes influence development and contribute to risk for psychopathology and health disorders.

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