Effects of Early Life Adversity on Substance Use Problems in Adolescents: Biobehavioral Risk Mechanisms - Substance use disorders (SUDs) have substantial healthcare and economic costs as well as accidental deaths from drug overdose. Adolescence is a critical period in which exposure to alcohol and other drugs markedly increases the risk for SUD. Early-life adversity (ELA), including interpersonal trauma and loss, family dysfunction and poverty, is highly prevalent and a well-established risk factor for SUD. Individuals with ELA have an earlier age of onset for the initiation and transition to SUD, greater severity and a more pernicious course, marked by a greater risk for relapse and poor treatment response, compared to counterparts without ELA. The neuroimmune network hypothesis postulates that ELA sensitizes the brain circuits involved in threat and reward processing via inflammation, initiating positive feedback loops between these systems. Also, inflammatory mediators engage these neural circuits, predisposing individuals to emotional dysregulation, and “self-medicating” behaviors, such as smoking and drug use. Such self-medicating behaviors in adolescence, a period of high neuronal plasticity, can exacerbate the neurotoxic effects of ELA, with a quicker transition from use to disorder. To our knowledge, this theory has not been tested empirically. Adolescent studies characterizing inflammatory processes in relation to ELA focused on non-specific systemic markers of inflammation which may lack sensitivity in young, healthy persons to detect the early signs of pathogenesis, and the mechanistic specificity to inform modifiable pathways, by which health disparities emerge during this developmental period. The proposed investigation addresses these theoretical and methodological issues in the following ways: (1) we will recruit adolescents, stratified based on ELA and oversampling the high-ELA group, without a prior history of substance misuse or SUD, to examine the probability of SUD onset over a 24-month prospective follow-up; (2) examine whether an inflammatory index comprising of vertically integrated measures (namely upregulated proinflammatory and reciprocal downregulated antiviral type 1 interferon genes, diminished intracellular glucocorticoid receptor signaling, increased circulating cytokines, and c-reactive protein) accounts for, partly, the association between ELA and SUD onset; (3) assess whether ELA interacts with certain clinical, biobehavioral and family-contextual factors in predicting vulnerability to, or protection against, SUD; and (4) explore whether SUD onset has a modulating influence on psychiatric, biobehavioral and family-contextual factors. By identifying the biobehavioral risk and protective factors during a critical developmental period, the study findings may help shift ELA research toward prevention and resilience and identify novel biobehavioral targets for clinical trials. The identified biobehavioral targets may elucidate for whom the intervention programs engage the underlying psychobiological processes that precede the emergence of behavioral symptoms and determine their role in the pathogenesis of SUD in this high-risk group. Ultimately, such knowledge can enhance precision care in mitigating SUD risk in ELA-exposed youth and allowing them to reach their full potential as adults and reducing the socioeconomic burden associated with early-onset SUD.
