Neurobehavioral pathways of polygenic and polyenvironmental effects on the onset and maintenance of substance involvement

PROJECT SUMMARY/ABSTRACT
Problematic substance use is associated with significant personal and socioeconomic costs (accounting for
approximately 5% of global disease burden and worldwide deaths). Substance use initiation, progression to
heavy use, and early onset substance use disorders (SUDs) commonly emerge during adolescence and young
adulthood. This developmental period of risk is theorized to result from typical patterns of regionally
asynchronous brain maturation (i.e., rapid and early development of limbic regions alongside relatively immature
prefrontal and multimodal association cortices) resulting in a diminished ability to suppress inappropriate
emotions, desires, and actions when salient environmental cues are present. During later young adulthood the
stabilization, reduction, or desistance of heavy use typically occurs alongside maturing cognitive control and
emotional regulation abilities coinciding with cortical development. Brain and behavioral maturation may also be
influenced by substance use. As genetic and environmental risk factors for substance involvement are
predominantly shared across substances, understanding the behavioral and neural mechanisms underlying
these shared risk factors in a developmental context will broadly improve our etiologic understanding of
substance involvement liability and refine treatment and prevention. In this 5-year R01 (responding to PAR-19-
162), we propose to test whether putative behavioral and neural mechanisms of stage-based addiction may link
broad spectrum SUD genomic liability and environmental risk to substance involvement trajectories from
childhood – young adulthood using longitudinal data from the Adolescent Brain and Cognitive Development
(ABCD) Study (N=11,875 followed from ages 9-16) along with other samples that uniquely extend the temporal
scope of ABCD to comprehensively examine brain-behavior developmental interplay related to substance use
and misuse (e.g., National Consortium on Alcohol and Neurodevelopment in Adolescence followed 830
individuals from ages 12-32). Disentangling the behavioral and neural mechanisms underlying broad spectrum
genetic and environmental liability to SUD will inform our etiologic understanding of substance use initiation,
escalation, and desistence that may ultimately contribute to substance-related policy, education, nosology,
prevention, and treatment. Primary deliverables from this project will be manuscripts evaluating whether behavior
and neural phenotypes may represent mechanisms underlying polygenic and polyenvironmental risk for
substance use disorders.

Grant Number: 5R01DA054750-05
NIH Institute/Center: NIH
Principal Investigator: RYAN BOGDAN