Developmental variation in dopamine neurobiology, neurocognitive functioning, and impulsivity shape substance use trajectories in youth

Parr, A. C.; Ojha, A.; Petrie, D.; Calabro, F.; Tervo-Clemmens, B.; Foran, W.; Fitzgerald, D.; Tapert, S.; Nooner, K.; Thompson, W.; Goldston, D.; Clark, D.; Luna, B.

doi:10.1101/2025.10.24.684358

bioRxiv · 10.1101/2025.10.24.684358

Developmental variation in dopamine neurobiology, neurocognitive functioning, and impulsivity shape substance use trajectories in youth

Parr, A. C.·Ojha, A.·Petrie, D.·Calabro, F.·Tervo-Clemmens, B.·Foran, W.·Fitzgerald, D.·Tapert, S.·Nooner, K.·Thompson, W.·Goldston, D.·Clark, D.·Luna, B.

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Abstract

Theoretical neurodevelopmental models implicate increases in dopamine (DA) function and limitations in neurocognitive control in risk-taking behavior, including substance use, during the transition from adolescence to adulthood. However, developmental relationships between DA, neurocognitive control, and the emergence of substance use are poorly understood. Here, we tested the role of basal ganglia tissue iron, reflecting DA neurophysiology, as well as impulsivity and inhibitory control in longitudinal developmental trajectories of substance use. We leveraged the National Consortium on Alcohol and NeuroDevelopment in Adolescence and Adulthood (NCANDA-A) cohort, a large, multisite longitudinal neuroimaging study of 807 participants (baseline ages 12 - 22 years old, 50% female, 1 - 9 annual visits per participant, 6164 sessions total). Substance use, inhibitory control, and tissue iron increased non-linearly during adolescence into young adulthood, concurrent with decreases in impulsivity. Non-linear Growth Mixture Models identified four common trajectories of substance use: low (no- or low levels of use across visits; 30% of participants), youth peak (peak use in adolescence/young adulthood followed by declines; 26%), adolescent increasing (early, steep linear increases in use from adolescence into adulthood; 17%), and adult increasing (low use in adolescence, followed by late linear increases into adulthood; 26%). We show that increased substance use was associated with a phenotype of high impulsivity, low inhibitory control, and low basal ganglia tissue iron, particularly in early adolescence in individuals who displayed youth peak patterns in substance use trajectories. These findings highlight that early developmental differences in DA-related neurobiology and associated impulsivity and cognitive control shape distinct trajectories of adolescent substance use, underscoring adolescence as a critical window for the early identification and implementation of neurodevelopmentally sensitive interventions for substance use disorders.

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Parr, A. C., Ojha, A., Petrie, D., Calabro, F., Tervo-Clemmens, B., Foran, W., Fitzgerald, D., Tapert, S., Nooner, K., Thompson, W., Goldston, D., Clark, D., Luna, B.. 2025-10-24. Developmental variation in dopamine neurobiology, neurocognitive functioning, and impulsivity shape substance use trajectories in youth. https://doi.org/10.1101/2025.10.24.684358

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