Adolescent THC Redirected Dopamine Wiring in Male Mice But Not Females | Research

The takeaway

THC exposure during adolescence diverted dopamine axon growth from the medial prefrontal cortex to the orbitofrontal cortex in male mice, altering impulse control, while female mice showed different molecular responses that may have protected their brain wiring.

Developmental neuroscientists, adolescent health researchers, parents, cannabis policy researchers

THC diverted dopamine axon growth from medial to orbitofrontal cortex in male mice only

What the researchers found

In males, adolescent THC reduced dopamine axon volume in the medial prefrontal cortex and reduced presynaptic sites, while increasing dopamine innervation in the orbitofrontal cortex, suggesting axons were rerouted. Males also showed increased premature responses but fewer commission errors on impulse control tasks. Females showed no dopamine wiring changes. Molecularly, males had increased DCC receptor and decreased miR-218 levels, while females showed decreased DCC without miR-218 changes and smaller microglia, potentially providing protection.

Why it matters

This study provides a specific biological mechanism for how adolescent THC disrupts brain development differently in males and females: by dysregulating a molecular guidance system (miR-218/DCC pathway) that directs where dopamine axons grow, causing them to wire to the wrong brain region in males.

The numbers in context

Males: reduced dopamine axon volume in medial PFC, reduced presynaptic site density, increased orbitofrontal innervation, increased premature responses, fewer commission errors; females: no dopamine changes, smaller microglia; males: increased DCC, decreased miR-218; females: decreased DCC, no miR-218 change

How the study worked

Adolescent mice received THC, and adult brains were analyzed for dopamine axon distribution, presynaptic sites, and molecular markers. Impulse control was assessed using the Go-No/Go task. Molecular analysis measured DCC receptor, miR-218, and microglial characteristics.

What this study cannot tell us

Mouse model may not translate to humans, specific THC doses and timing may differ from human adolescent use, only two brain regions assessed, single behavioral test for impulse control, no dose-response analysis, no recovery time assessed

How to read the evidence

Single animal study with novel mechanistic findings including molecular pathway identification; important sex-specific data but mouse model

When this study was published

Published 2025

The bigger picture

The finding that THC literally redirects where dopamine axons grow in the developing male brain is a more concerning mechanism than simple disruption. It suggests adolescent THC does not just impair the brain temporarily but may permanently alter its wiring diagram.

Questions still open

Does THC similarly redirect dopamine axon growth in human adolescents? Is this rewiring permanent or can it normalize with abstinence? Could the miR-218/DCC pathway be targeted to prevent or reverse THC-induced changes?

Common questions

Does THC affect the developing brain differently in males and females?

In mice, adolescent THC diverted dopamine wiring in male brains but not female brains. Males showed a molecular pathway disruption (miR-218/DCC) that caused dopamine axons to grow to the wrong brain region, while females had a protective response involving smaller microglia.

What does "redirected dopamine wiring" mean?

Dopamine axons normally grow from deeper brain regions to the medial prefrontal cortex during adolescence. THC disrupted the molecular guidance system in males, causing axons to grow to the orbitofrontal cortex instead, altering the brain's impulse control circuitry.

Read the original research

Divergent outcomes of delta 9 - tetrahydrocannabinol (THC) in adolescence on mesocortical dopamine and cognitive development in male and female mice.

Psychopharmacology, 242(10), 2181-2199

View on PubMed ↗Publisher’s paper ↗

Citation

Capolicchio, Tanya; Hernandez, Giovanni; Shi, Sammy Shun Wai; Dube, Emilie; Estrada, Katherina; Giroux, Michel; Nieman, Brian J; Pausova, Zdenka; Flores, Cecilia. (2025). Divergent outcomes of delta 9 - tetrahydrocannabinol (THC) in adolescence on mesocortical dopamine and cognitive development in male and female mice.. Psychopharmacology, 242(10), 2181-2199. https://doi.org/10.1007/s00213-025-06791-1