Adolescent THC Redirected Dopamine Wiring in Male Mice But Not Females

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.

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.

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 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.

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