Divergent outcomes of delta 9 - tetrahydrocannabinol (THC) in adolescence on mesocortical dopamine and cognitive development in male and female mice.
Tanya Capolicchio, Giovanni Hernandez, Sammy Shun Wai Shi, Emilie Dube, Katherina Estrada, Michel Giroux, Brian J Nieman, Zdenka Pausova, Cecilia Flores
Psychopharmacology October 2025 DOI: 10.1007/s00213-025-06791-1 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental animal study Peer reviewed |
|---|---|
| Population | Adolescent mice (males and females) later assessed in adulthood |
| Intervention | delta 9-tetrahydrocannabinol (THC) |
| Measures | Go-No/Go task |
| Topics | Cannabis |
| Keywords | Adolescence Dcc Dopamine Impulsivity Mir- 218 Mice Microglia Prefrontal cortex |
| Key findings | Adolescent THC exposure in male mice reduced dopamine axon volume and presynaptic site density in the medial prefrontal cortex while increasing dopamine innervation in the orbitofrontal cortex, and altered impulse control (more premature responses, fewer commission errors). Females showed no dopamine innervation changes. The authors propose that THC dysregulates the miR-218/DCC pathway in males, mistargeting dopamine axons, and highlight sex-specific molecular and epigenetic processes. |
Abstract
The increasing exposure to delta 9-tetrahydrocannabinol (THC) in youth sparks concerns about disruption of ongoing neurodevelopment. During adolescence, dopamine axons continue to grow from the striatum to the prefrontal cortex, promoting the refinement of inhibitory control. This process is coordinated by the Netrin-1 receptor, DCC, which is regulated by microRNA miR-218. In addition, microglial actions significantly influence adolescent cortical refinement. Here, we show that THC in adolescent mice has sex-specific effects on dopamine innervation in the adult prefrontal cortex. While females show no changes, in males, THC leads to a reduction in the volume occupied by dopamine axons in the medial prefrontal cortex and a decrease in the density of their presynaptic sites. However, it increases dopamine innervation in the orbitofrontal cortex. Assessment of the effects of THC in adolescence on impulse control in adulthood, using the Go-No/Go task, revealed male-specific alterations - THC increased premature responding but reduced the number of commission errors. Molecular analysis showed that, one week after adolescent THC, males display increased Dcc and decreased miR-218 levels. In contrast, females exhibit decreased Dcc levels without changes in miR-218. Furthermore, in the medial prefrontal cortex, females show smaller microglia soma size, potentially mitigating the impact of decreased Dcc on dopamine development. These findings suggest that in adolescent males, THC dysregulates the miR-218/DCC pathway, prompting mistargeting of dopamine axons and diverting their growth from medial to orbitofrontal regions. This work highlights the sex-specific impact of adolescent THC on dopamine and impulse control development and uncovers potential divergent molecular and epigenetic processes.
Comparable studies
Other preclinical and animal studies on cannabis, most cited first.
Citations in the library
Cites 11
- Chronic adolescent exposure to cannabis in mice leads to sex-biased changes in gene expression networks across brain regions Neuropsychopharmacology August 22, 2022
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- Investigating the "two-hit hypothesis": Effects of prenatal maternal immune activation and adolescent cannabis use on neurodevelopment in mice. Progress in Neuro-Psychopharmacology and Biological Psychiatry January 10, 2023
- Sex and age specific effects of delta-9-tetrahydrocannabinol during the periadolescent period in the rat: The unique susceptibility of the prepubescent animal. Neurotoxicology and Teratology 2016
- Adolescent exposure to THC in female rats disrupts developmental changes in the prefrontal cortex. Neurobiology of Disease 2015
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