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

doi:10.1007/s00213-025-06791-1

. 2025 Jul 14.

doi: 10.1007/s00213-025-06791-1. Online ahead of print.

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

Tanya Capolicchio^{1

2}, Giovanni Hernandez², Sammy Shun Wai Shi^{3

4}, Emilie Dube², Katherina Estrada², Michel Giroux², Brian J Nieman^{3

4

5

6}, Zdenka Pausova^{7

8}, Cecilia Flores^{9

10

11

12}

Affiliations

¹ Integrated Program in Neuroscience, McGill University, Montréal, QC, Canada.
² Douglas Mental Health University Institute, 6875 Boulevard LaSalle, Montreal, QC, H4H 1R3, Canada.
³ The Hospital for Sick Children, Translational Medicine, Toronto, ON, Canada.
⁴ Mouse Imaging Centre, Hospital for Sick Children, Toronto, ON, Canada.
⁵ Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
⁶ Ontario Institute for Cancer Research, Toronto, ON, Canada.
⁷ Departments of Physiology and Nutritional Sciences, University of Montreal, Montreal, QC, Canada.
⁸ CHU-St. Justine, Montreal, QC, Canada.
⁹ Douglas Mental Health University Institute, 6875 Boulevard LaSalle, Montreal, QC, H4H 1R3, Canada. Florescecilia.flores@mcgill.ca.
¹⁰ Department of Psychiatry, McGill University, Montréal, QC, Canada. Florescecilia.flores@mcgill.ca.
¹¹ Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada. Florescecilia.flores@mcgill.ca.
¹² Ludmer Centre for Neuroinformatics & Mental Health, McGill University, Montréal, QC, Canada. Florescecilia.flores@mcgill.ca.

PMID: 40658196
DOI: 10.1007/s00213-025-06791-1

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

Tanya Capolicchio et al. Psychopharmacology (Berl). 2025.

. 2025 Jul 14.

doi: 10.1007/s00213-025-06791-1. Online ahead of print.

Authors

Affiliations

¹ Integrated Program in Neuroscience, McGill University, Montréal, QC, Canada.
² Douglas Mental Health University Institute, 6875 Boulevard LaSalle, Montreal, QC, H4H 1R3, Canada.
³ The Hospital for Sick Children, Translational Medicine, Toronto, ON, Canada.
⁴ Mouse Imaging Centre, Hospital for Sick Children, Toronto, ON, Canada.
⁵ Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
⁶ Ontario Institute for Cancer Research, Toronto, ON, Canada.
⁷ Departments of Physiology and Nutritional Sciences, University of Montreal, Montreal, QC, Canada.
⁸ CHU-St. Justine, Montreal, QC, Canada.
⁹ Douglas Mental Health University Institute, 6875 Boulevard LaSalle, Montreal, QC, H4H 1R3, Canada. Florescecilia.flores@mcgill.ca.
¹⁰ Department of Psychiatry, McGill University, Montréal, QC, Canada. Florescecilia.flores@mcgill.ca.
¹¹ Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada. Florescecilia.flores@mcgill.ca.
¹² Ludmer Centre for Neuroinformatics & Mental Health, McGill University, Montréal, QC, Canada. Florescecilia.flores@mcgill.ca.

PMID: 40658196
DOI: 10.1007/s00213-025-06791-1

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.

Keywords: Adolescence; Dcc; Dopamine; Impulsivity; MiR- 218; Mice; Microglia; Prefrontal cortex; THC.

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Conflict of interest statement

Declarations. Ethical approval: Experimental procedures were all performed in accordance with the guidelines of the Canadian Council of Animal Care and approved by the McGill University and the Douglas Hospital Animal Care Committee. Competing interest: The authors declare no conflict of interest.

References

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1. Avramescu RG, Hernandez G, Flores C (2024) Rewiring the future: drugs abused in adolescence may predispose to mental illness in adult life by altering dopamine axon growth. J Neural Transmiss 131(5):461–7. https://doi.org/10.1007/s00702-023-02722-6 - DOI

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[1] Areal LB, Blakely RD (2020) Neurobehavioral changes arising from early life dopamine signaling perturbations. Neurochem Int 137:104747. https://doi.org/10.1016/j.neuint.2020.104747 - DOI - PubMed - PMC

[2] Areal LB, Blakely RD (2020) Neurobehavioral changes arising from early life dopamine signaling perturbations. Neurochem Int 137:104747. https://doi.org/10.1016/j.neuint.2020.104747 - DOI - PubMed - PMC

[3] Auger ML, Schmidt ERE, Manitt C et al (2013) unc5c haploinsufficient phenotype: striking similarities with the dcc haploinsufficiency model. Eur J Neurosci 38:2853–2863. https://doi.org/10.1111/ejn.12270 - DOI - PubMed

[4] Auger ML, Schmidt ERE, Manitt C et al (2013) unc5c haploinsufficient phenotype: striking similarities with the dcc haploinsufficiency model. Eur J Neurosci 38:2853–2863. https://doi.org/10.1111/ejn.12270 - DOI - PubMed

[5] Avants BB, Tustison N, Song G. Advanced normalization tools (ANTS). Insight J. 2009 2(365):1-35. https://doi.org/10.54294/uvnhin

[6] Avants BB, Tustison N, Song G. Advanced normalization tools (ANTS). Insight J. 2009 2(365):1-35. https://doi.org/10.54294/uvnhin

[7] Avramescu RG, Flores C (2023) We’re not in Kansas anymore: ectopic dopaminergic terminals as an explanation for the positive symptoms in psychiatric pathology. J Psychiatry Neurosci 48:E74–E77. https://doi.org/10.1503/jpn.230015 - DOI - PubMed - PMC

[8] Avramescu RG, Flores C (2023) We’re not in Kansas anymore: ectopic dopaminergic terminals as an explanation for the positive symptoms in psychiatric pathology. J Psychiatry Neurosci 48:E74–E77. https://doi.org/10.1503/jpn.230015 - DOI - PubMed - PMC

[9] Avramescu RG, Hernandez G, Flores C (2024) Rewiring the future: drugs abused in adolescence may predispose to mental illness in adult life by altering dopamine axon growth. J Neural Transmiss 131(5):461–7. https://doi.org/10.1007/s00702-023-02722-6 - DOI

[10] Avramescu RG, Hernandez G, Flores C (2024) Rewiring the future: drugs abused in adolescence may predispose to mental illness in adult life by altering dopamine axon growth. J Neural Transmiss 131(5):461–7. https://doi.org/10.1007/s00702-023-02722-6 - DOI

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

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

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