Protective Role of Netrin‐1 in the Female Nucleus Accumbens Following Amphetamine Exposure in Adolescence
5 affiliations
- 1Integrated Program in Neuroscience McGill University Montreal Quebec Canada
- 2Douglas Mental Health University Institute Montreal Quebec Canada
- 3Department of Psychiatry, Faculty of Medicine McGill University Montreal Quebec Canada
- 4Department of Neurology and Neurosurgery, Faculty of Medicine McGill University Montreal Quebec Canada
- 5Ludmer Centre for Neuroinformatics & Mental Health McGill University Montreal Quebec Canada
Abstract
Adolescence is a period of mesocorticolimbic dopamine remodelling, when exposure to drugs of abuse can alter axon targeting and synaptic maturation. In adolescent male rodents, amphetamine causes dopamine axon mistargeting and long‐term cognitive deficits via downregulation of the Netrin‐1/DCC guidance system. In females, compensatory Netrin‐1 protein upregulation in the nucleus accumbens protects against these effects. How Netrin‐1 expression in the nucleus accumbens is regulated and what role it plays in local synaptic architecture remain unclear. Here, we mapped Netrin‐1 mRNA (Ntn1) across development in nucleus accumbens medium spiny neurons, assessed the role of dopamine D1 and D2 receptor signalling in Netrin‐1 protein expression and examined whether Netrin‐1 maintains medium spiny neuron dendritic spine architecture following adolescent amphetamine exposure. We found that medium spiny neurons, particularly those co‐expressing D1 and D2 receptors, were the principal source of Ntn1 mRNA in the nucleus accumbens in both sexes, with expression declining from early adolescence to adulthood. In adolescent females, systemic blockade of either D1 or D2 receptors reduced nucleus accumbens Netrin‐1 protein levels under both baseline and amphetamine‐exposed conditions. Although amphetamine did not alter Ntn1 mRNA in the nucleus accumbens, it increased its expression in the ventral tegmental area, suggesting a potential contribution from afferent projections. These findings indicate that Netrin‐1 upregulation in adolescent females is dopamine‐dependent and may protect against amphetamine‐induced circuit disruption, possibly involving pre‐ and postsynaptic mechanisms.
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BibTeX
@article{teixeira2026protective,
title = {{Protective Role of Netrin‐1 in the Female Nucleus Accumbens Following Amphetamine Exposure in Adolescence}},
author = {Maxime Teixeira and Del MacGowan and Radu Gabriel Avramescu and Annabel Zhu and Zhipeng Niu and Ashraf Mahmud and Giovanni Hernandez and Cecilia Flores},
journal = {The European Journal of Neuroscience},
year = {2026},
month = nov,
doi = {10.1111/ejn.70743},
url = {https://doi.org/10.1111/ejn.70743},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Protective Role of Netrin‐1 in the Female Nucleus Accumbens Following Amphetamine Exposure in Adolescence
AU - Maxime Teixeira
AU - Del MacGowan
AU - Radu Gabriel Avramescu
AU - Annabel Zhu
AU - Zhipeng Niu
AU - Ashraf Mahmud
AU - Giovanni Hernandez
AU - Cecilia Flores
PY - 2026
DA - 2026/11/04
JO - The European Journal of Neuroscience
DO - 10.1111/ejn.70743
UR - https://doi.org/10.1111/ejn.70743
AB - Adolescence is a period of mesocorticolimbic dopamine remodelling, when exposure to drugs of abuse can alter axon targeting and synaptic maturation. In adolescent male rodents, amphetamine causes dopamine axon mistargeting and long‐term cognitive deficits via downregulation of the Netrin‐1/DCC guidance system. In females, compensatory Netrin‐1 protein upregulation in the nucleus accumbens protects against these effects. How Netrin‐1 expression in the nucleus accumbens is regulated and what role it plays in local synaptic architecture remain unclear. Here, we mapped Netrin‐1 mRNA (Ntn1) across development in nucleus accumbens medium spiny neurons, assessed the role of dopamine D1 and D2 receptor signalling in Netrin‐1 protein expression and examined whether Netrin‐1 maintains medium spiny neuron dendritic spine architecture following adolescent amphetamine exposure. We found that medium spiny neurons, particularly those co‐expressing D1 and D2 receptors, were the principal source of Ntn1 mRNA in the nucleus accumbens in both sexes, with expression declining from early adolescence to adulthood. In adolescent females, systemic blockade of either D1 or D2 receptors reduced nucleus accumbens Netrin‐1 protein levels under both baseline and amphetamine‐exposed conditions. Although amphetamine did not alter Ntn1 mRNA in the nucleus accumbens, it increased its expression in the ventral tegmental area, suggesting a potential contribution from afferent projections. These findings indicate that Netrin‐1 upregulation in adolescent females is dopamine‐dependent and may protect against amphetamine‐induced circuit disruption, possibly involving pre‐ and postsynaptic mechanisms.
SN - 0953-816X
SN - 1460-9568
ER -