Protective Role of Netrin‐1 in the Female Nucleus Accumbens Following Amphetamine Exposure in Adolescence

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.