Amphetamine disrupts dopamine axon growth in adolescence by a sex-specific mechanism in mice

• Published in: Nature communications 2023-07, Vol.14 (1), p.4035-4035, Article 4035
• Main Authors: Reynolds, Lauren M., Hernandez, Giovanni, MacGowan, Del, Popescu, Christina, Nouel, Dominique, Cuesta, Santiago, Burke, Samuel, Savell, Katherine E., Zhao, Janet, Restrepo-Lozano, Jose Maria, Giroux, Michel, Israel, Sonia, Orsini, Taylor, He, Susan, Wodzinski, Michael, Avramescu, Radu G., Pokinko, Matthew, Epelbaum, Julia G., Niu, Zhipeng, Pantoja-Urbán, Andrea Harée, Trudeau, Louis-Éric, Kolb, Bryan, Day, Jeremy J., Flores, Cecilia
• Format: Article
• Language: English
• Subjects: 13/106; 14/63; 42/35; 42/44; 42/89; 45/88; 631/378/2571/2576; 631/378/2649/2150; 631/378/3920; 64/60; 82/29; Addictions; Adolescence; Adolescents; Amphetamines; Axonogenesis; Axons; Child development; Cognitive ability; DCC protein; Dopamine; Drug abuse; Drug use; Females; Humanities and Social Sciences; Males; Mesolimbic system; Molecular machines; multidisciplinary; Netrin-1; Phenotypes; Prefrontal cortex; Science; Science (multidisciplinary); Sex
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-39665-1

Initiating drug use during adolescence increases the risk of developing addiction or other psychopathologies later in life, with long-term outcomes varying according to sex and exact timing of use. The cellular and molecular underpinnings explaining this differential sensitivity to detrimental drug effects remain unexplained. The Netrin-1/DCC guidance cue system segregates cortical and limbic dopamine pathways in adolescence. Here we show that amphetamine, by dysregulating Netrin-1/DCC signaling, triggers ectopic growth of mesolimbic dopamine axons to the prefrontal cortex, only in early-adolescent male mice, underlying a male-specific vulnerability to enduring cognitive deficits. In adolescent females, compensatory changes in Netrin-1 protect against the deleterious consequences of amphetamine on dopamine connectivity and cognitive outcomes. Netrin-1/DCC signaling functions as a molecular switch which can be differentially regulated by the same drug experience as function of an individual’s sex and adolescent age, and lead to divergent long-term outcomes associated with vulnerable or resilient phenotypes. Adolescent drug use augments psychiatric risk. Here the authors show that abused drugs dysregulate adolescent Netrin-1/DCC signaling, triggering ectopic long-distance dopamine axon growth in males while Netrin1 compensatory events protect females.