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

Lauren M. Reynolds, Giovanni Hernandez, Del MacGowan, Christina Popescu, Dominique Nouel, Santiago Cuesta, Samuel Burke, Katherine E. Savell, Janet Zhao, Jose Maria Restrepo-Lozano, Michel Giroux, Sonia Israel, Taylor Orsini, Susan He, Michael Wodzinski, Radu G. Avramescu, Matthew Pokinko, Julia G. Epelbaum, Zhipeng Niu, Andrea Harée Pantoja-Urbán, Louis-Éric Trudeau, Bryan Kolb, Jeremy J. Day and Cecilia Flores ()
Additional contact information
Lauren M. Reynolds: McGill University
Giovanni Hernandez: Douglas Mental Health University Institute
Del MacGowan: McGill University
Christina Popescu: McGill University
Dominique Nouel: Douglas Mental Health University Institute
Santiago Cuesta: Douglas Mental Health University Institute
Samuel Burke: Université de Montréal
Katherine E. Savell: University of Alabama at Birmingham
Janet Zhao: Douglas Mental Health University Institute
Jose Maria Restrepo-Lozano: McGill University
Michel Giroux: Douglas Mental Health University Institute
Sonia Israel: Douglas Mental Health University Institute
Taylor Orsini: Douglas Mental Health University Institute
Susan He: Douglas Mental Health University Institute
Michael Wodzinski: Douglas Mental Health University Institute
Radu G. Avramescu: Douglas Mental Health University Institute
Matthew Pokinko: McGill University
Julia G. Epelbaum: Douglas Mental Health University Institute
Zhipeng Niu: Douglas Mental Health University Institute
Andrea Harée Pantoja-Urbán: McGill University
Louis-Éric Trudeau: Université de Montréal
Bryan Kolb: University of Lethbridge
Jeremy J. Day: University of Alabama at Birmingham
Cecilia Flores: Douglas Mental Health University Institute

Nature Communications, 2023, vol. 14, issue 1, 1-22

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-39665-1

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