Amphetamine disrupts dopamine axon growth in adolescence by a sex-specific mechanism in mice
Lauren M. Reynolds, Giovanni Hernández, Del MacGowan, Christina Popescu, Dominique Nouel, Santiago Cuesta, Samuel Burke, Katherine E. Savell, Janet M. Zhao, Jose M. 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, Cecilia Flores
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.