Amphetamine disrupts dopamine axon growth in adolescence by a sex-specific mechanism in mice
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Published:2023-07-07
Issue:1
Volume:14
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Reynolds Lauren M.ORCID, Hernandez Giovanni, MacGowan Del, Popescu ChristinaORCID, Nouel Dominique, Cuesta SantiagoORCID, Burke Samuel, Savell Katherine E.ORCID, Zhao Janet, Restrepo-Lozano Jose Maria, Giroux Michel, Israel SoniaORCID, Orsini Taylor, He Susan, Wodzinski Michael, Avramescu Radu G., Pokinko Matthew, Epelbaum Julia G., Niu Zhipeng, Pantoja-Urbán Andrea Harée, Trudeau Louis-ÉricORCID, Kolb Bryan, Day Jeremy J.ORCID, Flores CeciliaORCID
Abstract
AbstractInitiating 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.
Funder
U.S. Department of Health & Human Services | NIH | National Institute on Drug Abuse Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada Gouvernement du Canada | Canadian Institutes of Health Research
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
Reference117 articles.
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