DCC-related developmental effects of abused- versus therapeutic-like amphetamine doses in adolescence.

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  • Additional Information
    • Affiliation:
      Department of Psychiatry and Department of Neurology and Neurosurgery, McGill University, Douglas Mental Health University Institute, Montreal, Quebec, Canada
      Integrated Program in Neuroscience, McGill University, Montreal, Quebec, Canada
      Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore Maryland
    • Abstract:
      The guidance cue receptor DCC controls mesocortical dopamine development in adolescence. Repeated exposure to an amphetamine regimen of 4 mg/kg during early adolescence induces, in male mice, downregulation of DCC expression in dopamine neurons by recruiting the Dcc microRNA repressor, microRNA-218 (miR-218). This adolescent amphetamine regimen also disrupts mesocortical dopamine connectivity and behavioral control in adulthood. Whether low doses of amphetamine in adolescence induce similar molecular and developmental effects needs to be established. Here, we quantified plasma amphetamine concentrations in early adolescent mice following a 4 or 0.5 mg/kg dose and found peak levels corresponding to those seen in humans following recreational and therapeutic settings, respectively. In contrast to the high doses, the low amphetamine regimen does not alter Dcc mRNA or miR-218 expression; instead, it upregulates DCC protein levels. Furthermore, high, but not low, drug doses downregulate the expression of the DCC receptor ligand, Netrin-1, in the nucleus accumbens and prefrontal cortex. Exposure to the low-dose regimen did not alter the expanse of mesocortical dopamine axons or their number/density of presynaptic sites in adulthood. Strikingly, adolescent exposure to the low-dose drug regimen does not impair behavioral inhibition in adulthood; instead, it induces an overall increase in performance in a go/no-go task. These results show that developmental consequences of exposure to therapeutic- versus abused-like doses of amphetamine in adolescence have dissimilar molecular signatures and opposite behavioral effects. These findings have important clinical relevance since amphetamines are widely used for therapeutic purposes in youth.
    • Journal Subset:
      Biomedical; Peer Reviewed; USA
    • ISSN:
      1355-6215
    • MEDLINE Info:
      PMID: NLM31192517 NLM UID: 9604935
    • Grant Information:
      F31 DA041188/DA/NIDA NIH HHS/United States; MOP-74709//CIHR/Canada; R01 DA037911/DA/NIDA NIH HHS/United States
    • Publication Date:
      In Process
    • Publication Date:
      20200804
    • DOI:
      http://dx.doi.org/10.1111/adb.12791
    • Accession Number:
      143798223
  • Citations
    • ABNT:
      CUESTA, S. et al. DCC-related developmental effects of abused- versus therapeutic-like amphetamine doses in adolescence. Addiction Biology, [s. l.], v. 25, n. 4, p. 1–11, 2020. DOI 10.1111/adb.12791. Disponível em: http://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=rzh&AN=143798223. Acesso em: 12 ago. 2020.
    • AMA:
      Cuesta S, Restrepo LJM, Popescu C, et al. DCC-related developmental effects of abused- versus therapeutic-like amphetamine doses in adolescence. Addiction Biology. 2020;25(4):1-11. doi:10.1111/adb.12791
    • APA:
      Cuesta, S., Restrepo, L. J. M., Popescu, C., He, S., Reynolds, L. M., Israel, S., Hernandez, G., Rais, R., Slusher, B. S., Flores, C., & Restrepo-Lozano, J. M. (2020). DCC-related developmental effects of abused- versus therapeutic-like amphetamine doses in adolescence. Addiction Biology, 25(4), 1–11. https://doi.org/10.1111/adb.12791
    • Chicago/Turabian: Author-Date:
      Cuesta, Santiago, Lozano, José Maria Restrepo, Christina Popescu, Susan He, Lauren M. Reynolds, Sonia Israel, Giovanni Hernandez, et al. 2020. “DCC-Related Developmental Effects of Abused- versus Therapeutic-like Amphetamine Doses in Adolescence.” Addiction Biology 25 (4): 1–11. doi:10.1111/adb.12791.
    • Harvard:
      Cuesta, S. et al. (2020) ‘DCC-related developmental effects of abused- versus therapeutic-like amphetamine doses in adolescence’, Addiction Biology, 25(4), pp. 1–11. doi: 10.1111/adb.12791.
    • Harvard: Australian:
      Cuesta, S, Restrepo, LJM, Popescu, C, He, S, Reynolds, LM, Israel, S, Hernandez, G, Rais, R, Slusher, BS, Flores, C & Restrepo-Lozano, JM 2020, ‘DCC-related developmental effects of abused- versus therapeutic-like amphetamine doses in adolescence’, Addiction Biology, vol. 25, no. 4, pp. 1–11, viewed 12 August 2020, .
    • MLA:
      Cuesta, Santiago, et al. “DCC-Related Developmental Effects of Abused- versus Therapeutic-like Amphetamine Doses in Adolescence.” Addiction Biology, vol. 25, no. 4, July 2020, pp. 1–11. EBSCOhost, doi:10.1111/adb.12791.
    • Chicago/Turabian: Humanities:
      Cuesta, Santiago, Lozano, José Maria Restrepo, Christina Popescu, Susan He, Lauren M. Reynolds, Sonia Israel, Giovanni Hernandez, et al. “DCC-Related Developmental Effects of Abused- versus Therapeutic-like Amphetamine Doses in Adolescence.” Addiction Biology 25, no. 4 (July 2020): 1–11. doi:10.1111/adb.12791.
    • Vancouver/ICMJE:
      Cuesta S, Restrepo LJM, Popescu C, He S, Reynolds LM, Israel S, et al. DCC-related developmental effects of abused- versus therapeutic-like amphetamine doses in adolescence. Addiction Biology [Internet]. 2020 Jul [cited 2020 Aug 12];25(4):1–11. Available from: http://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=rzh&AN=143798223