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

Addict Biol. 2020 Jul;25(4):e12791. doi: 10.1111/adb.12791. Epub 2019 Jun 13.


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.

Keywords: Netrin-1; Prefrontal cortex; cognitive control; guidance cues.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amphetamine / administration & dosage
  • Amphetamine / pharmacology*
  • Amphetamine-Related Disorders
  • Animals
  • Behavior, Animal / drug effects
  • Central Nervous System Stimulants / administration & dosage
  • Central Nervous System Stimulants / pharmacology*
  • DCC Receptor / drug effects*
  • DCC Receptor / genetics
  • DCC Receptor / metabolism
  • Dopaminergic Neurons / drug effects*
  • Dose-Response Relationship, Drug
  • Inhibition, Psychological
  • Male
  • Mice
  • MicroRNAs / drug effects*
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • Netrin-1 / drug effects
  • Netrin-1 / metabolism
  • Neural Pathways
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / metabolism
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / metabolism
  • RNA, Messenger / drug effects
  • RNA, Messenger / metabolism


  • Central Nervous System Stimulants
  • DCC Receptor
  • Dcc protein, mouse
  • MIRN218 microRNA, mouse
  • MicroRNAs
  • Ntn1 protein, mouse
  • RNA, Messenger
  • Netrin-1
  • Amphetamine