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

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. Exposure to psychostimulants during adolescence increases psychiatric vulnerability by disrupting prefrontal cortex maturation. Here, we administered therapeutic‐ or recreational‐like amphetamine doses to adolescent male mice to assess (a) miR‐218/DCC/Netrin‐1 expression and (b) mesocortical dopamine development and behavioral control in adulthood. The recreational‐like regimen disrupts miR218/DCC/Netrin‐1 expression, leading to reduced mesocortical dopamine connectivity and to increased impulsivity. In stark contrast, therapeutic doses increase DCC expression, do not deplete mesocortical dopamine axons from presynaptic sites, and actually improve overall cognitive performance.