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

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.

Dopamine Axon Targeting in the Nucleus Accumbens in Adolescence Requires Netrin-1

“…Environmental risk or protective factors for psychopathology may impact the development of this system by regulating DCC and/or Netrin-1 expression in adolescence. Adolescent exposure to recreational-like doses of amphetamine [i.e., doses that reach peak plasma concentrations within the range of those seen in recreational use ( Cuesta et al, 2019 )] downregulates both DCC in dopamine neurons and Netrin-1 in the NAcc, disrupting the development of dopamine circuitry and of cognitive control ( Yetnikoff et al, 2010 ; Reynolds et al, 2015 , 2018 ; Cuesta et al, 2018 , 2019 ; Reynolds and Flores, 2019 ). In contrast, therapeutic-like doses of amphetamine [i.e., doses that reach peak plasma concentrations within the range of those observed in therapeutic settings ( Cuesta et al, 2019 )] upregulate DCC protein expression without altering Netrin-1, leading to protective-like phenotypes.…”

Mesocorticolimbic Dopamine Pathways Across Adolescence: Diversity in Development

“…Exposure to recreational-like doses of amphetamine in early adolescence, but not later in life, leads to a dramatic increase in the volume of PFC DA innervation, altered DA function, and long-term impairments in cognitive control in male mice (Reynolds et al, 2015Hoops et al, 2018;Reynolds and Flores, 2019). These effects are not observed following exposure to therapeutic-like amphetamine doses, which instead increases DCC protein expression in the VTA and leads to the overall improvement in cognitive performance in adulthood (Cuesta et al, 2019), in line with reports in non-human primates (Soto et al, 2012). Studies of how experience regulates Netrin-1/DCC expression in female mice are ongoing, but their bidirectional regulation already observed in male mice indicates that the Netrin-1/DCC system can be viewed more as a molecular target of plasticity rather than a target of vulnerability.…”

“…Both Netrin-1 and DCC levels expression can encode the effects of experience on DA circuitry. Notably, repeated exposure to amphetamine downregulates DCC in the VTA and Netrin-1 in the NAc, in early adolescence (Yetnikoff et al, 2007(Yetnikoff et al, , 2011(Yetnikoff et al, , 2014bCuesta et al, 2018Cuesta et al, , 2019, overlapping with the period that mesolimbic DA axons are undergoing targeting events. Drug-induced DCC downregulation requires D2 receptor signaling (Cuesta et al, 2018), reinforcing the link between DCC function and mesolimbic DA axon targeting in adolescence, as mesocortical DA neurons lack D2 receptors (Lammel et al, 2008).…”

The Netrin-1/DCC guidance system: dopamine pathway maturation and psychiatric disorders emerging in adolescence

“…In adulthood, but not in adolescence, Netrin-1 haploinsufficient mice exhibit increased medial PFC (mPFC) dopamine concentrations and reduced sensitivity to the behavioral effects of amphetamine [48]. Finally, adolescent amphetamine administration alters the expression of both DCC in dopamine neurons and Netrin-1 in the NAcc and mPFC [52].…”