# Amphetamine in adolescence induces a sex-specific mesolimbic dopamine phenotype in the adult prefrontal cortex

## TL;DR

Amphetamine use in adolescent males reroutes dopamine pathways to the prefrontal cortex, increasing drug vulnerability in adulthood.

## Contribution

The study reveals a sex-specific mechanism linking adolescent amphetamine exposure to adult dopamine dysfunction in males.

## Key findings

- Amphetamine in adolescence reroutes dopamine axons to the prefrontal cortex in male mice.
- This leads to increased dopamine transporter expression and exaggerated responses to methylphenidate in adulthood.
- CRISPRa upregulation of DCC prevents these effects in adolescent males.

## Abstract

Drugs of abuse in adolescence impact brain maturation and increase psychiatric risk, with differences in sensitivity between males and females. Amphetamine in early adolescence (postnatal day; PND 21 ± 1–32 ± 1) in male, but not female mice, causes dopamine axons intended to innervate the nucleus accumbens and to grow ectopically to the prefrontal cortex (PFC). This is mediated by drug-induced downregulation of the Netrin-1 receptor DCC. How off-target dopamine axons function in the adult PFC remains to be determined. Here we report that males and females show place preference for amphetamine in early adolescence. However, only in males, amphetamine increases PFC dopamine transporter expression in adulthood (PND 101 ± 15): leading to aberrant baseline dopamine transients, faster dopamine release, and exaggerated responses to acute methylphenidate. Upregulation of DCC in adolescence, using CRISPRa, prevents all these changes. Mesolimbic dopamine axons rerouted to the PFC in adolescence retain anatomical and functional phenotypes of their intended target, rendering males enduringly vulnerable to the harmful effects of drugs of abuse.

In males, amphetamine in adolescence misroutes mesolimbic dopamine axons to the PFC, increasing DAT levels and methylphenidate-induced dopamine release in the adult PFC; CRISPRa-driven DCC receptor upregulation in adolescence prevents these effects.