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Initiation of drug use during adolescence is a strong predictor of both the incidence and severity of addiction throughout the lifetime. Intriguingly, adolescence is a period of dynamic refinement in the organization of neuronal connectivity, in particular medial prefrontal cortex (mPFC) dopamine circuitry. The guidance cue receptor, DCC (deleted in colorectal cancer), is highly expressed by dopamine neurons and orchestrates their innervation to the mPFC during adolescence. Furthermore, we have shown that amphetamine in adolescence regulates DCC expression in dopamine neurons. Drugs in adolescence may therefore induce their enduring behavioral effects via DCC-mediated disruption in mPFC dopamine development. In this study, we investigated the impact of repeated exposure to amphetamine during adolescence on both the development of mPFC dopamine connectivity and on salience attribution to drug context in adulthood. We compare these effects to those induced by adult exposure to an identical amphetamine regimen. Finally, we determine whether DCC signaling within dopamine neurons is necessary for these events. Exposure to amphetamine in adolescence, but not in adulthood, leads to an increase in the span of dopamine innervation to the mPFC, but a reduction of presynaptic sites present on these axons. Amphetamine treatment in adolescence, but not in adulthood, also produces an increase in salience attribution to a previously drug-paired context in adulthood. Remarkably, DCC signaling within dopamine neurons is required for both of these effects. Drugs of abuse in adolescence may therefore induce their detrimental behavioral consequences by disrupting mesocortical dopamine development through alterations in the DCC signaling cascade.

Amphetamine in Adolescence Disrupts the Development of Medial Prefrontal Cortex Dopamine Connectivity in a dcc-Dependent Manner