Nicotine in adolescence freezes dopamine circuits in an immature state

Nicotine use during adolescence is largely associated with negative long-term outcomes, including addiction to nicotine in adulthood. How nicotine acts on developing neurocircuitry in adolescence remains largely unknown, but may hold the key for informing more effective intervention efforts. We found transient nicotine exposure in early adolescence was sufficient for adult mice to show a marked vulnerability to nicotine. Brain-wide activity mapping showed that these mice had an enhanced response to an acute nicotine injection and widespread disruption of functional connectivity in comparison to controls, particularly within dopaminergic networks. Neurophysiological analysis further revealed that their ventral tegmental area (VTA) dopamine neurons show an immature basal plasticity signature and an adolescent-like imbalance in nicotine-induced activity between nucleus accumbens (NAc) and amygdala (AMG)-projecting pathways, known to respectively produce the reinforcing and anxiogenic effects of nicotine. The anxiogenic effect of nicotine is abolished in adult mice treated with nicotine in adolescence, strongly resembling the normal phenotype of young mice. Together these results suggest that nicotine exposure in adolescence somehow "froze" both their neural circuit and behavioral reaction to nicotine, carrying an adolescent-like vulnerability to the drug into adulthood. Finally, we are able to "thaw" the behavioral response to acute nicotine in adolescent-exposed mice by chemogenetically resetting the balance between the underlying NAc- and AMG-projecting dopamine circuits, restoring a mature anxiety-like response to acute nicotine. Together, our results highlight how diverse dopamine pathways can be impacted by experience in adolescence, and further suggest that the perseverance of a developmental imbalance between dopamine pathways may alter vulnerability profiles for later dopamine-dependent psychopathologies.