Adolescent nicotine induces depressive and anxiogenic effects through ERK 1‐2 and Akt‐GSK‐3 pathways and neuronal dysregulation in the nucleus accumbens

Long‐term tobacco dependence typically develops during adolescence and neurodevelopmental nicotine exposure is associated with affective disturbances that manifest as a variety of neuropsychiatric comorbidities in clinical and preclinical studies, including mood and anxiety‐related disorders. The nucleus accumbens shell (NASh) is critically involved in regulating emotional processing, and both molecular and neuronal disturbances in this structure are associated with mood and anxiety‐related pathologies. In the present study, we used a rodent model of adolescent neurodevelopmental nicotine exposure to examine the expression of several molecular biomarkers associated with mood/anxiety‐related phenotypes. We report that nicotine exposure during adolescence (but not adulthood) induces profound upregulation of the ERK 1‐2 and Akt‐GSK‐3 signalling pathways directly within the NASh, as well as downregulation of local D1R expression that persists into adulthood. These adaptations were accompanied by decreases in τ, α, β, and γ‐band oscillatory states, hyperactive medium spiny neuron activity with depressed bursting rates, and anxiety and depressive‐like behavioural abnormalities. Pharmacologically targeting these molecular and neuronal adaptations revealed that selective inhibition of local ERK 1‐2 and Akt‐GSK‐3 signalling cascades rescued nicotine‐induced high‐γ‐band oscillatory signatures and phasic bursting rates in the NASh, suggesting that they are involved in mediating adolescent nicotine‐induced depressive and anxiety‐like neuropathological trajectories. Adolescent nicotine exposure is linked to development of mood and anxiety disorders; however, the neurobiological mechanisms underlying this relationship are not understood. Using a preclinical adolescent nicotine exposure model, we identify the ERK1‐2 and Akt‐GSK‐3 signaling pathways in the nucleus accumbens shell as critical biomarkers underlying the persistent anhedonic and anxiety‐like phenotypes elicited by adolescent nicotine exposure. We also demonstrate reinstatement of GSK‐3 signaling restores high‐gamma amplitude in the NASh, mitigating behavioural and neuronal indices of mood and anxiety‐related phenotypes.