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

Abstract

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.

Nicotine on the developing brain

“…In addition to being an important hub for reward processing, the NAc shell is critically involved in regulating emotional processing [ 152 , 153 ]. As with the PFC, nicotine exposure during adolescence (P35–44) upregulates ERK 1/2 and Akt-GSK-3 signaling pathways within the NAc and downregulates D1R expression into adulthood [ 154 ]. These changes are accompanied by alterations in neuronal firing patterns within the NAc, and anxiety and depressive-like behavioral abnormalities.…”

Akt and its phosphorylation in nucleus accumbens mediate heroin‐seeking behavior induced by cues in rats

“…Methamphetamine‐induced behavioral sensitization required increased levels of the NMDA Receptor 2B (GluN2B)‐PP2A‐Akt cascade in the dorsal striatum 11 . Nicotine exposure during adolescence induces the profound upregulation of the Akt‐ glycogen synthase kinase 3(GSK‐3) signaling pathways directly within the NAc 12 . Furthermore, the p‐Akt level in the NAc is reduced when rats are re‐exposed to the cues associated cocaine memories in conditioned place preference model 13 .…”

“… 11 Nicotine exposure during adolescence induces the profound upregulation of the Akt‐ glycogen synthase kinase 3(GSK‐3) signaling pathways directly within the NAc. 12 Furthermore, the p‐Akt level in the NAc is reduced when rats are re‐exposed to the cues associated cocaine memories in conditioned place preference model. 13 However, the mechanisms underlying the regulation of p‐Akt in the incubation of heroin seeking after withdrawal or cues‐induced heroin‐seeking behavior remains largely unknown.…”

Does nicotine exposure during adolescence modify the course of schizophrenia-like symptoms? Behavioral analysis in a phencyclidine-induced mice model

“…In SCHZ, the hyperfunctioning of this system may be due to an imbalance in mesolimbic signaling through VTA dopaminergic neurons and their output D1 and D2 receptor substrates in the nucleus accumbens, which results in D2 receptors overactivation [ 26 ]. In turn, in rats treated with nicotine during adolescence but not at adulthood, a marked decrease in the expression of accumbal D1 receptors was evident following exposure, which lasted until young adulthood [ 80 ]. Considering that the coordinated activation of D1 and D2 receptors is necessary for proper reward-guided behaviors to take place [ 81 ], this D1 receptors downregulation may counterbalance the D2 overactivation that is characteristic of SCHZ and, as a result, contribute both to the reduced locomotor activity in adolescent PCP-NIC mice when compared to PCP ones and to hampering the development of phencyclidine-evoked locomotor sensitization in PCP-NIC mice.…”