Addiction Research Group, University of Western Ontario, London, Ontario, Canada.
Department of Anatomy and Cell Biology, University of Western Ontario London, London, Ontario, Canada.
Addict Biol. 2021 Mar;26(2):e12891. doi: 10.1111/adb.12891. Epub 2020 Mar 5.
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.
长期的烟草依赖通常在青少年时期发展，神经发育性尼古丁暴露与情感障碍有关，这些障碍在临床和临床前研究中表现为各种神经精神共病，包括情绪和焦虑相关障碍。伏隔核壳（NASh）在调节情绪处理方面起着至关重要的作用，该结构中的分子和神经元紊乱与情绪和焦虑相关的病理有关。在本研究中，我们使用了一种青少年神经发育性尼古丁暴露的啮齿动物模型，研究了与情绪/焦虑相关表型相关的几种分子生物标志物的表达。我们报告说，青春期（而非成年期）的尼古丁暴露会直接在 NASh 中引起 ERK 1-2 和 Akt-GSK-3 信号通路的深刻上调，以及局部 D1R 表达的下调，这种下调会持续到成年期。这些适应性变化伴随着 τ、α、β 和 γ 波段振荡状态的减少、中脑多巴胺能神经元活动的过度活跃和爆发率的降低，以及焦虑和抑郁样行为异常。针对这些分子和神经元适应性的药理学靶向治疗表明，局部 ERK 1-2 和 Akt-GSK-3 信号级联的选择性抑制可挽救尼古丁诱导的 NASh 中的高γ波段振荡特征和相位爆发率，表明它们参与介导青少年尼古丁诱导的抑郁和焦虑样神经病理学轨迹。
