The nicotinic acetylcholine receptors (nAChRs) are essential for acetylcholine-mediated signaling. Two major functional subtypes of nAChR in the brain, α7-type and α4β2-type, have a high affinity for nicotine. Here, we demonstrated that chronic exposure to nicotine at 0.03–0.3 mg/kg for 14 days rescued depressive-like behavior in calcium/calmodulin-dependent protein kinase IV (CaMKIV) null mice. Chronic exposure to nicotine together with methyllycaconitine, an α7-type nAChR antagonist, but not with dihydro-β-erythroidine, an α4β2-type nAChR antagonist, failed to rescue the depressive-like behavior and restore the reduced number of BrdU-positive cells in the dentate gyrus (DG) of CaMKIV null mice. Furthermore, chronic exposure to nicotine enhanced the PI3K/Akt and ERK/CREB pathways and increased BDNF expression in the DG of CaMKIV null mice. Similar to chronic exposure to nicotine, both PNU-282987 and GTS-21, α7-type nAChR agonists, significantly rescued depressive-like behavior, with a reduction in the number of BrdU-positive cells in the DG of CaMKIV null mice. Both PNU-282987 and GTS-21 also enhanced the PI3K/Akt and ERK/CREB pathways and increased brain-derived neurotrophic factor (BDNF) expression in the DG of CaMKIV null mice. Taken together, we demonstrated that chronic exposure to nicotine rescues depressive-like behavior via α7-type nAChR through the activation of both PI3K/Akt and ERK/CREB pathways in CaMKIV null mice.

烟碱乙酰胆碱受体（nAChRs）对于乙酰胆碱介导的信号传导至关重要。大脑中nAChR的两个主要功能亚型，α7型和α4β2型，对尼古丁具有高亲和力。在这里，我们证明了在0.03–0.3 mg / kg的情况下长期暴露于烟碱中14天可以挽救钙/钙调蛋白依赖性蛋白激酶IV（CaMKIV）缺失小鼠的抑郁样行为。长期暴露于尼古丁与α7型nAChR拮抗剂甲基卡可尼碱一起但未与α4β2型nAChR拮抗剂二氢β-赤藓类素长期接触，未能挽救抑郁样行为并恢复减少的BrdU阳性细胞CaMKIV空小鼠的齿状回（DG）。此外，长期暴露于尼古丁可增强CaMKIV缺失小鼠DG中的PI3K / Akt和ERK / CREB途径并增加BDNF表达。与长期暴露于尼古丁相似，PNU-282987和GTS-21（α7型nAChR激动剂）均能有效挽救抑郁样行为，同时减少CaMKIV缺失小鼠DG中BrdU阳性细胞的数量。PNU-282987和GTS-21均在CaMKIV缺失小鼠的DG中也增强了PI3K / Akt和ERK / CREB途径，并增加了脑源性神经营养因子（BDNF）的表达。两者合计，我们证明了长期暴露于尼古丁可以通过激活CaMKIV缺失小鼠中的PI3K / Akt和ERK / CREB途径，通过α7型nAChR拯救抑郁样行为。PNU-282987和GTS-21均在CaMKIV缺失小鼠的DG中也增强了PI3K / Akt和ERK / CREB途径，并增加了脑源性神经营养因子（BDNF）的表达。两者合计，我们证明了长期暴露于尼古丁可以通过激活CaMKIV缺失小鼠中的PI3K / Akt和ERK / CREB途径，通过α7型nAChR拯救抑郁样行为。PNU-282987和GTS-21均在CaMKIV缺失小鼠的DG中也增强了PI3K / Akt和ERK / CREB途径，并增加了脑源性神经营养因子（BDNF）的表达。两者合计，我们证明了长期暴露于尼古丁可以通过激活CaMKIV缺失小鼠中的PI3K / Akt和ERK / CREB途径，通过α7型nAChR拯救抑郁样行为。