Nicotine Enhances Excitability of Medial Habenular Neurons via Facilitation of Neurokinin Signaling
Nicotine Enhances Excitability of Medial Habenular Neurons via Facilitation of Neurokinin Signaling
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DOI：
10.1523/jneurosci.2736-13.2014
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发表时间：
2014-03-19
影响因子：
5.3
通讯作者：
De Biasi, Mariella
中科院分区：
文献类型：
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作者：
Dao, Dang Q.;Perez, Erika E.;De Biasi, Mariella
内侧缰核（MHb）密集表达烟碱乙酰胆碱受体（nAChR），并参与尼古丁相关行为，如尼古丁戒断和调节尼古丁摄入。虽然特定的nAChR亚基被确定为参与戒断行为，但尼古丁引起这种厌恶体验的细胞机制尚不清楚。在这里，我们展示了尼古丁和神经激肽信号系统之间的相互作用，这可能是尼古丁戒断过程中出现的一些症状的基础。使用膜片钳电生理学在小鼠脑片，我们表明，尼古丁（1 μ M）增加内在的兴奋性MHb神经元。这种尼古丁诱导的现象需要含有α 5的nAChR，并依赖于完整的神经激肽信号传导。该作用通过与神经激肽1（NK 1; L-732138，10 μ M）和NK 3（SB 222200，2 μ M）拮抗剂预孵育而被阻断，并通过NK 1（P物质，100 nM）和NK 3（神经激肽B [NKB]，100 nM）激动剂模拟。MHb微量注射（1 μ l）L-732138（50 nM）和SB 222200（100 nM）可诱导慢性尼古丁治疗（8.4 mg/kg/d，2周）小鼠的戒断行为。相反，在尼古丁处理的小鼠或用溶剂溶液长期处理的小鼠的外侧缰中进行类似的显微注射，不存在戒断行为。此外，慢性尼古丁降低尼古丁对内在兴奋性的急性调节，同时保留NKB的调节。我们的工作阐明了大脑中两个神经调节信号系统之间的相互作用，尼古丁通过这两个信号系统影响内在兴奋性。更重要的是，我们记录了这种机制对慢性尼古丁暴露的神经适应，并暗示这些机制共同参与尼古丁戒断行为的出现。
The medial habenula (MHb) densely expresses nicotinic acetylcholine receptors (nAChRs) and participates in nicotine-related behaviors such as nicotine withdrawal and regulating nicotine intake. Although specific nAChR subunits are identified as being involved in withdrawal behavior, the cellular mechanisms through which nicotine acts to cause this aversive experience is unclear. Here, we demonstrate an interaction between the nicotinic and neurokinin signaling systems that may form the basis for some symptoms experienced during nicotine withdrawal. Using patch-clamp electrophysiology in mouse brain slices, we show that nicotine (1 mu M) increases intrinsic excitability in MHb neurons. This nicotine-induced phenomenon requires alpha 5-containing nAChRs and depends on intact neurokinin signaling. The effect is blocked by preincubation with neurokinin 1 (NK1; L-732138, 10 mu M) and NK3 (SB222200, 2 mu M) antagonists and mimicked by NK1 (substance P, 100 nM) and NK3 (neurokinin B [NKB], 100 nM) agonists. Microinjections (1 mu l) of L-732138 (50 nM) and SB222200 (100 nM) into the MHb induces withdrawal behavior in chronic nicotine-treated (8.4 mg/kg/d, 2 weeks) mice. Conversely, withdrawal behavior is absent with analogous microinjections into the lateral habenula of nicotine-treated mice or in mice chronically treated with a vehicle solution. Further, chronic nicotine reduces nicotine's acute modulation of intrinsic excitability while sparing modulation by NKB. Our work elucidates the interplay between two neuromodulatory signaling systems in the brain through which nicotine acts to influence intrinsic excitability. More importantly, we document a neuroadaptation of this mechanism to chronic nicotine exposure and implicate these mechanisms collectively in the emergence of nicotine withdrawal behavior.