Department of Physiology & Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Department of Physiology & Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Neuropharmacology. 2022 May 1;208:108987. doi: 10.1016/j.neuropharm.2022.108987. Epub 2022 Feb 12.
The interpeduncular nucleus (IPN) plays a key role in nicotine dependence and is involved in regulation of fear responses, affective states, and novelty processing. IPN neurons express nicotinic acetylcholine receptors (nAChR) and receive strong cholinergic innervation from the ventral medial habenula. Dorsal medial habenula neurons are primarily peptidergic, releasing substance P (SP) mainly onto IPN neurons in the lateral subnucleus (IPL). IPL neurons are sensitive to SP, but it is not known if they are involved in cholinergic transmission like other IPN neurons. We examined nAChR subunit gene expression in IPL neurons, revealing that Chrna7 (α7 nAChR subunit) is expressed in a subset of GABAergic IPL neurons. In patch-clamp recordings from IPL neurons, ACh-evoked inward currents were attenuated by methyllycaconitine (α7 nAChR antagonist) and potentiated by NS1738 (α7 Type I positive allosteric modulator). We confirmed α7 functional expression in IPL neurons by also showing that ACh-evoked currents were potentiated by PNU-120596 (Type II positive allosteric modulator). Additional pharmacological experiments show that IPN neurons expressing α7 nAChRs also express α3β4 nAChRs. Finally, we used 2-photon laser scanning microscopy and nicotine uncaging to directly examine the morphology of IPL neurons that express α7 nAChRs. These results highlight a novel aspect of α7 nAChR neurobiology, adding to the complexity of cholinergic modulation by nAChRs in the IPN.
被盖间核（IPN）在尼古丁依赖中起关键作用，参与调节恐惧反应、情绪状态和新颖性加工。IPN 神经元表达烟碱型乙酰胆碱受体（nAChR），并接受来自腹内侧缰核的强烈胆碱能支配。背内侧缰核神经元主要是肽能的，主要将 P 物质（SP）释放到外侧 subnucleus（IPL）的 IPN 神经元上。IPL 神经元对 SP 敏感，但尚不清楚它们是否像其他 IPN 神经元一样参与胆碱能传递。我们检查了 IPL 神经元中的 nAChR 亚基基因表达，发现 Chrna7（α7 nAChR 亚基）在 GABAergic IPL 神经元的亚群中表达。在来自 IPL 神经元的膜片钳记录中，ACh 诱导的内向电流被甲基马钱子碱（α7 nAChR 拮抗剂）减弱，并被 NS1738（α7 型 I 正变构调节剂）增强。我们通过还表明 ACh 诱导的电流被 PNU-120596（II 型正变构调节剂）增强来证实 IPL 神经元中 α7 的功能表达。此外的药理学实验表明，表达 α7 nAChRs 的 IPN 神经元还表达 α3β4 nAChRs。最后，我们使用双光子激光扫描显微镜和尼古丁光解来直接检查表达 α7 nAChRs 的 IPL 神经元的形态。这些结果突出了 α7 nAChR 神经生物学的一个新方面，增加了 nAChRs 在 IPN 中对胆碱能调制的复杂性。
