α6 型烟碱型乙酰胆碱受体在酒精诱导的伏隔核 GABA 能突触传递和可塑性中的作用。
Role of α6-Nicotinic Receptors in Alcohol-Induced GABAergic Synaptic Transmission and Plasticity to Cholinergic Interneurons in the Nucleus Accumbens.
机构信息
Department of Psychology and Neuroscience, Brigham Young University, 1050 KMBL, Provo, UT, 84602, USA.
Department of Pharmacology, Graduate Program in Neuroscience, University of Minnesota, Minneapolis, MN, 55455, USA.
出版信息
Mol Neurobiol. 2023 Jun;60(6):3113-3129. doi: 10.1007/s12035-023-03263-5. Epub 2023 Feb 18.
The prevailing view is that enhancement of dopamine (DA) transmission in the mesolimbic system, consisting of DA neurons in the ventral tegmental area (VTA) that project to the nucleus accumbens (NAc), underlies the reward properties of ethanol (EtOH) and nicotine (NIC). We have shown previously that EtOH and NIC modulation of DA release in the NAc is mediated by α6-containing nicotinic acetylcholine receptors (α6*-nAChRs), that α6*-nAChRs mediate low-dose EtOH effects on VTA GABA neurons and EtOH preference, and that α6*-nAChRs may be a molecular target for low-dose EtOH. However, the most sensitive target for reward-relevant EtOH modulation of mesolimbic DA transmission and the involvement of α6*-nAChRs in the mesolimbic DA reward system remains to be elucidated. The aim of this study was to evaluate EtOH effects on GABAergic modulation of VTA GABA neurons and VTA GABAergic input to cholinergic interneurons (CINs) in the NAc. Low-dose EtOH enhanced GABAergic input to VTA GABA neurons that was blocked by knockdown of α6*-nAChRs. Knockdown was achieved either by α6-miRNA injected into the VTA of VGAT-Cre/GAD67-GFP mice or by superfusion of the α-conotoxin MII[H9A;L15A] (MII). Superfusion of MII blocked EtOH inhibition of mIPSCs in NAc CINs. Concomitantly, EtOH enhanced CIN firing rate, which was blocked by knockdown of α6*-nAChRs with α6-miRNA injected into the VTA of VGAT-Cre/GAD67-GFP mice. The firing rate of CINs was not enhanced by EtOH in EtOH-dependent mice, and low-frequency stimulation (LFS; 1 Hz, 240 pulses) caused inhibitory long-term depression at this synapse (VTA-NAc CIN-iLTD) which was blocked by knockdown of α6*-nAChR and MII. Ethanol inhibition of CIN-mediated evoked DA release in the NAc was blocked by MII. Taken together, these findings suggest that α6*-nAChRs in the VTA-NAc pathway are sensitive to low-dose EtOH and play a role in plasticity associated with chronic EtOH.
目前的观点认为，中脑边缘系统（由腹侧被盖区（VTA）中的多巴胺神经元投射到伏隔核（NAc）组成）中多巴胺（DA）传递的增强是乙醇（EtOH）和尼古丁（NIC）奖赏特性的基础。我们之前已经表明，NAc 中 DA 释放的 EtOH 和 NIC 调制是由含有α6 的烟碱型乙酰胆碱受体（α6*-nAChRs）介导的，α6*-nAChRs 介导低剂量 EtOH 对 VTA GABA 神经元的影响和 EtOH 偏好，并且α6*-nAChRs 可能是低剂量 EtOH 的分子靶标。然而，对于中脑边缘系统 DA 传递的奖赏相关 EtOH 调制最敏感的靶点以及α6*-nAChRs 在中脑边缘系统 DA 奖赏系统中的作用仍有待阐明。本研究旨在评估 EtOH 对 VTA GABA 神经元 GABA 能调制和 VTA GABA 能传入到 NAc 胆碱能中间神经元（CINs）的影响。低剂量 EtOH 增强了 VTA GABA 神经元的 GABA 能传入，该传入被α6*-nAChRs 的敲低所阻断。敲低是通过注射到 VGAT-Cre/GAD67-GFP 小鼠 VTA 中的α6-miRNA 或通过超级灌注α-筒箭毒碱 MII[H9A；L15A]（MII）来实现的。MII 的超级灌注阻断了 EtOH 对 NAc CIN 中 mIPSCs 的抑制。同时，EtOH 增强了 CIN 的放电频率，该频率被注射到 VGAT-Cre/GAD67-GFP 小鼠 VTA 中的α6-miRNA 敲低所阻断。在依赖 EtOH 的小鼠中，EtOH 不会增强 CIN 的放电频率，低频刺激（LFS；1Hz，240 个脉冲）在该突触处引起抑制性长时程抑制（VTA-NAc CIN-iLTD），该抑制被α6*-nAChR 的敲低和 MII 阻断。MII 阻断了 EtOH 对 NAc 中 CIN 介导的诱发 DA 释放的抑制。总之，这些发现表明，VTA-NAc 通路中的α6*-nAChRs 对低剂量 EtOH 敏感，并在与慢性 EtOH 相关的可塑性中发挥作用。
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