Mechanisms underlying regulation of respiratory pattern by nicotine in preBotzinger complex
Mechanisms underlying regulation of respiratory pattern by nicotine in preBotzinger complex
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DOI：
10.1152/jn.2001.85.6.2461
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发表时间：
2001-06-01
影响因子：
2.5
通讯作者：
Feldman, JL
中科院分区：
文献类型：
--
作者：
Shao, XM;Feldman, JL
胆碱能神经传递在呼吸模式的调节中发挥作用。香烟烟雾中的尼古丁会影响呼吸，是婴儿猝死综合症 (SIDS) 和睡眠呼吸障碍的危险因素。这种调节背后的细胞和突触机制尚不清楚。使用新生大鼠的髓质切片制剂，其中含有 preBotzinger 复合物 (preBotC)（呼吸节律产生的假设位点），并在体外产生呼吸相关节律，我们检查了尼古丁对影响 preBotC 中吸气神经元的兴奋性神经传递和舌下神经 (XIIn) 的呼吸相关运动活动的影响。将尼古丁微量注射到 preBotC 中会增加呼吸频率并降低吸气爆发的幅度，而当注射到 XII 核中时会引起强直活动和幅度增加，但不会增加 XIIn 的吸气爆发频率。尼古丁浴（0.2-0.5 μM，大约是吸烟后立即的动脉血尼古丁浓度）使呼吸频率以浓度依赖性方式增加至对照的 280%。尼古丁将 XIIn 吸气爆发的振幅降低至 82%，并将持续时间延长至 124%。在电压钳位的 preBotC 吸气神经元（包括具有起搏器特性的神经元）中，尼古丁诱导了 -19.4 +/- 13.4 pA 的强直内向电流，与基线噪声的增加相关。呼气期间出现的自发兴奋性突触后电流 (sEPSC) 频率增加至对照值的 176%，幅度增加至对照值的 117%；阶段性吸气驱动内向电流的幅度降低至对照值的 66%，持续时间降低至对照值的 89%。美加明 (Meca) 可以阻断尼古丁的作用。在尼古丁存在或不存在的情况下，6-氰基-7-硝基喹喔啉-2,3-二酮 (CNQX) 完全消除了吸气驱动电流和 sEPSC。在河豚毒素（TTX）存在的情况下，低浓度的尼古丁不会引起任何强直电流或基线噪声的任何增加，也不会影响吸气神经元的输入阻力。在这项研究中，我们证明尼古丁通过调节 preBotC 的兴奋性神经传递来增加呼吸频率并调节呼吸模式。烟碱乙酰胆碱受体（nAChR）的激活增强了对包括起搏神经元在内的吸气神经元的强直兴奋性突触输入，同时抑制了这些神经元之间的阶段性兴奋性耦合。这些机制可能解释了呼吸频率和模式的胆碱能调节。
Cholinergic neurotransmission plays a role in regulation of respiratory pattern. Nicotine from cigarette smoke affects respiration and is a risk factor for sudden infant death syndrome (SIDS) and sleep-disordered breathing. The cellular and synaptic mechanisms underlying this regulation are not understood. Using a medullary slice preparation from neonatal rat that contains the preBotzinger Complex (preBotC), the hypothesized site for respiratory rhythm generation, and generates respiratory-related rhythm in vitro, we examined the effects of nicotine on excitatory neurotransmission affecting inspiratory neurons in preBotC and on the respiratory-related motor activity from hypoglossal nerve (XIIn). Microinjection of nicotine into preBotC increased respiratory frequency and decreased the amplitude of inspiratory bursts, whereas when injected into XII nucleus induced a tonic activity and an increase in amplitude but not in frequency of inspiratory bursts from XIIn. Bath application of nicotine (0.2-0.5 muM, approximately the arterial blood nicotine concentration immediately after smoking a cigarette) increased respiratory frequency up to 280% of control in a concentration-dependent manner. Nicotine decreased the amplitude to 82% and increased the duration to 124% of XIIn inspiratory bursts. In voltage-clamped preBotC inspiratory neurons (including neurons with pacemaker properties), nicotine induced a tonic inward current of -19.4 +/- 13.4 pA associated with an increase in baseline noise. Spontaneous excitatory postsynaptic currents (sEPSCs) present during the expiratory period increased in frequency to 176% and in amplitude to 117% of control values; the phasic inspiratory drive inward currents decreased in amplitude to 66% and in duration to 89% of control values. The effects of nicotine were blocked by mecamylamine (Meca). The inspiratory drive current and sEPSCs were completely eliminated by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) in the presence or absence of nicotine. In the presence of tetrodotoxin (TTX), low concentrations of nicotine did not induce any tonic current or any increase in baseline noise, nor affect the input resistance in inspiratory neurons. In this study, we demonstrated that nicotine increased respiratory frequency and regulated respiratory pattern by modulating the excitatory neurotransmission in preBotC. Activation of nicotinic acetylcholine receptors (nAChRs) enhanced the tonic excitatory synaptic input to inspiratory neurons including pacemaker neurons and at the same time, inhibited the phasic excitatory coupling between these neurons. These mechanisms may account for the cholinergic regulation of respiratory frequency and pattern.