Department of Neonatology, Tübingen University Hospital , Tübingen , Germany.
Department of Neurology and Epileptology, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
J Neurophysiol. 2019 Apr 1;121(4):1102-1110. doi: 10.1152/jn.00304.2018. Epub 2019 Jan 30.
Doxapram is a respiratory stimulant used for decades as a treatment option in apnea of prematurity refractory to methylxanthine treatment. Its mode of action, however, is still poorly understood. We investigated direct effects of doxapram on the pre-Bötzinger complex (PreBötC) and on a downstream motor output system, the hypoglossal nucleus (XII), in the transverse brainstem slice preparation. While doxapram has only a modest stimulatory effect on frequency of activity generated within the PreBötC, a much more robust increase in the amplitude of population activity in the subsequent motor output generated in the XII was observed. In whole cell patch-clamp recordings of PreBötC and XII neurons, we confirmed significantly increased firing of evoked action potentials in XII neurons in the presence of doxapram, while PreBötC neurons showed no significant alteration in firing properties. Interestingly, the amplitude of activity in the motor output was not increased in the presence of doxapram compared with control conditions during hypoxia. We conclude that part of the stimulatory effects of doxapram is caused by direct input on brainstem centers with differential effects on the rhythm generating kernel (PreBötC) and the downstream motor output (XII). NEW & NOTEWORTHY The clinically used respiratory stimulant doxapram has distinct effects on the rhythm generating kernel (pre-Bötzinger complex) and motor output centers (nucleus hypoglossus). These effects are obliterated during hypoxia and are mediated by distinct changes in the intrinsic properties of neurons of the nucleus hypoglossus and synaptic transmission received by pre-Bötzinger complex neurons.
多沙普仑是一种呼吸兴奋剂，已被临床使用数十年，作为治疗早产儿呼吸暂停的一种治疗选择，这种疾病对甲基黄嘌呤治疗无效。然而，其作用机制仍知之甚少。我们在横切脑片标本中研究了多沙普仑对 PreBötzinger 复合体（PreBötC）和下游运动输出系统舌下神经核（XII）的直接作用。虽然多沙普仑对 PreBötC 内产生的活动频率仅有适度的刺激作用，但在随后的 XII 运动输出中观察到群体活动幅度的增加更为显著。在 PreBötC 和 XII 神经元的全细胞膜片钳记录中，我们证实了在多沙普仑存在的情况下，XII 神经元诱发动作电位的放电显著增加，而 PreBötC 神经元的放电特性没有明显改变。有趣的是，与对照条件相比，在缺氧条件下，运动输出的活动幅度并没有因多沙普仑的存在而增加。我们得出的结论是，多沙普仑的部分刺激作用是由对脑干中枢的直接输入引起的，对节律产生核（PreBötC）和下游运动输出（XII）有不同的影响。新的和值得注意的是，临床上使用的呼吸兴奋剂多沙普仑对节律产生核（前脑桥核）和运动输出中心（舌下神经核）有明显的作用。这些作用在缺氧时被消除，是由舌下神经核神经元的内在特性和 PreBötzinger 复合体神经元的突触传递的明显变化介导的。
