Kubin L, Reignier C, Tojima H, Taguchi O, Pack A I, Davies R O
Department of Animal Biology, University of Pennsylvania, Philadelphia 19104.
Brain Res. 1994 May 9;645(1-2):291-302. doi: 10.1016/0006-8993(94)91663-2.
The excitability of hypoglossal (XII) motoneurons innervating genioglossal muscles is markedly suppressed during the rapid-eye-movement (REM) stage of sleep. This may contribute to airway obstructions in sleep apnea patients. Based on our earlier studies in decerebrate cats using injections of carbachol into the pons to induce a REM sleep-like atonia and microinjections of serotonin (5HT) into the XII motor nucleus, we hypothesized that a sleep-related withdrawal of the serotonergic excitatory input to XII motoneurons may play a major role in these processes. To test one aspect of this hypothesis, we inserted microdialysis probes into the XII nucleus region of decerebrate, paralyzed, vagotomized and artificially ventilated cats. The probes were perfused without or with the addition of a 5HT reuptake blocker, clomipramine. The levels of 5HT and its metabolite, 5-hydroxyindoleacetic acid (5HIAA), were determined using HPLC and electrochemical detection in dialysate samples collected over successive 20 min periods under four successive experimental conditions: control (at least 2 h after probe insertion); during the postural atonia and respiratory depression produced by pontine microinjection of carbachol; recovery from the effects of carbachol produced by pontine microinjection of atropine; and, to verify that the presence of 5HT in the dialysate was related to the activity of serotonergic cells of the brainstem, following administration of 8-OH-DPAT, a 5HT 1A receptor agonist known to suppress activity in the serotonergic cells of the raphe system. After correcting for recovery rates of individual probes, the mean control 5HT level in the extracellular space of the XII nucleus region was 7.9 +/- 4.4 nM (S.D.) in eight experiments without reuptake blockers. During the carbachol-induced depression, it was reduced to 70 +/- 20% of the pre-carbachol level. It increased to the original control level 98 +/- 27% after pontine injection of atropine. 8-OH-DPAT reduced the 5HT level to 43 +/- 14% of the post-atropine level. Changes in the 5HIAA level were not as consistent as for 5HT and did not reach statistical significance under any of the experimental conditions. Thus, a functionally significant amount of 5HT is present in the extracellular space within the XII nucleus region, and its decrement during carbachol-induced, REM sleep-like atonia is likely to reflect that occurring during natural REM sleep; this may contribute to the decreased tone of upper airway muscles and airway patency.
在快速眼动（REM）睡眠阶段，支配颏舌肌的舌下神经（XII）运动神经元的兴奋性会受到显著抑制。这可能是导致睡眠呼吸暂停患者气道阻塞的原因之一。基于我们早期在去大脑猫身上的研究，通过向脑桥注射卡巴胆碱诱导出类似REM睡眠的肌张力缺失，并向舌下神经运动核微量注射5-羟色胺（5HT），我们推测，与睡眠相关的5HT能兴奋性输入从舌下神经运动神经元撤回，可能在这些过程中起主要作用。为了验证这一假设的一个方面,我们将微透析探针插入到去大脑、瘫痪、切断迷走神经并进行人工通气的猫的舌下神经核区域。在不添加或添加5HT再摄取阻滞剂氯米帕明的情况下对探针进行灌注。在四个连续的实验条件下，每隔20分钟收集一次透析液样本，使用高效液相色谱法和电化学检测法测定5HT及其代谢产物5-羟吲哚乙酸（5HIAA）的水平：对照组（探针插入后至少2小时）；脑桥微量注射卡巴胆碱引起姿势性肌张力缺失和呼吸抑制期间；脑桥微量注射阿托品后从卡巴胆碱的作用中恢复期间；以及，为了验证透析液中5HT的存在与脑干5HT能细胞的活性有关，在给予8-OH-DPAT后，8-OH-DPAT是一种已知能抑制中缝系统5HT能细胞活性的5HT 1A受体激动剂。在对各个探针的回收率进行校正后，在八个未使用再摄取阻滞剂的实验中，舌下神经核区域细胞外空间的平均对照5HT水平为7.9±4.4 nM（标准差）。在卡巴胆碱诱导的抑制期间，它降至卡巴胆碱注射前水平的70±20%。脑桥注射阿托品后，它增加到原始对照水平的98±27%。8-OH-DPAT将5HT水平降至阿托品注射后水平的43±14%。5HIAA水平的变化不如5HT一致，在任何实验条件下均未达到统计学显著性。因此，在舌下神经核区域的细胞外空间中存在功能上显著量的5HT，并且其在卡巴胆碱诱导的类似REM睡眠的肌张力缺失期间的减少可能反映了自然REM睡眠期间发生的情况；这可能导致上气道肌肉张力降低和气道通畅性下降。
