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Respiratory Research
Published in: Respiratory Research 1/2022

Open Access 01-12-2022 | Research

Role of raphe magnus 5-HT1A receptor in increased ventilatory responses induced by intermittent hypoxia in rats

Authors: Jiao Su, Yang Meng, Yifei Fang, Linge Sun, Mengge Wang, Yanjun Liu, Chunling Zhao, Liping Dai, Songyun Ouyang

Published in: Respiratory Research | Issue 1/2022

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Abstract

Background

Intermittent hypoxia induces increased ventilatory responses in a 5-HT-dependent manner. This study aimed to explore that effect of raphe magnus serotonin 1A receptor (5-HT1A) receptor on the increased ventilatory responses induced by intermittent hypoxia.

Methods

Stereotaxic surgery was performed in adult male rats, and acute and chronic intermittent hypoxia models were established after recovery from surgery. The experimental group received microinjections of 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) into the raphe magnus nucleus (RMg). Meanwhile, the control group received microinjections of artificial cerebrospinal fluid instead of 8-OH-DPAT. Ventilatory responses were compared among the different groups of oxygen status. 5-HT expressions in the RMg region were assessed by immunohistochemistry after chronic intermittent hypoxia.

Results

Compared with the normoxia group, the acute intermittent hypoxia group exhibited higher ventilatory responses (e.g., shorter inspiratory time and higher tidal volume, frequency of breathing, minute ventilation, and mean inspiratory flow) (P < 0.05). 8-OH-DPAT microinjection partly weakened these changes in the acute intermittent hypoxia group. Further, compared with the acute intermittent hypoxia group, rats in chronic intermittent hypoxia group exhibited higher measures of ventilatory responses after 1 day of intermittent hypoxia (P < 0.05). These effects peaked after 3 days of intermittent hypoxia treatment and then decreased gradually. Moreover, these changes were diminished in the experimental group. 5-HT expression in the RMg region increased after chronic intermittent hypoxia, which was consistent with the changing trend of ventilatory responses. While activation of the 5-HT1A receptor in the RMg region alleviated this phenomenon.

Conclusions

The results indicate that RMg 5-HT1A receptor, via changing the expression level of 5-HT in the RMg region, is involved in the modulation of the increased ventilatory responses induced by intermittent hypoxia.
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Literature
1.
Eckert DJ, Catcheside PG, McDonald R, Adams AM, Webster KE, Hlavac MC, et al. Sustained hypoxia depresses sensory processing of respiratory resistive loads. Am J Respir Crit Care Med. 2005;172(8):1047–54.PubMed
2.
Stryker C, Camperchioli DW, Mayer CA, Alilain WJ, Martin RJ, MacFarlane PM. Respiratory dysfunction following neonatal sustained hypoxia exposure during a critical window of brain stem extracellular matrix formation. Am J Physiol Regul Integr Comp Physiol. 2018;314(2):R216–27.PubMed
3.
Mateika JH, El-Chami M, Shaheen D, Ivers B. Intermittent hypoxia: a low-risk research tool with therapeutic value in humans. J Appl Physiol (1985). 2015;118(5):520–32.
4.
Mitchell GS, Baker TL, Nanda SA, Fuller DD, Zabka AG, Hodgeman BA, et al. Invited review: Intermittent hypoxia and respiratory plasticity. J Appl Physiol (1985). 2001;90(6):2466–75.
5.
Jordan AS, McSharry DG, Malhotra A. Adult obstructive sleep apnoea. Lancet. 2014;383(9918):736–47.PubMed
6.
Przygodda F, Manfredi LH, Machado J, Gonçalves DAP, Zanon NM, Bonagamba LGH, et al. Acute intermittent hypoxia in rats activates muscle proteolytic pathways through a gluccorticoid-dependent mechanism. J Appl Physiol (1985). 2017;122(5):1114–24.
7.
Lemes EV, Aiko S, Orbem CB, Formentin C, Bassi M, Colombari E, Zoccal DB. Long-term facilitation of expiratory and sympathetic activities following acute intermittent hypoxia in rats. Acta Physiol (Oxf). 2016;217(3):254–66.
8.
McGuire M, Zhang Y, White DP, Ling L. Chronic intermittent hypoxia enhances ventilatory long-term facilitation in awake rats. J Appl Physiol. 2003;95:1499–508.PubMed
9.
Navarrete-Opazo A, Mitchell GS. Therapeutic potential of intermittent hypoxia: a matter of dose. Am J Physiol Regul Integr Comp Physiol. 2014;307(10):R1181-1197.PubMedPubMedCentral
10.
Badran M, Khalyfa A, Ericsson A, Gozal D. Fecal microbiota transplantation from mice exposed to chronic intermittent hypoxia elicits sleep disturbances in naïve mice. Exp Neurol. 2020;334: 113439.PubMedPubMedCentral
11.
Gerst DG, Yokhana SS, Carney LM, Lee DS, Badr MS, Qureshi T, et al. The hypoxic ventilatory response and ventilatory long-term facilitation are altered by time of day and repeated daily exposure to intermittent hypoxia. J Appl Physiol (1985). 2011;110(1):15–28.
12.
Baker TL, Mitchell GS. Episodic, but not continuous hypoxia elicits long-term facilitation of phrenic motor output. J Physiol (Lond). 2000;529(Pt1):215–9.
13.
Olson EB Jr, Bohne CJ, Dwinell MR, Podolsky A, Vidruk EH, Fuller DD, Powell FL, Mitchel GS. Ventilatory long-term facilitation in unanesthetized rats. J Appl Physiol. 2001;91:709–16.PubMed
14.
Gonzalez-Rothi EJ, Lee KZ, Dale EA, Reier PJ, Mitchell GS, Fuller DD. Intermittent hypoxia and neurorehabilitation. J Appl Physiol (1985). 2015;119(12):1455–65.
15.
Barker JR, Thomas CF, Behan M. 5-HT projections from the caudal raphe nuclei to the hypoglossal nucleus in male and female rats. Respir Physiol Neurobiol. 2009;165:175–84.PubMed
16.
Hosogai M, Matsuo S, Sibahara T, Kawai Y. Projection of respiratory neurons in rat medullary raphe nuclei to the phrenic nucleus. Respir Physiol. 1998;112(1):37–50.PubMed
17.
Morinaga R, Nakamuta N, Yamamoto Y. Serotonergic projections to the ventral respiratory column from raphe nuclei in rats. Neurosci Res. 2019;143:20–30.PubMed
18.
Lindsey BG, Arata A, Morris KF, Hernandez YM, Shannon R. Medullary raphe neurones and baroreceptor modulation of the respiratory motor pattern in the cat. J Physiol. 1998;512(Pt 3):863–82.PubMedPubMedCentral
19.
Holtman JR Jr, Marion LJ, Speck DF. Origin of serotonin-containing projections to the ventral respiratory group in the rat. Neuroscience. 1990;37(2):541–52.PubMed
20.
Connelly CA, Ellenberger HH, Feldman JL. Are there serotonergic projections from raphe and retrotrapezoid nuclei to the ventral respiratory group in the rat? Neurosci Lett. 1989;105(1–2):34–40.PubMed
21.
Lalley PM. Responses of phrenic motoneurones of the cat to stimulation of medullary raphe nuclei. J Physiol. 1986;380:349–71.PubMedPubMedCentral
22.
Lalley PM. Serotoninergic and non-serotoninergic responses of phrenic motoneurones to raphe stimulation in the cat. J Physiol. 1986;380:373–85.PubMedPubMedCentral
23.
Besnard S, Denise P, Cappelin B, Dutschmann M, Gestreau C. Stimulation of the rat medullary raphe nuclei induces differential responses in respiratory muscle activity. Respir Physiol Neurobiol. 2009;165(2–3):208–14.PubMed
24.
Gargaglioni LH, Coimbra NC, Branco LG. The nucleus raphe magnus modulates hypoxia-induced hyperventilation but not anapyrexia in rats. Neurosci Lett. 2003;347(2):121–5.PubMed
25.
Su J, Wang W, Sun L, Li T, Kong D, Kang J. Raphe serotonergic neurons modulate genioglossus corticomotor activity in intermittent hypoxic rats. Respir Res. 2014;15(1):76.PubMedPubMedCentral
26.
Richter DW, Manzke T, Wilken B, Ponimaskin E. Serotonin receptors: guardians of stable breathing. Trends Mol Med. 2003;9:542–8.PubMed
27.
Verge D, Daval G, Patey A, Gozlan H, Mestikawy S, Hamon M. Presynaptic 5-HT autoreceptors on serotonergic cell bodies and/or dendrites but not terminals are of 5-HT1A subtype. Eur J Pharmacol. 1985;113:463–4.
28.
Barnes NM, Sharp T. A review of central 5-HT receptors and their function. Neuropharmacology. 1999;38:1083–152.PubMed
29.
Hamon M, Lanfumey L, el Mestikawy S, Boni C, Miquel MC, Bolaños F, et al. The main features of central 5-HT1A receptors. Neuropsychopharmacology. 1990;3(5–6):349–60.PubMed
30.
Koyama S, Matsumoto N, Murakami N, Kubo C, Nabekura J, Akaike N. Role of presynaptic 5-HT1A and 5-HT3 receptors in modulation of synaptic GABA transmission in dissociated rat basolateral amygdala neurons. Life Sci. 2002;72:375–87.PubMed
31.
Dodig IP, Pecotic R, Valic A, Dogas Z. Acute intermittent hypoxia induces phrenic long-term facilitation which is modulated by 5-HT1A receptor in the caudal raphe region of the rat. J Sleep Res. 2012;21:195–203.
32.
Nucci TB, Branco LG, Gargaglioni LH. 5-HT1A, but not 5-HT2 and 5-HT7, receptors in the nucleus raphe magnus modulate hypoxia-induced hyperpnoea. Acta Physiol (Oxf). 2008;193:403–14.
33.
Taylor NC, Li A, Nattie EE. Medullary serotonergic neurones modulate the ventilatory response to hypercapnia, but not hypoxia in conscious rats. J Physiol. 2005;566:543–57.PubMedPubMedCentral
34.
Paxinos G, Watson C. The brain in stereotaxic coordinates. 6th ed. San Diego, CA: Academic; 2007.
35.
Li W, Wang A, Jin H, Zou Y, Wang Z, Wang W, Kang J. Transient upregulation of TASK-1 expression in the hypoglossal nucleus during chronic intermittent hypoxia is reduced by serotonin 2A receptor antagonist. J Cell Physiol. 2019;234(10):17886–95.PubMed
36.
Grace KP, Liu H, Horner RL. 5-HT1A receptor-responsive pedunculopontine tegmental neurons suppress REM sleep and respiratory motor activity. J Neurosci. 2012;32:1622–33.PubMedPubMedCentral
37.
Portas CM, Thakkar M, Rainnie D, McCarley RW. Microdialysis perfusion of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) in the dorsal raphe nucleus decreases serotonin release and increases rapid eye movement sleep in the freely moving cat. J Neurosci. 1996;16:2820–8.PubMedPubMedCentral
38.
Sood S, Raddatz E, Liu X, Liu H, Horner RL. Inhibition of 5-HT medullary raphe obscurus neurons suppresses genioglossus and diaphragm activities in anesthetized but conscious rats. J Appl Physiol. 2006;100:1807–21.PubMed
39.
Ouahchi Y, Bon-Mardion N, Marie JP, Verin E. Involvement of the aero-digestive tract in swallowing-ventilation coordination: an animal study. Neurogastroenterol Motil. 2011;23(3):e136–40.PubMed
40.
Reeves SR, Gozal D. Changes in ventilatory adaptations associated with long-term intermittent hypoxia across the age spectrum in the rat. Respir Physiol Neurobiol. 2006;150(2–3):135–43.PubMed
41.
Ray CJ, Dow B, Kumar P, Coney AM. Mild chronic intermittent hypoxia in Wistar rats evokes significant cardiovascular pathophysiology but no overt changes in carotid body-mediated respiratory responses. Adv Exp Med Biol. 2015;860:245–54.PubMed
42.
Edge D, Skelly JR, Bradford A, O’Halloran KD. Ventilatory drive is enhanced in male and female rats following chronic intermittent hypoxia. Adv Exp Med Biol. 2009;648:337–44.PubMed
43.
44.
45.
Darnall RA, Schneider RW, Tobia CM, Commons KG. Eliminating medullary 5-HT neurons delays arousal and decreases the respiratory response to repeated episodes of hypoxia in neonatal rat pups. J Appl Physiol (1985). 2016;120(5):514–25.
46.
Kim CS, McNamara MC, Lauder JM, Lawson EE. Immunocytochemical detection of serotonin content in raphe neurons of newborn and young adult rabbits before and after acute hypoxia. Int J Dev Neurosci. 1994;12:499–505.PubMed
47.
Poncet L, Denoroy L, Dalmaz Y, Pequignot JM. Activity of tryptophan hydroxylase and content of indolamines in discrete brain regions after a long-term hypoxic exposure in the rat. Brain Res. 1997;8(765):122–8.
48.
Rukhadze I, Fenik VB, Benincasa KE, Price A, Kubin L. Chronic intermittent hypoxia alters density of aminergic terminals and receptors in the hypoglossal motor nucleus. Am J Respir Crit Care Med. 2010;182(10):1321–9.PubMedPubMedCentral
Metadata
Title
Role of raphe magnus 5-HT1A receptor in increased ventilatory responses induced by intermittent hypoxia in rats
Authors
Jiao Su
Yang Meng
Yifei Fang
Linge Sun
Mengge Wang
Yanjun Liu
Chunling Zhao
Liping Dai
Songyun Ouyang
Publication date
01-12-2022
Publisher
BioMed Central
Published in
Respiratory Research / Issue 1/2022
Electronic ISSN: 1465-993X
DOI
https://doi.org/10.1186/s12931-022-01970-6

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