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The States of Different 5-HT Receptors Located in the Dorsal Raphe Nucleus Are Crucial for Regulating the Awakening During General Anesthesia

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A Correction to this article was published on 17 August 2023

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Abstract

General anesthesia is widely used in various clinical practices due to its ability to cause loss of consciousness. However, the exact mechanism of anesthesia-induced unconsciousness remains unclear. It is generally thought that arousal-related brain nuclei are involved. 5-Hydroxytryptamine (5-HT) is closely associated with sleep arousal. Here, we explore the role of the 5-HT system in anesthetic awakening through pharmacological interventions and optogenetic techniques. Our data showed that exogenous administration of 5-hydroxytryptophan (5-HTP) and optogenetic activation of 5-HT neurons in the dorsal raphe nucleus (DR) could significantly shorten the emergence time of sevoflurane anesthesia in mice, suggesting that regulation of the 5-HT system using both endogenous and exogenous approaches could mediate delayed emergence. In addition, we first discovered that the different 5-HT receptors located in the DR, known as 5-HT autoreceptors, are essential for the regulation of general anesthetic awakening, with 5-HT1A and 5-HT2A/C receptors playing a regulatory role. These results can provide a reliable theoretical basis as well as potential targets for clinical intervention to prevent delayed emergence and some postoperative risks.

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The data supporting the findings of this study are available within the article. Data will be made available upon reasonable request.

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References

  1. Brown EN, Purdon PL, Van Dort CJ (2011) General anesthesia and altered states of arousal: a systems neuroscience analysis. Annu Rev Neurosci 34:601–628

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Ching S, Brown EN (2014) Modeling the dynamical effects of anesthesia on brain circuits. Curr Opin Neurobiol 25:116–122

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Aggarwal A, Brennan C, Shortal B, Contreras D, Kelz MB, Proekt A (2019) Coherence of visual-evoked gamma oscillations is disrupted by propofol but preserved under equipotent doses of isoflurane. Front Syst Neurosci 13:19

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Land R, Engler G, Kral A, Engel AK (2012) Auditory evoked bursts in mouse visual cortex during isoflurane anesthesia. PLoS One 7(11):e49855

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Yli-Hankala A, Jäntti V, Pyykkö I, Lindgren L (1993) Vibration stimulus induced EEG bursts in isoflurane anaesthesia. Electroencephalogr Clin Neurophysiol 87(4):215–220

    Article  PubMed  CAS  Google Scholar 

  6. Mason SE, Noel-Storr A, Ritchie CW (2010) The impact of general and regional anesthesia on the incidence of post-operative cognitive dysfunction and post-operative delirium: a systematic review with meta-analysis. J Alzheimers Dis: JAD 22(Suppl 3):67–79

    Article  PubMed  Google Scholar 

  7. Neto S, Hemmes SN, Barbas CS, Beiderlinden M, Fernandez-Bustamante A, Futier E, Gajic O, El-Tahan MR, Ghamdi AA, Günay E, Jaber S, Kokulu S, Kozian A, Licker M, Lin WQ, Maslow AD, Memtsoudis SG, Reis Miranda D, Moine P, Ng T, Paparella D, Ranieri VM, Scavonetto F, Schilling T, Selmo G, Severgnini P, Sprung J, Sundar S, Talmor D, Treschan T, Unzueta C, Weingarten TN, Wolthuis EK, Wrigge H, Amato MB, Costa EL, de Abreu MG, Pelosi P, Schultz MJ (2016) Association between driving pressure and development of postoperative pulmonary complications in patients undergoing mechanical ventilation for general anaesthesia: a meta-analysis of individual patient data, The Lancet. Respir Med 4(4):272–80

    Google Scholar 

  8. Harris M, Chung F (2013) Complications of general anesthesia. Clin Plast Surg 40(4):503–513

    Article  PubMed  Google Scholar 

  9. Franks NP, Zecharia AY (2011) Sleep and general anesthesia. Can J Anaesth= J Can d’anesth 58(2):139–48

    Article  Google Scholar 

  10. Monti JM (2011) Serotonin control of sleep-wake behavior. Sleep Med Rev 15(4):269–281

    Article  PubMed  Google Scholar 

  11. Okaty BW, Commons KG, Dymecki SM (2019) Embracing diversity in the 5-HT neuronal system. Nat Rev Neurosci 20(7):397–424

    Article  PubMed  CAS  Google Scholar 

  12. Mukaida K, Shichino T, Koyanagi S, Himukashi S, Fukuda K (2007) Activity of the serotonergic system during isoflurane anesthesia. Anesth Analg 104(4):836–839

    Article  PubMed  CAS  Google Scholar 

  13. Monti JM (2010) The structure of the dorsal raphe nucleus and its relevance to the regulation of sleep and wakefulness. Sleep Med Rev 14(5):307–317

    Article  PubMed  Google Scholar 

  14. Ren J, Friedmann D, **ong J, Liu CD, Ferguson BR, Weerakkody T, DeLoach KE, Ran C, Pun A, Sun Y, Weissbourd B, Neve RL, Huguenard J, Horowitz MA, Luo L (2018) Anatomically defined and functionally distinct dorsal raphe serotonin sub-systems. Cell 175(2):472-487.e20

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Paul ED, Lowry CA (2013) Functional topography of serotonergic systems supports the Deakin/Graeff hypothesis of anxiety and affective disorders. J Psychopharmacol (Oxford, England) 27(12):1090–1106

    Article  CAS  Google Scholar 

  16. Miguelez C, Morera-Herreras T, Torrecilla M, Ruiz-Ortega JA, Ugedo L (2014) Interaction between the 5-HT system and the basal ganglia: functional implication and therapeutic perspective in Parkinson’s disease. Front Neural Circ 8:21

    Google Scholar 

  17. Li A, Li R, Ouyang P, Li H, Wang S, Zhang X, Wang D, Ran M, Zhao G, Yang Q, Zhu Z, Dong H, Zhang H (2021) Dorsal raphe serotonergic neurons promote arousal from isoflurane anesthesia. CNS Neurosci Ther 27(8):941–950

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Sakai EM, Connolly LA, Klauck JA (2005) Inhalation anesthesiology and volatile liquid anesthetics: focus on isoflurane, desflurane, and sevoflurane. Pharmacotherapy 25(12):1773–1788

    Article  PubMed  CAS  Google Scholar 

  19. Nagai Y, Takayama K, Nishitani N, Andoh C, Koda M, Shirakawa H, Nakagawa T, Nagayasu K, Yamanaka A, Kaneko S (2020) The role of dorsal raphe serotonin neurons in the balance between reward and aversion. Int J Mol Sci 21:E2160. https://doi.org/10.3390/ijms21062160

    Article  CAS  Google Scholar 

  20. Haas HL, Sergeeva OA, Selbach O (2008) Histamine in the nervous system. Physiol Rev 88(3):1183–1241

    Article  PubMed  CAS  Google Scholar 

  21. Hasegawa E, Miyasaka A, Sakurai K, Cherasse Y, Li Y, Sakurai T (2022) Rapid eye movement sleep is initiated by basolateral amygdala dopamine signaling in mice. Science (New York, NY) 375(6584):994–1000

    Article  CAS  Google Scholar 

  22. Osorio-Forero A, Cardis R, Vantomme G, Guillaume-Gentil A, Katsioudi G, Devenoges C, Fernandez LMJ, Lüthi A (2021) Noradrenergic circuit control of non-REM sleep substates. Curr Biol: CB 31(22):5009-5023.e7

    Article  PubMed  CAS  Google Scholar 

  23. Peng W, Wu Z, Song K, Zhang S, Li Y, Xu M (2020) Regulation of sleep homeostasis mediator adenosine by basal forebrain glutamatergic neurons. Science (New York, N.Y.) 369(6508)

  24. Brown RE, Basheer R, McKenna JT, Strecker RE, McCarley RW (2012) Control of sleep and wakefulness. Physiol Rev 92(3):1087–1187

    Article  PubMed  CAS  Google Scholar 

  25. Zhou W, Cheung K, Kyu S, Wang L, Guan Z, Kurien PA, Bickler PE, Jan LY (2018) Activation of orexin system facilitates anesthesia emergence and pain control. Proc Natl Acad Sci USA 115(45):E10740-e10747

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Fiske E, Portas CM, Grønli J, Sørensen E, Bjorvatn B, Bjørkum AA, Ursin R (2008) Increased extracellular 5-HT but no change in sleep after perfusion of a 5-HT1A antagonist into the dorsal raphe nucleus of rats. Acta Physiol (Oxf) 193(1):89–97

    Article  PubMed  CAS  Google Scholar 

  27. Kirby LG, Pernar L, Valentino RJ, Beck SG (2003) Distinguishing characteristics of serotonin and non-serotonin-containing cells in the dorsal raphe nucleus: electrophysiological and immunohistochemical studies. Neuroscience 116(3):669–683

    Article  PubMed  CAS  Google Scholar 

  28. Oikonomou G, Altermatt M, Zhang RW, Coughlin GM, Montz C, Gradinaru V, Prober DA (2019) The serotonergic raphe promote sleep in zebrafish and mice. Neuron 103(4):686-701.e8

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Imeri L, Mancia M, Bianchi S, Opp MR (2000) 5-Hydroxytryptophan, but not L-tryptophan, alters sleep and brain temperature in rats. Neuroscience 95(2):445–452

    Article  PubMed  CAS  Google Scholar 

  30. Morrow JD, Vikraman S, Imeri L, Opp MR (2008) Effects of serotonergic activation by 5-hydroxytryptophan on sleep and body temperature of C57BL/6J and interleukin-6-deficient mice are dose and time related. Sleep 31(1):21–33

    Article  PubMed  PubMed Central  Google Scholar 

  31. Yin XL, Li JC, Xue R, Li S, Zhang Y, Dong HJ, Li Y, Wang HL, Zhang YZ (2022) Melatonin pretreatment prevents propofol-induced sleep disturbance by modulating circadian rhythm in rats. Exp Neurol 354:114086

    Article  PubMed  CAS  Google Scholar 

  32. Maffei ME (2020) 5-Hydroxytryptophan (5-HTP): Natural occurrence, analysis, biosynthesis, biotechnology, physiology and toxicology. Int J Mol Sci 22(1)

  33. Filip M, Bader M (2009) Overview on 5-HT receptors and their role in physiology and pathology of the central nervous system. Pharmacol Rep: PR 61(5):761–777

    Article  PubMed  CAS  Google Scholar 

  34. Hoyer D (2017) 5-HT receptor nomenclature: naming names, does it matter? A tribute to Maurice Rapport. ACS Chem Neurosci 8(5):908–919

    Article  PubMed  CAS  Google Scholar 

  35. Oh E, Maejima T, Liu C, Deneris E, Herlitze S (2010) Substitution of 5-HT1A receptor signaling by a light-activated G protein-coupled receptor. J Biol Chem 285(40):30825–30836

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Day HE, Greenwood BN, Hammack SE, Watkins LR, Fleshner M, Maier SF, Campeau S (2004) Differential expression of 5HT-1A, alpha 1b adrenergic, CRF-R1, and CRF-R2 receptor mRNA in serotonergic, gamma-aminobutyric acidergic, and catecholaminergic cells of the rat dorsal raphe nucleus. J Comp Neurol 474(3):364–378

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Sun N, Qin YJ, Xu C, **a T, Du ZW, Zheng LP, Li AA, Meng F, Zhang Y, Zhang J, Liu X, Li TY, Zhu DY, Zhou QG (2022) Design of fast-onset antidepressant by dissociating SERT from nNOS in the DRN. Science (New York, NY) 378(6618):390–398

    Article  CAS  Google Scholar 

  38. Koyama S, Kubo C, Rhee JS, Akaike N (1999) Presynaptic serotonergic inhibition of GABAergic synaptic transmission in mechanically dissociated rat basolateral amygdala neurons. J Physiol 518(Pt 2):525–38

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Mirkes SJ, Bethea CL (2001) Oestrogen, progesterone and serotonin converge on GABAergic neurones in the monkey hypothalamus. J Neuroendocrinol 13(2):182–192

    Article  PubMed  CAS  Google Scholar 

  40. Serrats J, Mengod G, Cortés R (2005) Expression of serotonin 5-HT2C receptors in GABAergic cells of the anterior raphe nuclei. J Chem Neuroanat 29(2):83–91

    Article  PubMed  CAS  Google Scholar 

  41. López-Giménez JF, Vilaró MT, Palacios JM, Mengod G (2001) Map** of 5-HT2A receptors and their mRNA in monkey brain: [3H]MDL100,907 autoradiography and in situ hybridization studies. J Comp Neurol 429(4):571–589

    Article  PubMed  Google Scholar 

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Acknowledgements

We thank YuDong Zhou and Yi Shen for their help in experimental design.

Funding

The work was supported by the National Natural Science Foundation of China (Grant. No: 81974205 and 81771403); by the Natural Science Foundation of Zhejiang Province (LZ20H090001); by the Program of New Century 131 outstanding young talent plan top-level of Hang Zhou to HHZ; and by Zhejiang Health Science and Technology Plan (Grant. No: 2022KY248) to **aoLing Liu.

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Authors and Affiliations

  1. Department of Anesthesiology, The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310006, China

    Hai**ang Ma, LeYuan Gu, YuLing Wang, Yuanli Zhang, WeiHui Shao, Qian Yu, JiaXuan Gu & HongHai Zhang

  2. Medical College of **ing Medical University, Ningji, 272067, Shandong, China

    Hai**ang Ma & HongHai Zhang

  3. Department of Anesthesiology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China

    Qing Xu, **Ting Lian, Lu Liu, **aoLing Liu & HongHai Zhang

  4. Department of Anesthesia, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China

    Na Ji

  5. Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, 606-8501, Japan

    Kazuki Nagayasu

  6. Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, 310006, China

    HongHai Zhang

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  1. Hai**ang Ma
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Contributions

HHZ designed the study and wrote the paper. HXM, LYG, YLW, XTL, QX, and WHS performed and analyzed most of the experiments. LL, JXG, YS, NJ, YLZ, and XLL helped with the analysis of experiments. Kazuki Nagayasu contributed intellectually to the manuscript concerning the plasmid design for TPH2-ChETA.

Corresponding author

Correspondence to HongHai Zhang.

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All procedures were in accordance with the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals and were approved by the Animal Advisory Committee of Zhejiang University.

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Hai**ang Ma, LeYuan Gu, YuLing Wang, QingXu, Yuanli Zhang, and WeiHui Shao contributed equally to this work.

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Ma, H., Gu, L., Wang, Y. et al. The States of Different 5-HT Receptors Located in the Dorsal Raphe Nucleus Are Crucial for Regulating the Awakening During General Anesthesia. Mol Neurobiol 60, 6931–6948 (2023). https://doi.org/10.1007/s12035-023-03519-0

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