Skip to main content

Advertisement

SpringerLink
Log in

GABAergic Neurons in the Nucleus Accumbens are Involved in the General Anesthesia Effect of Propofol

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

The mechanism underlying the hypnosis effect of propofol is still not fully understood. In essence, the nucleus accumbens (NAc) is crucial for regulating wakefulness and may be directly engaged in the principle of general anesthesia. However, the role of NAc in the process of propofol-induced anesthesia is still unknown. We used immunofluorescence, western blotting, and patch-clamp to access the activities of NAc GABAergic neurons during propofol anesthesia, and then we utilized chemogenetic and optogenetic methods to explore the role of NAc GABAergic neurons in regulating propofol-induced general anesthesia states. Moreover, we also conducted behavioral tests to analyze anesthetic induction and emergence. We found out that c-Fos expression was considerably dropped in NAc GABAergic neurons after propofol injection. Meanwhile, patch-clamp recording of brain slices showed that firing frequency induced by step currents in NAc GABAergic neurons significantly decreased after propofol perfusion. Notably, chemically selective stimulation of NAc GABAergic neurons during propofol anesthesia lowered propofol sensitivity, prolonged the induction of propofol anesthesia, and facilitated recovery; the inhibition of NAc GABAergic neurons exerted opposite effects. Furthermore, optogenetic activation of NAc GABAergic neurons promoted emergence whereas the result of optogenetic inhibition was the opposite. Our results demonstrate that NAc GABAergic neurons modulate propofol anesthesia induction and emergence.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data Availability

The datasets and/or analysis are available from the corresponding author upon reasonable request.

References

  1. Bao WW, Jiang S, Qu WM, Li WX, Miao CH, Huang ZA-O (2023) Understanding the neural mechanisms of general anesthesia from interaction with sleep-wake state: a decade of discovery. Pharmacol Rev 75(3):532–553 (1521-0081 (Electronic)). https://doi.org/10.1124/pharmrev.122.000717

    Article  CAS  PubMed  Google Scholar 

  2. 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. https://doi.org/10.1146/annurev-neuro-060909-153200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Yang QZ, Zhou F, Li A, Dong HL (2022) Neural substrates for the regulation of sleep and general anesthesia. Curr Neuropharmacol 20(1):72–84. https://doi.org/10.2174/1570159x19666211214144639

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Berthoud MC, Reilly CS (1992) Adverse effects of general anesthetics. Drug Saf 7(6):434–459. https://doi.org/10.2165/00002018-199207060-00005

    Article  CAS  PubMed  Google Scholar 

  5. Sahinovic MM, Struys M, Absalom AR (2018) Clinical pharmacokinetics and pharmacodynamics of propofol. Clin Pharmacokinet 57(12):1539–1558. https://doi.org/10.1007/s40262-018-0672-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Moody OA, Zhang ER, Vincent KF, Kato R, Melonakos ED, Nehs CJ, Solt K (2021) The neural circuits underlying general anesthesia and sleep. Anesth Analg 132(5):1254–1264. https://doi.org/10.1213/ANE.0000000000005361

    Article  PubMed  PubMed Central  Google Scholar 

  7. Franks NP (2008) General anaesthesia: from molecular targets to neuronal pathways of sleep and arousal. Nat Rev Neurosci 9(5):370–386. https://doi.org/10.1038/nrn2372

    Article  CAS  PubMed  Google Scholar 

  8. Zecharia AY, Nelson LE, Gent TC, Schumacher M, Jurd R, Rudolph U, Brickley SG, Maze M et al (2009) The involvement of hypothalamic sleep pathways in general anesthesia: testing the hypothesis using the GABAA receptor beta3N265M knock-in mouse. J Neurosci 29(7):2177–2187. https://doi.org/10.1523/JNEUROSCI.4997-08.2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Liu Y, Chen B, Cai Y, Han Y, Xia Y, Li N, Fan B, Yuan T et al (2021) Activation of anterior thalamic reticular nucleus GABAergic neurons promotes arousal from propofol anesthesia in mice. Acta Biochim Biophys Sin 53(7):883–892. https://doi.org/10.1093/abbs/gmab056

    Article  CAS  PubMed  Google Scholar 

  10. Flores FJ, Hartnack KE, Fath AB, Kim S-E, Wilson MA, Brown EN, Purdon PL (2017) Thalamocortical synchronization during induction and emergence from propofol-induced unconsciousness. Proc Natl Acad Sci U S A 114(32):E6660–E6668. https://doi.org/10.1073/pnas.1700148114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Wang L, Zhang W, Wu Y, Gao Y, Sun N, Ding H, Ren J, Yu L et al (2021) Cholinergic-induced specific oscillations in the medial prefrontal cortex to reverse propofol anesthesia. Front Neurosci 15:664410. https://doi.org/10.3389/fnins.2021.664410

    Article  PubMed  PubMed Central  Google Scholar 

  12. Scofield MD, Heinsbroek JA, Gipson CD, Kupchik YM, Spencer S, Smith AC, Roberts-Wolfe D, Kalivas PW (2016) The nucleus accumbens: mechanisms of addiction across drug classes reflect the importance of glutamate homeostasis. Pharmacol Rev 68(3):816–871. https://doi.org/10.1124/pr.116.012484

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. David Smith A, Paul Bolam J (1990) The neural network of the basal ganglia as revealed by the study of synaptic connections of identified neurones. Trends Neurosci 13(7):259–265. https://doi.org/10.1016/0166-2236(90)90106-K

    Article  Google Scholar 

  14. Floresco SB (2015) The nucleus accumbens: an interface between cognition, emotion, and action. Annu Rev Psychol 66:25–52. https://doi.org/10.1146/annurev-psych-010213-115159

    Article  PubMed  Google Scholar 

  15. Stuber GD, Sparta DR, Stamatakis AM, van Leeuwen WA, Hardjoprajitno JE, Cho S, Tye KM, Kempadoo KA et al (2011) Excitatory transmission from the amygdala to nucleus accumbens facilitates reward seeking. Nature 475(7356):377–380. https://doi.org/10.1038/nature10194

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. McCullough KM, Missig G, Robble MA, Foilb AR, Wells AM, Hartmann J, Anderson KJ, Neve RL et al (2021) Nucleus Accumbens medium spiny neuron subtypes differentially regulate stress-associated alterations in sleep architecture. Biol Psychiatry 89(12):1138–1149. https://doi.org/10.1016/j.biopsych.2020.12.030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Seminowicz DA, Remeniuk B, Krimmel SR, Smith MT, Barrett FS, Wulff AB, Furman AJ, Geuter S et al (2019) Pain-related nucleus accumbens function: modulation by reward and sleep disruption. Pain 160(5):1196–1207. https://doi.org/10.1097/j.pain.0000000000001498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Yu X, Li W, Ma Y, Tossell K, Harris JJ, Harding EC, Ba W, Miracca G et al (2019) GABA and glutamate neurons in the VTA regulate sleep and wakefulness. Nat Neurosci 22(1):106–119. https://doi.org/10.1038/s41593-018-0288-9

    Article  CAS  PubMed  Google Scholar 

  19. Luo YJ, Li YD, Wang L, Yang SR, Yuan XS, Wang J, Cherasse Y, Lazarus M et al (2018) Nucleus accumbens controls wakefulness by a subpopulation of neurons expressing dopamine D(1) receptors. Nat Commun 9(1):1576. https://doi.org/10.1038/s41467-018-03889-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yuan XS, Wang L, Dong H, Qu WM, Yang SR, Cherasse Y, Lazarus M, Schiffmann SN et al (2017) Striatal adenosine A(2A) receptor neurons control active-period sleep via parvalbumin neurons in external globus pallidus. Elife 6:e29055. https://doi.org/10.7554/eLife.29055

    Article  PubMed  PubMed Central  Google Scholar 

  21. Raguz M, Predrijevac N, Dlaka D, Oreskovic D, Rotim A, Romic D, Almahariq F, Marcinkovic P et al (2021) Structural changes in brains of patients with disorders of consciousness treated with deep brain stimulation. Sci Rep 11(1):4401. https://doi.org/10.1038/s41598-021-83873-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Reitz SL, Wasilczuk AZ, Beh GH, Proekt A, Kelz MB (2021) Activation of preoptic tachykinin 1 neurons promotes wakefulness over sleep and volatile anesthetic-induced unconsciousness. Curr Biol 31(2):394–405 e394. https://doi.org/10.1016/j.cub.2020.10.050

    Article  CAS  PubMed  Google Scholar 

  23. Wang D, Guo Q, Zhou Y, Xu Z, Hu SW, Kong XX, Yu YM, Yang JX et al (2021) GABAergic neurons in the dorsal-intermediate lateral septum regulate sleep-wakefulness and anesthesia in mice. Anesthesiology 135(3):463–481. https://doi.org/10.1097/ALN.0000000000003868

    Article  PubMed  Google Scholar 

  24. Ma LH, Wan J, Yan J, Wang N, Liu YP, Wang HB, Zhou CH, Wu YQ (2022) Hippocampal SIRT1-mediated synaptic plasticity and glutamatergic neuronal excitability are involved in prolonged cognitive dysfunction of neonatal rats exposed to propofol. Mol Neurobiol 59(3):1938–1953. https://doi.org/10.1007/s12035-021-02684-4

    Article  CAS  PubMed  Google Scholar 

  25. Segev A, Garcia-Oscos F, Kourrich S (2016) Whole-cell patch-clamp recordings in brain slices. J Vis Exp 112:e54024. https://doi.org/10.3791/54024

    Article  Google Scholar 

  26. Yang E, Granata D, Eckenhoff RG, Carnevale V, Covarrubias M (2018) Propofol inhibits prokaryotic voltage-gated Na(+) channels by promoting activation-coupled inactivation. J Gen Physiol 150(9):1299–1316. https://doi.org/10.1085/jgp.201711924

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kennedy D (2005) What don’t we know. Science 309:75

    Article  CAS  PubMed  Google Scholar 

  28. Hemmings HC Jr, Riegelhaupt PM, Kelz MB, Solt K, Eckenhoff RG, Orser BA, Goldstein PA (2019) Towards a comprehensive understanding of anesthetic mechanisms of action: a decade of discovery. Trends Pharmacol Sci 40(7):464–481. https://doi.org/10.1016/j.tips.2019.05.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bao WW, Xu W, Pan GJ, Wang TX, Han Y, Qu WM, Li WX, Huang ZL (2021) Nucleus accumbens neurons expressing dopamine D1 receptors modulate states of consciousness in sevoflurane anesthesia. Curr Biol 31(9):1893–1902 e1895. https://doi.org/10.1016/j.cub.2021.02.011

    Article  CAS  PubMed  Google Scholar 

  30. Knapska E, Radwanska K, Werka T, Kaczmarek L (2007) Functional internal complexity of amygdala: focus on gene activity mapping after behavioral training and drugs of abuse. Physiol Rev 87(4):1113–1173. https://doi.org/10.1152/physrev.00037.2006

    Article  CAS  PubMed  Google Scholar 

  31. Bola M, Barrett AB, Pigorini A, Nobili L, Seth AK, Marchewka A (2018) Loss of consciousness is related to hyper-correlated gamma-band activity in anesthetized macaques and sleeping humans. Neuroimage 167:130–142. https://doi.org/10.1016/j.neuroimage.2017.11.030

    Article  PubMed  Google Scholar 

  32. Gray JA (1995) Dopamine release in the nucleus accumbens: the perspective from aberrations of consciousness in schizophrenia. Neuropsychologia 33(9):1143–1153. https://doi.org/10.1016/0028-3932(95)00054-7

    Article  CAS  PubMed  Google Scholar 

  33. Chen L, Li S, Zhou Y, Liu T, Cai A, Zhang Z, Xu F, Manyande A et al (2021) Neuronal mechanisms of adenosine A(2A) receptors in the loss of consciousness induced by propofol general anesthesia with functional magnetic resonance imaging. J Neurochem 156(6):1020–1032. https://doi.org/10.1111/jnc.15146

    Article  CAS  PubMed  Google Scholar 

  34. Liu X, Lauer KK, Douglas Ward B, Roberts C, Liu S, Gollapudy S, Rohloff R, Gross W et al (2017) Propofol attenuates low-frequency fluctuations of resting-state fMRI BOLD signal in the anterior frontal cortex upon loss of consciousness. Neuroimage 147:295–301. https://doi.org/10.1016/j.neuroimage.2016.12.043

    Article  CAS  PubMed  Google Scholar 

  35. Leung LS, Luo T, Ma J, Herrick I (2014) Brain areas that influence general anesthesia. Prog Neurobiol 122:24–44. https://doi.org/10.1016/j.pneurobio.2014.08.001

    Article  PubMed  Google Scholar 

  36. Engelhardt T, Lowe PR, Galley HF, Webster NR (2006) Inhibition of neuronal nitric oxide synthase reduces the propofol requirements in wild-type and nNOS knockout mice. Eur J Anaesthesiol 23(3):197–201. https://doi.org/10.1017/S0265021505002188

    Article  CAS  PubMed  Google Scholar 

  37. Koukouli F, Rooy M, Changeux J-P, Maskos U (2016) Nicotinic receptors in mouse prefrontal cortex modulate ultraslow fluctuations related to conscious processing. Proc Natl Acad Sci 113(51):14823–14828. https://doi.org/10.1073/pnas.1614417113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Laverty D, Desai R, Uchanski T, Masiulis S, Stec WJ, Malinauskas T, Zivanov J, Pardon E et al (2019) Cryo-EM structure of the human alpha1beta3gamma2 GABA(A) receptor in a lipid bilayer. Nature 565(7740):516–520. https://doi.org/10.1038/s41586-018-0833-4

    Article  CAS  PubMed  Google Scholar 

  39. Pavel MA, Petersen EN, Wang H, Lerner RA, Hansen SB (2020) Studies on the mechanism of general anesthesia. Proc Natl Acad Sci U S A 117(24):13757–13766. https://doi.org/10.1073/pnas.2004259117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Stock L, Hosoume J, Cirqueira L, Treptow W (2018) Binding of the general anesthetic sevoflurane to ion channels. PLoS Comput Biol 14(11):e1006605. https://doi.org/10.1371/journal.pcbi.1006605

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Jiang-Xie LF, Yin L, Zhao S, Prevosto V, Han BX, Dzirasa K, Wang F (2019) A common neuroendocrine substrate for diverse general anesthetics and sleep. Neuron 102(5):1053–1065 e1054. https://doi.org/10.1016/j.neuron.2019.03.033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Hammes J, Theis H, Giehl K, Hoenig MC, Greuel A, Tittgemeyer M, Timmermann L, Fink GR et al (2019) Dopamine metabolism of the nucleus accumbens and fronto-striatal connectivity modulate impulse control. Brain 142(3):733–743. https://doi.org/10.1093/brain/awz007

    Article  PubMed  Google Scholar 

  43. Brand PA, Paris A, Bein B, Meybohm P, Scholz J, Ohnesorge H, Tonner PH (2008) Propofol sedation is reduced by delta9-tetrahydrocannabinol in mice. Anesth Analg 107(1):102–106. https://doi.org/10.1213/ane.0b013e318173287a

    Article  CAS  PubMed  Google Scholar 

  44. Mansouri MT, Fidler JA, Meng QC, Eckenhoff RG, Garcia PS (2019) Sex effects on behavioral markers of emergence from propofol and isoflurane anesthesia in rats. Behav Brain Res 367:59–67. https://doi.org/10.1016/j.bbr.2019.03.029

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Jia-Tao Lin, Shuai Li, and Cheng-Hua Zhou for their assistance during the preparation of this manuscript.

Funding

This research was supported by the National College Students Innovation and Entrepreneurship Training Program (202110313012Z) and the National Natural Science Foundation of China (81971051, 82171191, 82101281, 82271233, 81970994).

Author information

Author notes

  1. Jing Yan, Bei-Ning Hang, Lin-Hui Ma and Jia-Tao Lin contributed equally to this work.

Authors and Affiliations

  1. Jiangsu Province Key Laboratory of Anesthesiology/NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, 221004, China

    Jing Yan, Bei-Ning Hang, Lin-Hui Ma, Jia-Tao Lin, Yue Zhou, Xin-Hao Jiao, Ying-Xuan Yuan, Ke-Jie Shao, Le-Meng Zhang, Qi Xue, Zi-Yi Li, Hong-Xing Zhang, Jun-Li Cao & Yu-Qing Wu

  2. Department of Anesthesiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China

    Shuai Li & Hui Zheng

Authors
  1. Jing Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bei-Ning Hang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lin-Hui Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jia-Tao Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yue Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xin-Hao Jiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ying-Xuan Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ke-Jie Shao
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Le-Meng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Qi Xue
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Zi-Yi Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Hong-Xing Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Jun-Li Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Shuai Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Hui Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Yu-Qing Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Under the guidance and supervision of Yu-Qing Wu, Hui Zheng, and Shuai Li, Jing Yan completed its design, coordination, and optogenetic/chemical genetics experiment. Bei-Ning Hang and Lin-Hui Ma performed the propofol anesthesia, sample preparation, immunofluorescence staining, and electroencephalogram analysis. Jia-Tao Lin performed in vitro electrophysiology recordings. All the authors participated in data collection and statistical analysis. The manuscript was written by Jing Yan. All the authors have read and approved the final manuscript. Yu-Qing Wu, Hui Zheng, and Shuai Li secured funding for the project.

Corresponding authors

Correspondence to Shuai Li, Hui Zheng or Yu-Qing Wu.

Ethics declarations

Ethics Approval

Animal studies were authorized by the Institutional Animal Care and Use Committee of Xuzhou Medical University (IACUC no. 202205A249).

Consent to Participate

Not applicable, as no individual participant’s data is presented.

Consent for Publication

Not applicable, as no individual participant’s data is presented.

Competing Interests

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yan, J., Hang, BN., Ma, LH. et al. GABAergic Neurons in the Nucleus Accumbens are Involved in the General Anesthesia Effect of Propofol. Mol Neurobiol 60, 5789–5804 (2023). https://doi.org/10.1007/s12035-023-03445-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-023-03445-1

Keywords

Search

Navigation