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Effects of Etomidate on GABAergic and Glutamatergic Transmission in Rat Thalamocortical Slices

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Abstract

Although accumulative evidence indicates that the thalamocortical system is an important target for general anesthetics, the underlying mechanisms of anesthetic action on thalamocortical neurotransmission are not fully understood. The aim of the study is to explore the action of etomidate on glutamatergic and GABAergic transmission in rat thalamocortical slices by using whole cell patch-clamp recording. We found that etomidate mainly prolonged the decay time of spontaneous GABAergic inhibitory postsynaptic currents (sIPSCs), without changing the frequency. Furthermore, etomidate not only prolonged the decay time of miniature inhibitory postsynaptic currents (mIPSCs) but also increased the amplitude. On the other hand, etomidate significantly decreased the frequency of spontaneous glutamatergic excitatory postsynaptic currents (sEPSCs), without altering the amplitude or decay time in the absence of bicuculline. When GABAA receptors were blocked using bicuculline, the effects of etomidate on sEPSCs were mostly eliminated. These results suggest that etomidate enhances GABAergic transmission mainly through postsynaptic mechanism in thalamocortical neuronal network. Etomidate attenuates glutamatergic transmission predominantly through presynaptic action and requires presynaptic GABAA receptors involvement.

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Abbreviations

GABA:

γ-Aminobutyric acid

ACSF:

Artificial cerebrospinal fluid

S1BF:

The primary somatosensory barrel cortex

VPM:

The ventral posteromedial nucleus

sEPSCs:

Spontaneous excitatory postsynaptic currents

sIPSCs:

Spontaneous inhibitory postsynaptic currents

mEPSCs:

Miniature excitatory postsynaptic currents

mIPSCs:

Miniature inhibitory postsynaptic currents

VB:

The ventrobasal complex

RTN:

The reticular nucleus

References

  1. Rudolph U, Antkowiak B (2004) Molecular and neuronal substrates for general anaesthetics. Nat Rev Neurosci 5:709–720

    Article  CAS  PubMed  Google Scholar 

  2. Franks NP (2008) General anaesthesia: from molecular targets to neuronal pathways of sleep and arousal. Nat Rev Neurosci 9:370–386

    Article  CAS  PubMed  Google Scholar 

  3. Alkire MT, Hudetz AG, Tononi G (2008) Consciousness and anesthesia. Science 322:876–880

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Rath M, Fohr KJ, Weigt HU, Gauss A, Engele J, Georgieff M, Koster S, Adolph O (2008) Etomidate reduces glutamate uptake in rat cultured glial cells: involvement of PKA. Br J Pharmacol 155:925–933

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Li Z, Luo C, Sun YY, Chen J (2004) Effects of etomidate on local synaptic transmission in substantia gelatinosa neurons of the adult rat spinal cord. Sheng Li Xue Bao 56:413–418

    PubMed  Google Scholar 

  6. Edelman GM (2003) Naturalizing consciousness: a theoretical framework. Proc Natl Acad Sci USA 100:5520–5524

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Tononi G, Koch C (2008) The neural correlates of consciousness: an update. Ann N Y Acad Sci 1124:239–261

    Article  PubMed  Google Scholar 

  8. Zhang Y, Li Z, Dong H, Yu T (2014) Effects of general anesthesia with propofol on thalamocortical sensory processing in rats. J Pharmacol Sci 126:370–381

    Article  CAS  PubMed  Google Scholar 

  9. Zhang Y, Wang C, Zhang L, Yu T (2013) GABAA receptor in the thalamic specific relay system contributes to the propofol-induced somatosensory cortical suppression in rat. PLoS One 8:e82377

    Article  PubMed  PubMed Central  Google Scholar 

  10. Li Z, Liu X, Zhang Y, Shi J, Xie P, Yu T (2014) Connection changes in somatosensory cortex induced by different doses of propofol. PLoS One 9:e87829

    Article  PubMed  PubMed Central  Google Scholar 

  11. Zhang Y, He JC, Liu XK, Wang Y, Yu T (2014) Assessment of the effect of etomidate on voltage-gated sodium channels and action potentials in rat primary sensory cortex pyramidal neurons. Eur J Pharmacol 736:55–62

    Article  CAS  PubMed  Google Scholar 

  12. Tu Y, Yu T, Fu XY, Xie P, Lu S, Huang XQ, Gong QY (2011) Altered thalamocortical functional connectivity by propofol anesthesia in rats. Pharmacology 88:322–326

    Article  CAS  PubMed  Google Scholar 

  13. Ying SW, Goldstein PA (2005) Propofol suppresses synaptic responsiveness of somatosensory relay neurons to excitatory input by potentiating GABA(A) receptor chloride channels. Mol Pain 1:2

    Article  PubMed  PubMed Central  Google Scholar 

  14. Yang H, Wang Y, Zhang Y, Xu MS, Yuan J, Yu T (2016) Astrocytes contribute to the effects of etomidate on synaptic transmission in rat primary somatosensory cortex. Brain Res. doi:10.1016/j.brainres.2016.03.052

    Google Scholar 

  15. Kotani N, Wakita M, Shin MC, Ogawa S, Nonaka K, Akaike N (2012) Effects of halothane on GABAergic and glutamatergic transmission in isolated hippocampal nerve-synapse preparations. Brain Res 1473:9–18

    Article  CAS  PubMed  Google Scholar 

  16. Heinisch S, Kirby LG (2010) SDF-1alpha/CXCL12 enhances GABA and glutamate synaptic activity at serotonin neurons in the rat dorsal raphe nucleus. Neuropharmacology 58:501–514

    Article  CAS  PubMed  Google Scholar 

  17. Jang IS, Jeong HJ, Katsurabayashi S, Akaike N (2002) Functional roles of presynaptic GABA(A) receptors on glycinergic nerve terminals in the rat spinal cord. J Physiol 541:423–434

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Akeju O, Loggia ML, Catana C, Pavone KJ, Vazquez R, Rhee J, Contreras Ramirez V, Chonde DB, Izquierdo-Garcia D, Arabasz G, Hsu S, Habeeb K, Hooker JM, Napadow V, Brown EN, Purdon PL (2014) Disruption of thalamic functional connectivity is a neural correlate of dexmedetomidine-induced unconsciousness. Elife 3:e04499

    Article  PubMed  PubMed Central  Google Scholar 

  19. Liu X, Lauer KK, Ward BD, Li SJ, Hudetz AG (2013) Differential effects of deep sedation with propofol on the specific and nonspecific thalamocortical systems: a functional magnetic resonance imaging study. Anesthesiology 118:59–69

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Alkire MT, Haier RJ, Fallon JH (2000) Toward a unified theory of narcosis: brain imaging evidence for a thalamocortical switch as the neurophysiologic basis of anesthetic-induced unconsciousness. Conscious Cogn 9:370–386

    Article  CAS  PubMed  Google Scholar 

  21. Boveroux P, Vanhaudenhuyse A, Bruno MA, Noirhomme Q, Lauwick S, Luxen A, Degueldre C, Plenevaux A, Schnakers C, Phillips C, Brichant JF, Bonhomme V, Maquet P, Greicius MD, Laureys S, Boly M (2010) Breakdown of within- and between-network resting state functional magnetic resonance imaging connectivity during propofol-induced loss of consciousness. Anesthesiology 113:1038–1053

    Article  CAS  PubMed  Google Scholar 

  22. White NS, Alkire MT (2003) Impaired thalamocortical connectivity in humans during general-anesthetic-induced unconsciousness. Neuroimage 19:402–411

    Article  PubMed  Google Scholar 

  23. Verdonck O, Reed SJ, Hall J, Gotman J, Plourde G (2014) The sensory thalamus and cerebral motor cortex are affected concurrently during induction of anesthesia with propofol: a case series with intracranial electroencephalogram recordings. Can J Anaesth 61:254–262

    Article  PubMed  Google Scholar 

  24. Dai S, Perouansky M, Pearce RA (2009) Amnestic concentrations of etomidate modulate GABAA, slow synaptic inhibition in hippocampus. Anesthesiology 111:766–773

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Grasshoff C, Jurd R, Rudolph U, Antkowiak B (2007) Modulation of presynaptic beta3-containing GABAA receptors limits the immobilizing actions of GABAergic anesthetics. Mol Pharmacol 72:780–787

    Article  CAS  PubMed  Google Scholar 

  26. Banks MI, Pearce RA (1999) Dual actions of volatile anesthetics on GABA(A) IPSCs: dissociation of blocking and prolonging effects. Anesthesiology 90:120–134

    Article  CAS  PubMed  Google Scholar 

  27. Wakita M, Kotani N, Nonaka K, Shin MC, Akaike N (2013) Effects of propofol on GABAergic and glutamatergic transmission in isolated hippocampal single nerve-synapse preparations. Eur J Pharmacol 718:63–73

    Article  CAS  PubMed  Google Scholar 

  28. Jin YH, Zhang Z, Mendelowitz D, Andresen MC (2009) Presynaptic actions of propofol enhance inhibitory synaptic transmission in isolated solitary tract nucleus neurons. Brain Res 1286:75–83

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Maldifassi MC, Baur R, Sigel E (2016) Functional sites involved in modulation of the GABA receptor channel by the intravenous anesthetics propofol, etomidate and pentobarbital. Neuropharmacology 105:207–214

    Article  CAS  PubMed  Google Scholar 

  30. Labrakakis C, Rudolph U, De Koninck Y (2014) The heterogeneity in GABAA receptor-mediated IPSC kinetics reflects heterogeneity of subunit composition among inhibitory and excitatory interneurons in spinal lamina II. Front Cell Neurosci 8:424

    Article  PubMed  PubMed Central  Google Scholar 

  31. Mody I, Pearce RA (2004) Diversity of inhibitory neurotransmission through GABA(A) receptors. Trends Neurosci 27:569–575

    Article  CAS  PubMed  Google Scholar 

  32. Sassoe-Pognetto M, Panzanelli P, Sieghart W, Fritschy JM (2000) Colocalization of multiple GABA(A) receptor subtypes with gephyrin at postsynaptic sites. J Comp Neurol 420:481–498

    Article  CAS  PubMed  Google Scholar 

  33. Browne SH, Kang J, Akk G, Chiang LW, Schulman H, Huguenard JR, Prince DA (2001) Kinetic and pharmacological properties of GABA(A) receptors in single thalamic neurons and GABA(A) subunit expression. J Neurophysiol 86:2312–2322

    CAS  PubMed  Google Scholar 

  34. Okada M, Onodera K, Van Renterghem C, Sieghart W, Takahashi T (2000) Functional correlation of GABA(A) receptor alpha subunits expression with the properties of IPSCs in the developing thalamus. J Neurosci 20:2202–2208

    CAS  PubMed  Google Scholar 

  35. Pirker S, Schwarzer C, Wieselthaler A, Sieghart W, Sperk G (2000) GABA(A) receptors: immunocytochemical distribution of 13 subunits in the adult rat brain. Neuroscience 101:815–850

    Article  CAS  PubMed  Google Scholar 

  36. Kitamura A, Marszalec W, Yeh JZ, Narahashi T (2003) Effects of halothane and propofol on excitatory and inhibitory synaptic transmission in rat cortical neurons. J Pharmacol Exp Ther 304:162–171

    Article  CAS  PubMed  Google Scholar 

  37. Patel PM, Goskowicz RL, Drummond JC, Cole DJ (1995) Etomidate reduces ischemia-induced glutamate release in the hippocampus in rats subjected to incomplete forebrain ischemia. Anesth Analg 80:933–939

    CAS  PubMed  Google Scholar 

  38. Xie F, Li X, Bao M, Shi R, Yue Y, Guan Y, Wang Y (2015) Anesthetic propofol normalized the increased release of glutamate and gamma-amino butyric acid in hippocampus after paradoxical sleep deprivation in rats. Neurol Res 37:1102–1107

    Article  CAS  PubMed  Google Scholar 

  39. McDougall SJ, Bailey TW, Mendelowitz D, Andresen MC (2008) Propofol enhances both tonic and phasic inhibitory currents in second-order neurons of the solitary tract nucleus (NTS). Neuropharmacology 54:552–563

    Article  CAS  PubMed  Google Scholar 

  40. Yamamoto S, Yoshimura M, Shin MC, Wakita M, Nonaka K, Akaike N (2011) GABA(A) receptor-mediated presynaptic inhibition on glutamatergic transmission. Brain Res Bull 84:22–30

    Article  CAS  PubMed  Google Scholar 

  41. Wakita M, Kotani N, Kogure K, Akaike N (2014) Inhibition of excitatory synaptic transmission in hippocampal neurons by levetiracetam involves Zn(2)(+)-dependent GABA type A receptor-mediated presynaptic modulation. J Pharmacol Exp Ther 348:246–259

    Article  PubMed  Google Scholar 

  42. Cheng VY, Martin LJ, Elliott EM, Kim JH, Mount HT, Taverna FA, Roder JC, Macdonald JF, Bhambri A, Collinson N, Wafford KA, Orser BA (2006) Alpha5GABAA receptors mediate the amnestic but not sedative-hypnotic effects of the general anesthetic etomidate. J Neurosci 26:3713–3720

    Article  CAS  PubMed  Google Scholar 

  43. Belelli D, Callachan H, Hill-Venning C, Peters JA, Lambert JJ (1996) Interaction of positive allosteric modulators with human and Drosophila recombinant GABA receptors expressed in Xenopus laevis oocytes. Br J Pharmacol 118:563–576

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Zurek AA, Yu J, Wang DS, Haffey SC, Bridgwater EM, Penna A, Lecker I, Lei G, Chang T, Salter EW, Orser BA (2014) Sustained increase in alpha5GABAA receptor function impairs memory after anesthesia. J Clin Invest 124:5437–5441

    Article  PubMed  PubMed Central  Google Scholar 

  45. Mantz J, Lecharny JB, Laudenbach V, Henzel D, Peytavin G, Desmonts JM (1995) Anesthetics affect the uptake but not the depolarization-evoked release of GABA in rat striatal synaptosomes. Anesthesiology 82:502–511

    Article  CAS  PubMed  Google Scholar 

  46. Hill-Venning C, Belelli D, Peters JA, Lambert JJ (1997) Subunit-dependent interaction of the general anaesthetic etomidate with the gamma-aminobutyric acid type A receptor. Br J Pharmacol 120:749–756

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Antkowiak B, Rudolph U (2016) New insights in the systemic and molecular underpinnings of general anesthetic actions mediated by gamma-aminobutyric acid A receptors. Curr Opin Anaesthesiol 29:447–453

    Article  CAS  PubMed  Google Scholar 

  48. Amlong CA, Perkins MG, Houle TT, Miller KW, Pearce RA (2016) Contrasting effects of the gamma-aminobutyric acid type A receptor beta3 subunit N265M mutation on loss of righting reflexes induced by etomidate and the novel anesthetic barbiturate R-mTFD-MPAB. Anesth Analg. doi:10.1213/ANE.0000000000001358

  49. Maldifassi MC, Baur R, Sigel E (2016) Functional sites involved in modulation of the GABAA receptor channel by the intravenous anesthetics propofol, etomidate and pentobarbital. Neuropharmacology 105:207–214

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Supported by grants from the National Natural Science Foundation of China (NSFC, Grant No. 81060266 and 81571026). Thanks for Junwei Zeng (Zunyi Medical College, Zunyi, China) for carefully reading an early version of the manuscript.

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Correspondence to Tian Yu.

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The authors declare that there is no conflict of interests regarding the publication of this paper.

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Bao Fu and Yuan Wang have contributed to the work equally and should be regarded as co-first authors.

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Fu, B., Wang, Y., Yang, H. et al. Effects of Etomidate on GABAergic and Glutamatergic Transmission in Rat Thalamocortical Slices. Neurochem Res 41, 3181–3191 (2016). https://doi.org/10.1007/s11064-016-2042-6

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  • DOI: https://doi.org/10.1007/s11064-016-2042-6

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