, Volume 49, Issue 1, pp 19–29 | Cite as

GABAA Receptors: Involvement in the Formation of Respiratory Reactions to Hypoxic Stimulation under Conditions of Mitochondrial Dysfunction


In experiments on Wistar rats, the role of the state of GABAA receptors in the formation of respiratory responses to hypoxic loading was studied under conditions of the norm and experimental mitochondrial dysfunction; the latter was induced by single systemic injections of 3 mg/kg rotenone, a nonselective blocker of complex I in the respiratory chain of the mitochondria. Volume-time parameters of respiration were characterized according to the parameters of respiratory EMG discharges of the diaphragmatic muscle (amplitude, frequency, and integral intensity). Changes in EMG activity of the diaphragm induced by inhalation of a hypoxic gas mixture (12% О2 + 88% N2) were estimated prior to and after injections of the blocker of GABAA and GABAB receptors bicuculline (bicuculline methiodide, 1.0 mg/kg) in control rats and animals with mitochondrial dysfunction. The development of mitochondrial dysfunction was accompanied by suppression of the respiratory reaction to hypoxic loading, which was manifested in a dramatic decrease in the frequency and integral intensity of EMG discharges of the diaphragmatic muscle. These data can be considered an indication of the considerable involvement of GABAA receptors localized at the postsynaptic membranes of peripheral chemoreceptors in the formation of respiratory response to hypoxic stimulation (including the stage of depression of ventilation); this was observed in both control rats and animals with mitochondrial dysfunction. The involvement of a GABA-ergic link in the formation of respiratory activity related to hypoxic stimulation acquires special significance under conditions of experimental mitochondrial dysfunction leading to occlusion of afferent impulsation coming from peripheral chemoreceptors.


GABAA receptors hypoxia ventilatory response peripheral chemoreceptors EMG activity of the diaphragm 


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  1. 1.
    F. E. Bloom and L. L. Iversen, “Localizing 3H-GABA in nerve microscopic autoradiography,” Nature, 229, No. 5287, 628-630 (1971).CrossRefPubMedGoogle Scholar
  2. 2.
    R. A. Mueller, D. B. A. Lundberg, G. R. Breese, et al., “The neuropharmacology of respiratory control,” Pharmacol. Rev., 34, No. 3, 255-285 (1982).PubMedGoogle Scholar
  3. 3.
    C. A. Livingston and A. J. Berger, “Immunohistochemical localization of GABA in neurons projecting to the ventrolateral nucleus of the solitary tract,” Brain Res., 494, No. 1, 143-150 (1989).CrossRefPubMedGoogle Scholar
  4. 4.
    J. Lipski, H. J. Waldvogel, P. Pilowski, and C. Jiang, “GABA-immunoreactive boutons make synapses with inspiratory neurons of the dorsal respiratory group,” Brain Res., 529, Nos. 1/2, 309-314 (1990).CrossRefPubMedGoogle Scholar
  5. 5.
    I. R. Moss, M. Denavit-Saubie, F. L. Eldrige, et al., “Neuromodulators and transmitters in respiratory control,” Fed. Proc., 45, No. 7, 2133-2147 (1986).PubMedGoogle Scholar
  6. 6.
    Y. Oomori, K. Nakaya, H. Tanaka, et al., “Immunohistochemical and histochemical evidence for the presence of noradrenalin, serotonin and gammaaminobutyric acid in chief cells of the mouse carotid body,” Cell Tissue Res., 278, No. 2, 249-254 (1994).CrossRefPubMedGoogle Scholar
  7. 7.
    M. Pokorski and S. Ohtani, “GABA immunoreactivity in chemoreceptor cells of the cat carotid body,” Acta Histochem. Cytochem., 32, 179-182 (1999).CrossRefGoogle Scholar
  8. 8.
    I. M. Fearon, M. Zhang, C. Vollmer, and C. A. Nurse, “GABA mediates autoreceptor feedback inhibition in the rat carotid body via presynaptic GABAB receptors and TASK-1,” J. Physiol., 553, Part 3, 83-94 (2003).CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    M. Zhang, K. Clarke, H. Zhong, et al., “Postsynaptic action of GABA in modulating sensory transmission in co-culture of rat carotid body via GABAA receptors,” J. Physiol., 587, No. 2, 329-344 (2009).CrossRefPubMedGoogle Scholar
  10. 10.
    P. A. Easton, L. J. Slykerman, and N. R. Antoniesen, “Ventilatory response to sustained hypoxia in normal adults,” J. Appl. Physiol., 61, No. 3, 906-911 (1986).PubMedGoogle Scholar
  11. 11.
    G. E. Bisgard and J. A. Neubauer, “Peripheral and central effects of hypoxia,” in: Lung Biology in Health and Disease, Marcel Dekker, New York (1995), pp. 617-668.Google Scholar
  12. 12.
    J. Neubauer, J. E. Melton, and N. H. Edelman, “Modulation of respiration during brain hypoxia,” J. Appl. Physiol., 68, No. 2, 1462-1470 (1990).Google Scholar
  13. 13.
    L. J. Teppema and A. Dahan, “The ventilatory response to hypoxia in mammals: mechanisms, measurement, and analysis,” Physiol. Rev., 90, No. 2, 675-754 (2010).CrossRefPubMedGoogle Scholar
  14. 14.
    P. N. McWilliam and S. L. Shepeard, “A GABA-mediated inhibition of neurons of nucleus tractus solitarius of the cat that respond to electrical stimulation of the carotid sinus nerve,” Neurosci. Lett., 94, No. 3, 321-326 (1988).CrossRefPubMedGoogle Scholar
  15. 15.
    J. D. Wood, W. J. Watson, and A. J. Drucker, “The effect of hypoxia on brain gamma-amino butyric acid levels,” J. Neurochem., 15, No. 7, 603-608 (1968).CrossRefPubMedGoogle Scholar
  16. 16.
    J. E. Madl and S. M. Royer, “Glutamate dependence of GABA levels in neurons of hypoxic and hypoglycemic rat hippocampal slices,” Neuroscience, 96, No. 4, 657-664 (2000).CrossRefPubMedGoogle Scholar
  17. 17.
    M. Pokorski, E. Kolesnikova, M. Marczak, and K. Budzinska, “Neurotransmitter mechanisms in the enhancement of the hypoxic ventilatory response by antecedent hyperoxia in the anesthetized rat,” J. Physiol. Pharmacol. (Acta Pol.), 56, 433-446 (2005).Google Scholar
  18. 18.
    R. Betarbet, T. B. Sherer, G. MacKenzie, et al., “Chronic systemic pesticide exposure reproduces feature of Parkinson’s disease,” Nat. Neurosci., 3, No. 12, 1301-1306 (2000).CrossRefPubMedGoogle Scholar
  19. 19.
    E. É. Kolesnikova, V. I. Nosar’, I. N. Man’kovskaya, and T. V. Serebrovskaya, “Aging- and experimental mitochondrial dysfunction-related modifications of energy metabolism in brainstem neurons” Neurophysiology, 44, No. 1, 18-24 (2012).CrossRefGoogle Scholar
  20. 20.
    J. V. Weil, “Ventilatory response to CO2 and hypoxia after sustained hypoxia in awake cats,” J. Appl. Physiol., 76, No. 6, 2251-2252 (1994).PubMedGoogle Scholar
  21. 21.
    W. Q. Long, G. G. Giesbrecht, and N. R. Anthonisen, “Ventilatory response to moderate hypoxia in awake chemodenervated cats,” J. Appl. Physiol., 74, No. 2, 805-810 (1993).PubMedGoogle Scholar
  22. 22.
    H. Kimura, M. Tanaka, K. Nagao, et al., “A new aspect of the carotid body function controlling hypoxic ventilatory decline in humans,” Appl. Human Sci., 17, No. 4, 131- 137 (1998).CrossRefPubMedGoogle Scholar
  23. 23.
    R. C. Ang, B. Hoop, and H. Kazemi, “Role of glutamate as the central neurotransmitter in the hypoxic ventilatory response,” J. Appl. Physiol., 72, No. 4, 1480-1487 (1992).PubMedGoogle Scholar
  24. 24.
    B. Hoop, J. L. Beagle, T. J. Maher, and H. Kazemi, “Brainstem amino acid neurotransmitters and hypoxic ventilatory response,” Respir. Physiol., 118, 117-129 (1999).CrossRefPubMedGoogle Scholar
  25. 25.
    J. I. Melton, J. A. Neubauer, and N. H. Edelman, “GABA antagonism reverses hypoxic ventilatory depression in the cat,” J. Appl. Physiol., 69, No. 4, 1296-1301 (1990).PubMedGoogle Scholar
  26. 26.
    I. Soto-Arape, M. D. Burton, and H. Kazemi, “Central amino acid neurotransmitters and hypoxic ventilatory response,” Am. J. Respir. Crit. Care Med., 151, 1113-1120 (1995).PubMedGoogle Scholar
  27. 27.
    P. Ortega-Saenz, R. Pardal, M. Garcia-Fernandez, and J. Lopez-Barneo, “Rotenone selectively occludes sensitivity to hypoxia in rat carotid body glomus cells,” J. Physiol., 548, No. 3, 789-800 (2003).CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    N. K. Yelmen, “The role of gamma-aminobutyric acid and glutamate for hypoxic ventilatory response in anesthetized rabbit,” Tohoku J. Exp. Med., 203, 219-232 (2004).CrossRefPubMedGoogle Scholar
  29. 29.
    N. G. Man’shina and O. A. Vedyasova, “Comparative analysis of respiratory reactions to microinjections of GAB and penicillin in the Bötzinger’s complex and pre-Bötzinger’s complex in rats,” Vest. SamGU (Nat. Sci. Ser.), 94, Nos. 3/1, 210-218 (2012).Google Scholar
  30. 30.
    R. Itturiaga, R. Varas, and J. Alcayaga, “Electrical and pharmacological properties of petrosal ganglion neurons that innervate the carotid body,” Respirat. Physiol. Neurobiol., 157, 130-139 (2007).CrossRefGoogle Scholar
  31. 31.
    C. A. Nurse, “Neurotransmitter and neuromodulatory mechanisms at peripheral arterial chemoreceptors,” Exp. Physiol., 95, No. 6, 657-667 (2010).CrossRefPubMedGoogle Scholar
  32. 32.
    J. Buttigieg and C. A. Nurse, “Detection of hypoxiaevoked ATP release from chemoreceptor cells of the rat carotid body,” Biochem. Biophys. Res. Commun., 322, No. 1, 82-87 (2004).CrossRefPubMedGoogle Scholar
  33. 33.
    W. Rong, A. V. Gourine, D. A. Cockaine, et al., “Pivotal role of nucleotide P2X2 receptor subunit of the ATPgated ion channel mediating ventilatory response to hypoxia,” J. Neurosci., 23, No. 36, 11315-11321 (2003).PubMedGoogle Scholar
  34. 34.
    T.-B. Lin, M.-J. Lo, C.-Y. Huang, et al., “GABAergic modulation of ventilatory response to acute and sustained hypoxia in obese Zucker rats,” Int. J. Obesity, 29, 188-195 (2005).CrossRefGoogle Scholar
  35. 35.
    J. Champagnat, M. Denavit-Saubie, S. Moyanova, and G. Rondoum, “Involvement of amino acids in periodic inhibitions of bulbar respiratory neurons,” Brain Res., 237, No. 2, 351-365 (1982).CrossRefPubMedGoogle Scholar
  36. 36.
    A. M. Taveira-Da Silva, B. Hartley, P. Hamosh, et al., “Respiratory depressant effect of GABA alpha and betareceptor agonist in the cat,” J. Appl. Physiol., 62, No. 6, 2264-2272 (1987).CrossRefPubMedGoogle Scholar
  37. 37.
    M. Shirahata, “Neurotransmission in the carotid body and anesthesia,” J. Anesth., 16, No. 4, 298-309 (2002).CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.Bogomolets Institute of Physiology, National Academy of Sciences of UkraineKyivUkraine

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