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.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
F. E. Bloom and L. L. Iversen, “Localizing 3H-GABA in nerve microscopic autoradiography,” Nature, 229, No. 5287, 628-630 (1971).
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).
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).
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).
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).
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).
M. Pokorski and S. Ohtani, “GABA immunoreactivity in chemoreceptor cells of the cat carotid body,” Acta Histochem. Cytochem., 32, 179-182 (1999).
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).
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).
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).
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.
J. Neubauer, J. E. Melton, and N. H. Edelman, “Modulation of respiration during brain hypoxia,” J. Appl. Physiol., 68, No. 2, 1462-1470 (1990).
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).
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).
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).
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).
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).
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).
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).
J. V. Weil, “Ventilatory response to CO2 and hypoxia after sustained hypoxia in awake cats,” J. Appl. Physiol., 76, No. 6, 2251-2252 (1994).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
C. A. Nurse, “Neurotransmitter and neuromodulatory mechanisms at peripheral arterial chemoreceptors,” Exp. Physiol., 95, No. 6, 657-667 (2010).
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).
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).
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).
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).
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).
M. Shirahata, “Neurotransmission in the carotid body and anesthesia,” J. Anesth., 16, No. 4, 298-309 (2002).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kolesnikova, E.É. GABAA Receptors: Involvement in the Formation of Respiratory Reactions to Hypoxic Stimulation under Conditions of Mitochondrial Dysfunction. Neurophysiology 49, 19–29 (2017). https://doi.org/10.1007/s11062-017-9625-y
Received:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11062-017-9625-y