Pre-Botzinger complex

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PreBotzinger complex
NeuroLex ID PreBotzinger complex
Anatomical terms of neuroanatomy

The Pre-Bötzinger Complex (preBötC) is a cluster of interneurons in the ventrolateral medulla of the brainstem, which is essential to the generation of respiratory rhythm in mammals.[1] The exact mechanism of the rhythm generation and transmission to motor nuclei remains controversial and the topic of much present research.[2][3][4][5][6][7]

Several synthetic compounds have been shown to act on neurons specific to the preBötC, most being selective agonists or antagonists to receptor subtypes on neurons in the vicinity. Since many of these neurons express GABA, glutamate, serotonin[8] and adenosine receptors, chemicals custom tailored to bind at these sites are most effective at altering respiratory rhythm.

One such novel compound that acts on this area of the brain, called BIMU8, has been discovered. BIMU8, along with other selective serotonin 5HT4 receptor agonists such as zacopride, are thought to stimulate the preBötC, causing an increase in the rate of respiration which can block the respiratory depression produced by high doses of opioid drugs.[9][10] Several ampakine drugs, such as CX-546,[11] CX-717 and CX-1739, also stimulate this area, and some of these are being developed for use alongside opioids in human medicine.[12][13]

Adenosine modulates the preBötC output via activation of the A1 and A2A receptor subtypes.[14][15] An adenosine A1 receptor agonist called N6-Cyclopentyladenosine (NCPA) has been shown to depress preBötC rhythmogenesis independent of the neurotransmitters GABA and glycine in "in vitro" preparations from 0-7 day old mice.[16] Another synthetic drug specific to the adenosine A2A receptor subtype is CGS-21680 that has been shown to cause apneas in 14-21 day old rat pups in vivo. For this reason, it has been used as a model to study pathological conditions such as apnea of prematurity and SIDS in neonatal infants.

See also[edit]


  1. ^ Smith JC, Ellenberger HH, Ballanyi K, Richter DW, Feldman JL (November 1991). "Pre-Bötzinger complex: a brainstem region that may generate respiratory rhythm in mammals". Science 254 (5032): 726–9. doi:10.1126/science.1683005. PMC 3209964. PMID 1683005. 
  2. ^ Rybak IA, Abdala AP, Markin SN, Paton JF, Smith JC (2007). "Spatial organization and state-dependent mechanisms for respiratory rhythm and pattern generation". Progress in Brain Research. Progress in Brain Research 165: 201–20. doi:10.1016/S0079-6123(06)65013-9. ISBN 978-0-444-52823-0. PMC 2408750. PMID 17925248. 
  3. ^ Smith JC, Abdala AP, Koizumi H, Rybak IA, Paton JF (December 2007). "Spatial and Functional Architecture of the Mammalian Brain Stem Respiratory Network: A Hierarchy of Three Oscillatory Mechanisms". Journal of Neurophysiology 98 (6): 3370–87. doi:10.1152/jn.00985.2007. PMC 2225347. PMID 17913982. 
  4. ^ Gargaglioni LH, Bícegoa KC, Branco LG (December 2008). "Brain monoaminergic neurons and ventilatory control in vertebrates". Respiratory Physiology & Neurobiology 164 (1–2): 112–22. doi:10.1016/j.resp.2008.04.017. PMID 18550453. 
  5. ^ Rubin JE, Shevtsova NA, Ermentrout GB, Smith JC, Rybak IA (April 2009). "Multiple Rhythmic States in a Model of the Respiratory Central Pattern Generator". Journal of Neurophysiology 101 (4): 2146–65. doi:10.1152/jn.90958.2008. PMC 2695631. PMID 19193773. 
  6. ^ Viemari JC, Tryba AK (April 2009). "Bioaminergic neuromodulation of respiratory rhythm in vitro". Respiratory Physiology & Neurobiology 168 (1–2): 69–75. doi:10.1016/j.resp.2009.03.011. PMC 2791959. PMID 19538922. 
  7. ^ Abdala AP, Rybak IA, Smith JC, Zoccal DB, Machado BH, St-John WM, Paton JF (June 2009). "Multiple Pontomedullary Mechanisms of Respiratory Rhythmogenesis". Respiratory Physiology & Neurobiology 168 (1–2): 19–25. doi:10.1016/j.resp.2009.06.011. PMC 2734878. PMID 19540366. 
  8. ^ Peña F, Ramirez JM (December 2002). "Endogenous activation of serotonin-2A receptors is required for respiratory rhythm generation in vitro". J. Neurosci. 22 (24): 11055–64. PMID 12486201. 
  9. ^ Manzke T, Guenther U, Ponimaskin EG, Haller M, Dutschmann M, Schwarzacher S, Richter DW (July 2003). "5-HT4(a) receptors avert opioid-induced breathing depression without loss of analgesia". Science 301 (5630): 226–9. doi:10.1126/science.1084674. PMID 12855812. 
  10. ^ Meyer LC, Fuller A, Mitchell D (February 2006). "Zacopride and 8-OH-DPAT reverse opioid-induced respiratory depression and hypoxia but not catatonic immobilization in goats". American Journal of Physiology. Regulatory, Integrative and Comparative Physiology 290 (2): R405–13. doi:10.1152/ajpregu.00440.2005. PMID 16166206. 
  11. ^ Ren J, Poon BY, Tang Y, Funk GD, Greer JJ (December 2006). "Ampakines alleviate respiratory depression in rats". American Journal of Respiratory and Critical Care Medicine 174 (12): 1384–91. doi:10.1164/rccm.200606-778OC. PMID 16973981. 
  12. ^ Pattinson KT (June 2008). "Opioids and the control of respiration". British Journal of Anaesthesia 100 (6): 747–58. doi:10.1093/bja/aen094. PMID 18456641. 
  13. ^ Ren J, Ding X, Funk GD, Greer JJ (June 2009). "Ampakine CX717 protects against fentanyl-induced respiratory depression and lethal apnea in rats". Anesthesiology 110 (6): 1364–70. doi:10.1097/ALN.0b013e31819faa2a. PMID 19461299. 
  14. ^ Mayer CA, Haxhiu MA, Martin RJ, Wilson CG (January 2006). "Adenosine A2A receptors mediate GABAergic inhibition of respiration in immature rats". Journal of Applied Physiology 100 (1): 91–7. doi:10.1152/japplphysiol.00459.2005. PMID 16141383. 
  15. ^ Vandam RJ, Shields EJ, Kelty JD (2008). "Rhythm generation by the pre-Bötzinger Complex in medullary slice and island preparations: Effects of adenosine A1 receptor activation". BMC Neuroscience 9: 95. doi:10.1186/1471-2202-9-95. PMC 2567986. PMID 18826652. 
  16. ^ Kuwana S, Tsunekawa N, Yanagawa Y, Okada Y, Kuribayashi J, Obata K (February 2006). "Electrophysiological and morphological characteristics of GABAergic respiratory neurons in the mouse pre-Bötzinger complex". The European Journal of Neuroscience 23 (3): 667–74. doi:10.1111/j.1460-9568.2006.04591.x. PMID 16487148.