State-dependent and -independent effects of dialyzing excitatory neuromodulator receptor antagonists into the ventral respiratory column.
Unilateral dialysis of the broad-spectrum muscarinic receptor antagonist atropine (50 mM) into the ventral respiratory column [(VRC) including the pre-Bötzinger complex region] of awake goats increased pulmonary ventilation (V̇i) and breathing frequency (f), conceivably due to local compensatory increases in serotonin (5-HT) and substance P (SP) measured in effluent mock cerebral spinal fluid (mCSF). In contrast, unilateral dialysis of a triple cocktail of antagonists to muscarinic (atropine; 5 mM), neurokinin-1, and 5-HT receptors does not alter V̇i or f, but increases local SP. Herein, we tested hypotheses that1) local compensatory 5-HT and SP responses to 50 mM atropine dialyzed into the VRC of goats will not differ between anesthetized and awake states; and2) bilateral dialysis of the triple cocktail of antagonists into the VRC of awake goats will not alter V̇i or f, but will increase local excitatory neuromodulators. Through microtubules implanted into the VRC of goats, probes were inserted to dialyze mCSF alone (time control), 50 mM atropine, or the triple cocktail of antagonists. We found1) equivalent increases in local 5-HT and SP with 50 mM atropine dialysis during wakefulness compared with isoflurane anesthesia, but V̇i and f only increased while awake; and2) dialyses of the triple cocktail of antagonists increased V̇i, f, 5-HT, and SP (<0.05) during both day and night studies. We conclude that the mechanisms governing local neuromodulator levels are state independent, and that bilateral excitatory receptor blockade elicits an increase in breathing, presumably due to a local, (over)compensatory neuromodulator response.NEW & NOTEWORTHYThe two major findings are as follows: 1) during unilateral dialysis of 50 mM atropine into the ventral respiratory column to block excitatory muscarinic receptor activity, a compensatory increase in other neuromodulators was state independent, but the ventilatory response appears to be state dependent; and 2) the hypothesis that absence of decreased V̇i and f during unilateral dialysis of excitatory receptor antagonists was due to compensation by the contralateral VRC was not supported by findings herein.
Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin.
Thomas M
TM
Langer
Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin.
Suzanne E
SE
Neumueller
Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin.
Emma
E
Crumley
Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin.
Nicholas J
NJ
Burgraff
Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin.
Sawan
S
Talwar
Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin.|Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin; and.
Matthew R
MR
Hodges
Department of Physical Therapy, Marquette University, Milwaukee, Wisconsin.
Lawrence
L
Pan
Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin; bforster@mcw.edu.|Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin; and.|Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin.
Hubert V
HV
Forster
D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002555:Cerebrospinal Fluid / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D005260:Female; D006041:Goats; D017551:Microdialysis / Q000379:methods; D018727:Muscarinic Antagonists / Q000494:pharmacology; D018377:Neurotransmitter Agents / Q000494:pharmacology*; D012123:Pulmonary Ventilation / Q000187:drug effects*; D011976:Receptors, Muscarinic / Q000378:metabolism; D017981:Receptors, Neurotransmitter / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism; D012119:Respiration / Q000187:drug effects; D012125:Respiratory Center / Q000187:drug effects* / Q000378:metabolism*; D015656:Respiratory Mechanics / Q000187:drug effects; D012701:Serotonin / Q000378:metabolism; D012890:Sleep / Q000187:drug effects / Q000502:physiology; D013373:Substance P / Q000378:metabolism; D014851:Wakefulness / Q000187:drug effects
D018727:Muscarinic Antagonists; D018377:Neurotransmitter Agents; D011976:Receptors, Muscarinic; D017981:Receptors, Neurotransmitter; D011985:Receptors, Serotonin; D012701:Serotonin; D013373:Substance P; D001285:Atropine
breathing; neuromodulation; pre-Bötzinger complex; sleep; ventral respiratory column
Clin Exp Pharmacol Physiol. 2000 Jan-Feb;27(1-2):132-7
10696542
Neuron. 2012 Oct 4;76(1):1-11
23040802
J Neurosci. 2010 Jun 16;30(24):8251-62
20554877
Philos Trans R Soc Lond B Biol Sci. 2009 Sep 12;364(1529):2577-87
19651658
Curr Treat Options Neurol. 2015 Oct;17(10):375
26307329
Respir Physiol Neurobiol. 2008 Dec 10;164(1-2):96-104
18602029
Science. 1975 Jul 4;189(4196):55-8
1094539
J Appl Physiol (1985). 2010 Jul;109(1):159-70
20431024
Nat Neurosci. 2001 Sep;4(9):927-30
11528424
J Neurosci. 2002 Dec 15;22(24):11055-64
12486201
J Appl Physiol (1985). 2004 Nov;97(5):1620-8
15247160
J Neurosci. 2006 Mar 8;26(10):2623-34
16525041
J Appl Physiol (1985). 2015 Aug 1;119(3):308-20
26023224
J Neurophysiol. 2007 Dec;98(6):3370-87
17913982
J Physiol. 2013 Apr 1;591(7):1631-43
23266935
Nat Rev Neurosci. 2006 Jul;7(7):563-74
16791145
J Appl Physiol (1985). 2009 Feb;106(2):605-19
19095752
Neurosurgery. 2011 Oct;69(4):957-79; discussion 979
21716154
Respir Physiol Neurobiol. 2015 Jan 1;205:7-15
25262584
J Appl Physiol (1985). 2013 Oct 1;115(7):1088-98
23869058
Respir Physiol Neurobiol. 2005 Nov 15;149(1-3):17-27
16203211
CNS Neurol Disord Drug Targets. 2012 Sep;11(6):722-38
22963441
Am J Physiol Regul Integr Comp Physiol. 2008 Mar;294(3):R884-94
18094064
J Appl Physiol (1985). 2015 Mar 15;118(6):732-41
25635003
J Appl Physiol (1985). 2004 Nov;97(5):1629-36
15247161
Wiley Interdiscip Rev Membr Transp Signal. 2012 Nov-Dec;1(6):789-803
25774333
Am J Psychiatry. 2008 Dec;165(12):1594-603
18923069
J Appl Physiol (1985). 2009 Nov;107(5):1591-9
19745186
Med Hypotheses. 2012 May;78(5):594-600
22336089
J Appl Physiol (1985). 2013 Mar 1;114(5):694-704
23271698
J Physiol. 1999 Oct 1;520 Pt 1:303-14
10517821
Respir Physiol Neurobiol. 2002 Jul;131(1-2):135-44
12107001
Eur J Neurosci. 2005 Nov;22(10):2403-12
16307583