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Article ; Online: Benefit of buspirone on chemoreflex and central apnoeas in heart failure: a randomized controlled crossover trial.

Giannoni, Alberto / Borrelli, Chiara / Mirizzi, Gianluca / Richerson, George B / Emdin, Michele / Passino, Claudio

2020 Volume 23, Issue 2, Page(s) 312–320

Abstract: Aims: Increased chemosensitivity to carbon dioxide (CO: Methods and results: The BREATH study was a randomized, double-blind, placebo-controlled, crossover study (EudraCT-code 2015-005383-42). Outpatients with systolic HF (left ventricular ejection ... ...

Abstract	Aims: Increased chemosensitivity to carbon dioxide (CO Methods and results: The BREATH study was a randomized, double-blind, placebo-controlled, crossover study (EudraCT-code 2015-005383-42). Outpatients with systolic HF (left ventricular ejection fraction <50%) and moderate-severe CA [nocturnal apnoea-hypopnoea index (AHI) ≥15 events/h] were randomly assigned to either oral buspirone (15 mg thrice daily) or placebo for 1 week, with a crossover design (1 week of wash-out). The primary effectiveness endpoint was a decrease in CO Conclusions: Buspirone reduces CO
MeSH term(s)	Aged ; Animals ; Buspirone ; Cross-Over Studies ; Heart Failure ; Humans ; Male ; Sleep Apnea, Central ; Stroke Volume ; Ventricular Function, Left
Chemical Substances	Buspirone (TK65WKS8HL)
Language	English
Publishing date	2020-05-22
Publishing country	England
Document type	Journal Article ; Randomized Controlled Trial ; Research Support, N.I.H., Extramural
ZDB-ID	1483672-5
ISSN	1879-0844 ; 1388-9842
ISSN (online)	1879-0844
ISSN	1388-9842
DOI	10.1002/ejhf.1854
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Article: Short communication: Comparison of long-acting or conventional growth implants on growth performance in steers grazed for 108 days

Ball, J. J. / Kegley, E. B. / Richerson, J. T. / Rowe, M. P. / Powell, J. G.

Livestock science

2020 Volume 238, Issue -, Page(s) 104039

Language	English
Document type	Article
ZDB-ID	2226176-X
ISSN	1871-1413
Database	Current Contents Nutrition, Environment, Agriculture

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Article ; Online: Diphtheria toxin treatment of Pet-1-Cre floxed diphtheria toxin receptor mice disrupts thermoregulation without affecting respiratory chemoreception.

Cerpa, V / Gonzalez, A / Richerson, G B

Neuroscience

2014 Volume 279, Page(s) 65–76

Abstract: In genetically-modified Lmx1b(f/f/p) mice, selective deletion of LMX1B in Pet-1 expressing cells leads to failure of embryonic development of serotonin (5-HT) neurons. As adults, these mice have a decreased hypercapnic ventilatory response and abnormal ... ...

Abstract	In genetically-modified Lmx1b(f/f/p) mice, selective deletion of LMX1B in Pet-1 expressing cells leads to failure of embryonic development of serotonin (5-HT) neurons. As adults, these mice have a decreased hypercapnic ventilatory response and abnormal thermoregulation. This mouse model has been valuable in defining the normal role of 5-HT neurons, but it is possible that developmental compensation reduces the severity of observed deficits. Here we studied mice genetically modified to express diphtheria toxin receptors (DTR) on Pet-1 expressing neurons (Pet-1-Cre/floxed DTR or Pet1/DTR mice). These mice developed with a normal complement of 5-HT neurons. As adults, systemic treatment with 2-35μg of diphtheria toxin (DT) reduced the number of tryptophan hydroxylase-immunoreactive (TpOH-ir) neurons in the raphe nuclei and ventrolateral medulla by 80%. There were no effects of DT on minute ventilation (VE) or the ventilatory response to hypercapnia or hypoxia. At an ambient temperature (TA) of 24°C, all Pet1/DTR mice dropped their body temperature (TB) below 35°C after DT treatment, but the latency was shorter in males than females (3.0±0.37 vs. 4.57±0.29days, respectively; p<0.001). One week after DT treatment, mice were challenged by dropping TA from 37°C to 24°C, which caused TB to decrease more in males than in females (29.7±0.31°C vs. 33.0±1.3°C, p<0.01). We conclude that the 20% of 5-HT neurons that remain after DT treatment in Pet1/DTR mice are sufficient to maintain normal baseline breathing and a normal response to CO2, while those affected include some essential for thermoregulation, in males more than females. In comparison to models with deficient embryonic development of 5-HT neurons, acute deletion of 5-HT neurons in adults leads to a greater defect in thermoregulation, suggesting that significant developmental compensation can occur.
MeSH term(s)	Animals ; Body Temperature Regulation/physiology ; Diphtheria Toxin/pharmacology ; Female ; Heparin-binding EGF-like Growth Factor/genetics ; Heparin-binding EGF-like Growth Factor/metabolism ; Hypercapnia/physiopathology ; Hypoxia/physiopathology ; Male ; Medulla Oblongata/physiology ; Mice, Transgenic ; Neurons/physiology ; Raphe Nuclei/physiology ; Respiration ; Serotonin/metabolism ; Sex Characteristics ; Tryptophan Hydroxylase/metabolism
Chemical Substances	Diphtheria Toxin ; Heparin-binding EGF-like Growth Factor ; Serotonin (333DO1RDJY) ; Tryptophan Hydroxylase (EC 1.14.16.4)
Language	English
Publishing date	2014-08-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	196739-3
ISSN	1873-7544 ; 0306-4522
ISSN (online)	1873-7544
ISSN	0306-4522
DOI	10.1016/j.neuroscience.2014.08.018
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Article: Chloride: an anaplastic anion?

Richerson, G B

Neuroreport

1996 Volume 7, Issue 5, Page(s) 969–970

MeSH term(s)	Astrocytes/physiology ; Carcinoma/pathology ; Carcinoma/physiopathology ; Chloride Channels/physiology ; Humans ; Tumor Cells, Cultured
Chemical Substances	Chloride Channels
Language	English
Publishing date	1996-04-10
Publishing country	England
Document type	Comment ; Journal Article
ZDB-ID	1049746-8
ISSN	1473-558X ; 0959-4965
ISSN (online)	1473-558X
ISSN	0959-4965
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Article: Response to CO2 of neurons in the rostral ventral medulla in vitro.

Richerson, G B

Journal of neurophysiology

1995 Volume 73, Issue 3, Page(s) 933–944

Abstract: 1. It has been hypothesized that CO2-sensitive neurons are located in the rostral ventral medulla. To demonstrate this at the cellular level, perforated patch-clamp recordings were made from rat medullary slices in vitro. The effect of respiratory ... ...

Abstract	1. It has been hypothesized that CO2-sensitive neurons are located in the rostral ventral medulla. To demonstrate this at the cellular level, perforated patch-clamp recordings were made from rat medullary slices in vitro. The effect of respiratory acidosis/alkalosis on the electrophysiologic properties of neurons was studied by recording membrane potential while changing the CO2 of the bath solution and allowing pH to vary. 2. At baseline, most neurons in the rostral ventrolateral medulla (VLM) and rostral medullary raphe spontaneously fired repetitively at a regular rate (3.3 +/- 2.5 Hz, mean +/- SD) with a linear interspike ramp depolarization (n = 102 of 135). Spontaneous firing continued after synaptic blockade with high-magnesium, low-calcium solution (n = 14 of 15). Spontaneous firing of calcium spikes continued in tetrodotoxin (TTX; n = 13 of 13), but was blocked by TTX and cadmium (n = 4 of 4). 3. The effect of respiratory acidosis/alkalosis on neurons was examined by changing the CO2 of the bicarbonate-buffered bath solution within the range of 3-9%. Most neurons studied (n = 74 of 105) did not change their firing rate in response to this stimulus; however, some neurons were stimulated (n = 16) and other neurons were inhibited (n = 15) by increases in CO2. 4. In many CO2-stimulated neurons, the increase in firing rate caused by an increase in CO2 was associated with an increase in slope of the linear interspike ramp depolarization, whereas in many CO2-inhibited neurons the opposite occurred, i.e., an increase in CO2 resulted in a decrease in slope of the ramp depolarization. These changes occurred without a change in the level of afterhyperpolarization or spike threshold. 5. Whole cell patch-clamp recording invariably resulted in loss of spontaneous and stimulated repetitive firing over 10-40 min despite good resting potential, input resistance, and amplitude of single depolarization-evoked spikes. CO2 produced no change in membrane potential in neurons after rundown of repetitive firing. The loss of repetitive firing and CO2 sensitivity with whole cell recording required the use of perforated-patch recordings of membrane potential or cell-attached-patch recordings of spike transients to accurately study the baseline electrophysiologic properties and CO2 sensitivity of rostral medullary neurons. 6. Neuronal location was determined before each recording using direct visualization of living slices, and after some recordings using biocytin staining. CO2-stimulated and CO2-inhibited neurons were both found to have cell bodies in the rostral VLM, an area thought to contain central respiratory chemoreceptors.(ABSTRACT TRUNCATED AT 400 WORDS)
MeSH term(s)	Action Potentials/drug effects ; Animals ; Calcium/pharmacology ; Carbon Dioxide/pharmacology ; In Vitro Techniques ; Magnesium/pharmacology ; Medulla Oblongata/drug effects ; Neurons/drug effects ; Patch-Clamp Techniques ; Rats ; Rats, Sprague-Dawley ; Tetrodotoxin/toxicity ; Time Factors
Chemical Substances	Carbon Dioxide (142M471B3J) ; Tetrodotoxin (4368-28-9) ; Magnesium (I38ZP9992A) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	1995-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	80161-6
ISSN	1522-1598 ; 0022-3077
ISSN (online)	1522-1598
ISSN	0022-3077
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Article: Contributions of 5-HT neurons to respiratory control: neuromodulatory and trophic effects.

Hodges, Matthew R / Richerson, George B

Respiratory physiology & neurobiology

2008 Volume 164, Issue 1-2, Page(s) 222–232

Abstract: ... Each of these chemicals produce effects largely through G protein-coupled receptors, second messenger systems and subsequent ...

Abstract	Serotonin (5-hydroxytryptamine; 5-HT) is a neurotransmitter produced by a small number of neurons in the midbrain, pons and medulla. These neurons project widely throughout the neuraxis, where they release 5-HT and co-localized neuropeptides such as substance P (SP) and thyrotropin-releasing hormone (TRH). Each of these chemicals produce effects largely through G protein-coupled receptors, second messenger systems and subsequent neuromodulatory effects on target neurons. Emerging evidence suggests that 5-HT has additional modes of action during development and in adult mammals, including trophic effects (neurogenesis, cell differentiation, proliferation, migration and maturation) and influences on synaptic plasticity. Here, we discuss some of the neuromodulatory and trophic roles of 5-HT in general and in the context of respiratory control, as well as the regulation of release of modulatory neurotransmitters from 5-HT neurons. Future directions of study are also discussed.
MeSH term(s)	Animals ; Brain Stem/cytology ; Humans ; Motor Neurons/drug effects ; Motor Neurons/physiology ; Nerve Growth Factors/metabolism ; Nerve Growth Factors/pharmacology ; Neurotransmitter Agents/metabolism ; Neurotransmitter Agents/pharmacology ; Respiration/drug effects ; Respiratory System/metabolism ; Serotonin/metabolism ; Serotonin/pharmacology
Chemical Substances	Nerve Growth Factors ; Neurotransmitter Agents ; Serotonin (333DO1RDJY)
Language	English
Publishing date	2008-06-20
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	2077867-3
ISSN	1878-1519 ; 1569-9048
ISSN (online)	1878-1519
ISSN	1569-9048
DOI	10.1016/j.resp.2008.05.014
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Article: Chemosensitivity of non-respiratory rat CNS neurons in tissue culture.

Wang, W / Richerson, G B

Brain research

2000 Volume 860, Issue 1-2, Page(s) 119–129

Abstract: ... methods [W. Wang, J.H. Pizzonia, G.B. Richerson, Chemosensitivity of rat medullary raphe neurones ...

Abstract	Neurons from many brainstem nuclei involved in respiratory control increase their firing rate in response to acidosis in vitro, suggesting that they are central chemoreceptors. This property has been considered to be either unique to neurons involved in respiratory control, or at least very unusual for non-respiratory neurons. However, recordings of intrinsic pH responses of neurons have not been made from enough non-respiratory regions of the CNS to be certain this assumption is true. Here, we have quantified changes in firing rate of neurons cultured from the hippocampus (n=43), neocortex (n=33), and cerebellum (n=29) in response to changes in CO(2) between 3% and 9% (pH approximately 7.6-7.2) after blockade of glutamatergic and GABAergic transmission. The responses of neurons from these three regions were similar, with a subset of neurons (12% of the total 105) inhibited by acidosis, decreasing their firing rate to a mean of 70% of control in response to a decrease in pH of 0.2. Some neurons (5% of total) were stimulated by acidosis, with an increase in firing rate to a mean of 175% of control in response to a decrease in pH of 0.2. We previously quantified chemosensitivity of neurons from the medullary raphe using the same methods [W. Wang, J.H. Pizzonia, G.B. Richerson, Chemosensitivity of rat medullary raphe neurones in primary tissue culture, J. Physiol., 511 (1998) 433-450]. Compared to these non-respiratory neurons, more raphe neurons were stimulated by acidosis (22%), and the average response was greater (to 300% of control) in response to the same stimulus. Thus, over a physiologically relevant pH range, stimulation by acidosis occurs in a significant percentage of neurons not involved in respiratory chemoreception. However, the degree of chemosensitivity of these neurons was less than medullary raphe neurons under the same conditions. Chemosensitivity is not an all-or-none neuronal property, and the degree of chemosensitivity may be relevant to the role neurons play in sensing pH in vivo.
MeSH term(s)	2-Amino-5-phosphonovalerate/pharmacology ; 6-Cyano-7-nitroquinoxaline-2,3-dione/pharmacology ; Acidosis/metabolism ; Acidosis/pathology ; Action Potentials/drug effects ; Animals ; Animals, Newborn ; Cells, Cultured ; Cerebellum/cytology ; Cerebellum/metabolism ; Chemoreceptor Cells/drug effects ; Chemoreceptor Cells/metabolism ; Chemoreceptor Cells/physiology ; Fibroblast Growth Factor 2/pharmacology ; Fibroblast Growth Factor 5 ; Fibroblast Growth Factors/pharmacology ; Hippocampus/cytology ; Hippocampus/metabolism ; Hydrogen-Ion Concentration ; Neocortex/cytology ; Neocortex/metabolism ; Neurons/drug effects ; Neurons/physiology ; Raphe Nuclei/cytology ; Raphe Nuclei/metabolism ; Rats ; Respiratory Center/cytology ; Respiratory Center/physiology
Chemical Substances	Fgf5 protein, rat ; Fibroblast Growth Factor 2 (103107-01-3) ; Fibroblast Growth Factor 5 (129653-64-1) ; Fibroblast Growth Factors (62031-54-3) ; 6-Cyano-7-nitroquinoxaline-2,3-dione (6OTE87SCCW) ; 2-Amino-5-phosphonovalerate (76726-92-6)
Language	English
Publishing date	2000-03-31
Publishing country	Netherlands
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	1200-2
ISSN	1872-6240 ; 0006-8993
ISSN (online)	1872-6240
ISSN	0006-8993
DOI	10.1016/s0006-8993(00)02033-3
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Zs.A 161: Show issues

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Article: Development of chemosensitivity of rat medullary raphe neurons.

Wang, W / Richerson, G B

Neuroscience

1999 Volume 90, Issue 3, Page(s) 1001–1011

Abstract: In many neonatal mammals, including humans and rats, there is a developmental increase in the ventilatory response to elevated pCO2. This maturation of central respiratory chemoreception may result from maturation of intrinsic chemosensitivity of ... ...

Abstract	In many neonatal mammals, including humans and rats, there is a developmental increase in the ventilatory response to elevated pCO2. This maturation of central respiratory chemoreception may result from maturation of intrinsic chemosensitivity of brainstem neurons. We have examined age-related changes in chemosensitivity of neurons from the rat medullary raphe, a putative site for central chemoreception, using perforated patch-clamp recordings in vitro. In brain slices from rats younger than 12 days old, firing rate increased in 3% of neurons and decreased in 17% of neurons in response to respiratory acidosis (n = 36). In contrast, in slices from rats 12 days and older, firing rate increased in 18% of neurons and decreased in 15% of neurons in response to the same stimulus (n = 40). A tissue culture preparation of medullary raphe neurons was used to examine changes in chemosensitivity with age from three to 74 days in vitro. In cultured neurons younger than 12 days in vitro, firing rate increased in 4% of neurons and decreased in 44% of neurons in response to respiratory acidosis (n = 54). In contrast, in neurons 12 days in vitro and older, firing rate increased in 30% of neurons and decreased in 24% of neurons in response to respiratory acidosis (n = 105). In both types of chemosensitive neuron ("stimulated" and "inhibited"), the magnitudes of the changes in firing rate were greater in older neurons than in young neurons. These results indicate that the incidence and the degree of chemosensitivity of medullary raphe neurons increase with age in brain slices and in culture. This age-related increase in cellular chemosensitivity may underlie the development of respiratory chemoreception in vivo. Delays in this maturation process may contribute to developmental abnormalities of breathing, such as sudden infant death syndrome.
MeSH term(s)	Aging/physiology ; Animals ; Animals, Newborn/growth & development ; Animals, Newborn/physiology ; Chemoreceptor Cells/physiology ; Culture Techniques ; Electrophysiology ; Medulla Oblongata ; Neurons/physiology ; Raphe Nuclei/cytology ; Raphe Nuclei/physiology ; Rats ; Rats, Sprague-Dawley
Language	English
Publishing date	1999-03
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	196739-3
ISSN	1873-7544 ; 0306-4522
ISSN (online)	1873-7544
ISSN	0306-4522
DOI	10.1016/s0306-4522(98)00505-3
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Zs.A 1215: Show issues

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Article ; Online: Dual effects of 5-HT(1a) receptor activation on breathing in neonatal mice.

Corcoran, Andrea E / Commons, Kathryn G / Wu, Yuanming / Smith, Jeffrey C / Harris, Michael B / Richerson, George B

The Journal of neuroscience : the official journal of the Society for Neuroscience

2013 Volume 34, Issue 1, Page(s) 51–59

Abstract: Inhibitory 5-HT(1a) receptors are located on serotonin (5-HT) neurons (autoreceptors) as well as neurons of the respiratory network (heteroreceptors). Thus, effects on breathing of 5-HT(1a) agonists, such as (R)-(+)-8-hydroxy-2-(di-N-propylamino) ... ...

Abstract	Inhibitory 5-HT(1a) receptors are located on serotonin (5-HT) neurons (autoreceptors) as well as neurons of the respiratory network (heteroreceptors). Thus, effects on breathing of 5-HT(1a) agonists, such as (R)-(+)-8-hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT), could either be due to decreased firing of 5-HT neurons or direct effects on the respiratory network. Mice in which the transcription factor LMX1B is genetically deleted selectively in Pet1-1-expressing cells (Lmx1b(f/f/p)) essentially have complete absence of central 5-HT neurons, providing a unique opportunity to separate the effect of activation of downstream 5-HT(1a) heteroreceptors from that of autoreceptors. We used rhythmically active medullary slices from wild-type (WT) and Lmx1b(f/f/p) neonatal mice to differentiate autoreceptor versus heteroreceptor effects of 8-OH-DPAT on hypoglossal nerve respiratory output. 8-OH-DPAT transiently increased respiratory burst frequency in Lmx1b(f/f/p) preparations, but not in WT slices. This excitation was abolished when synaptic inhibition was blocked by GABAergic/glycinergic receptor antagonists. Conversely, after 10 min of application, frequency in Lmx1b(f/f/p) slices was not different from baseline, whereas it was significantly depressed in WT slices. In WT mice in vivo, subcutaneous injection of 8-OH-DPAT produced similar biphasic respiratory effects as in Lmx1b(f/f/p) mice. We conclude that 5-HT1a receptor agonists have two competing effects: rapid stimulation of breathing due to excitation of the respiratory network, and delayed inhibition of breathing due to autoreceptor inhibition of 5-HT neurons. The former effect is presumably due to inhibition of inhibitory interneurons embedded in the respiratory network.
MeSH term(s)	Animals ; Animals, Newborn ; Female ; Male ; Mice ; Mice, Knockout ; Organ Culture Techniques ; Protein Binding/physiology ; Receptor, Serotonin, 5-HT1A/metabolism ; Respiration/drug effects ; Respiratory Center/drug effects ; Respiratory Center/physiology ; Respiratory Mechanics/drug effects ; Respiratory Mechanics/physiology ; Serotonergic Neurons/drug effects ; Serotonergic Neurons/physiology ; Serotonin 5-HT1 Receptor Agonists/pharmacology
Chemical Substances	Serotonin 5-HT1 Receptor Agonists ; Receptor, Serotonin, 5-HT1A (112692-38-3)
Language	English
Publishing date	2013-12-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	604637-x
ISSN	1529-2401 ; 0270-6474
ISSN (online)	1529-2401
ISSN	0270-6474
DOI	10.1523/JNEUROSCI.0864-13.2014
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Article ; Online: Postictal serotonin levels are associated with peri-ictal apnea.

Murugesan, Arun / Rani, M R Sandhya / Vilella, Laura / Lacuey, Nuria / Hampson, Johnson P / Faingold, Carl L / Friedman, Daniel / Devinsky, Orrin / Sainju, Rup K / Schuele, Stephan / Diehl, Beate / Nei, Maromi / Harper, Ronald M / Bateman, Lisa M / Richerson, George / Lhatoo, Samden D

Neurology

2019 Volume 93, Issue 15, Page(s) e1485–e1494

Abstract: Objective: To determine the relationship between serum serotonin (5-HT) levels, ictal central apnea (ICA), and postconvulsive central apnea (PCCA) in epileptic seizures.: Methods: We prospectively evaluated video EEG, plethysmography, capillary ... ...

Abstract	Objective: To determine the relationship between serum serotonin (5-HT) levels, ictal central apnea (ICA), and postconvulsive central apnea (PCCA) in epileptic seizures. Methods: We prospectively evaluated video EEG, plethysmography, capillary oxygen saturation (SpO Results: Postictal serum 5-HT levels were increased over interictal levels for seizures without ICA ( Conclusions: The data suggest that significant seizure-related increases in serum 5-HT levels are associated with a lower incidence of seizure-related breathing dysfunction, and may reflect physiologic changes that confer a protective effect against deleterious phenomena leading to SUDEP. These results need to be confirmed with a larger sample size study.
MeSH term(s)	Adolescent ; Adult ; Aged ; Apnea/complications ; Apnea/metabolism ; Apnea/physiopathology ; Death, Sudden/etiology ; Electroencephalography/methods ; Epilepsy/complications ; Epilepsy/metabolism ; Epilepsy/physiopathology ; Female ; Humans ; Male ; Middle Aged ; Seizures/complications ; Seizures/physiopathology ; Serotonin/metabolism
Chemical Substances	Serotonin (333DO1RDJY)
Keywords	covid19
Language	English
Publishing date	2019-09-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	207147-2
ISSN	1526-632X ; 0028-3878
ISSN (online)	1526-632X
ISSN	0028-3878
DOI	10.1212/WNL.0000000000008244
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