scholarly journals α4-Containing nicotinic receptors contribute to the effects of perinatal nicotine on ventilatory and metabolic responses of neonatal mice to ambient cooling

2016 ◽  
Vol 311 (4) ◽  
pp. R727-R734
Author(s):  
Joanne Avraam ◽  
Kevin J. Cummings ◽  
Peter B. Frappell
Keyword(s):  
Acetylcholine Receptors ◽  
Nicotinic Receptors ◽  
Neonatal Period ◽  
Metabolic Response ◽  
Respiratory Control ◽  
Postnatal Period ◽  
Control Of Breathing ◽  
Nicotine Exposure ◽  
Wild Type ◽  
Ventilatory Responses

Among numerous studies, perinatal nicotine exposure (PN) has had variable effects on respiratory control in the neonatal period. The effects of acute nicotine exposure on breathing are largely mediated by α4-containing nicotine acetylcholine receptors (nAChRs). These receptors are also involved in thermoregulatory responses induced by both acetylcholine and nicotine. We therefore hypothesized that α4-containing nAChRs would mediate the effects of PN on the metabolic and ventilatory responses of neonates to modest cold exposure. Wild-type (WT) and α4 knockout (KO) mice were exposed to 6 mg·kg−1·day−1 nicotine or vehicle from embryonic day 14. At postnatal day (P) 7 mice were cooled from an ambient temperature (TA) of 32 to 20°C. Body temperature (TB), rate of O2 consumption (V̇o2), ventilation (V̇e), respiratory frequency (FB), and tidal volume (VT) were continually monitored. An absence of α4 had no effect on the metabolic response to ambient cooling. Surprisingly, PN selectively increased the metabolic response of KO pups to cooling. Regardless, KO pups became hypothermic to the same degree as WT pups, and for both genotypes the drop in TB was exacerbated by PN. PN led to hyperventilation in WT pups caused by an increase in VT, an effect that was absent in α4 KO littermates. We show that PN interacts with α4-containing nAChRs in unique ways to modulate the control of breathing and thermoregulation in the early postnatal period.

scholarly journals Acute Lung Injury in Cholinergic-Deficient Mice Supports Anti-Inflammatory Role of α7 Nicotinic Acetylcholine Receptor

2021 ◽  
Vol 22 (14) ◽  
pp. 7552
Author(s):  
Nathalia M. Pinheiro ◽  
Rosana Banzato ◽  
Iolanda Tibério ◽  
Marco A. M. Prado ◽  
Vânia F. Prado ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Nicotinic Receptor ◽  
Acetylcholine Receptors ◽  
Nicotinic Receptors ◽  
Radioligand Binding ◽  
Muscarinic Acetylcholine Receptors ◽  
Wild Type ◽  
Markers Of Inflammation ◽  
Anti Inflammatory

(1) Background: The lung cholinergic pathway is important for controlling pulmonary inflammation in acute lung injury, a condition that is characterized by a sudden onset and intense inflammation. This study investigated changes in the expression levels of nicotinic and muscarinic acetylcholine receptors (nAChR and mAChR) in the lung during acute lung injury. (2) Methods: acute lung injury (ALI) was induced in wild-type and cholinergic-deficient (VAChT-KDHOM) mice using intratracheal lipopolysaccharide (LPS) instillation with or without concurrent treatment with nicotinic ligands. Bronchoalveolar lavage fluid was collected to evaluate markers of inflammation, and then the lung was removed and processed for isolation of membrane fraction and determination of acetylcholine receptors level using radioligand binding assays. (3) Results: LPS-induced increase in lung inflammatory markers (e.g., neutrophils and IL-1β) was significantly higher in VAChT-KDHOM than wild-type mice. In contrast, LPS treatment resulted in a significant increase in lung’s α7 nicotinic receptor level in wild-type, but not in VAChT-KDHOM mice. However, treatment with PNU 282987, a selective α7 nicotinic receptor agonist, restored VAChT-KDHOM mice’s ability to increase α7 nicotinic receptor levels in response to LPS-induced acute lung injury and reduced lung inflammation. LPS also increased muscarinic receptors level in VAChT-KDHOM mice, and PNU 282987 treatment reduced this response. (4) Conclusions: Our data indicate that the anti-inflammatory effects of the lung cholinergic system involve an increase in the level of α7 nicotinic receptors. Pharmacological agents that increase the expression or the function of lung α7 nicotinic receptors have potential clinical uses for treating acute lung injury.

Brain activation by short-term nicotine exposure in anesthetized wild-type and beta2-nicotinic receptors knockout mice: a BOLD fMRI study

2008 ◽  
Vol 202 (4) ◽  
pp. 599-610 ◽  
Author(s):  
S. V. Suarez ◽  
A. Amadon ◽  
E. Giacomini ◽  
A. Wiklund ◽  
J.-P. Changeux ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Nicotinic Receptors ◽  
Brain Activation ◽  
Nicotine Exposure ◽  
Wild Type ◽  
Short Term ◽  
Bold Fmri ◽  
Fmri Study

Single Amino Acid Residue in the Extracellular Portion of Transmembrane Segment 2 in the Nicotinic α7 Acetylcholine Receptor Modulates Sensitivity to Ketamine

2004 ◽  
Vol 100 (3) ◽  
pp. 657-662 ◽  
Author(s):  
Kenny K. Ho ◽  
Pamela Flood
Keyword(s):  
Amino Acid ◽  
Amino Acid Residue ◽  
Nicotinic Acetylcholine Receptors ◽  
Nicotinic Receptor ◽  
Acetylcholine Receptors ◽  
Nicotinic Receptors ◽  
Single Amino Acid ◽  
Wild Type ◽  
Alpha7 Nicotinic Receptor ◽  
Homologous Amino Acid

Background Ketamine inhibits the activation of both heteromeric and homomeric nicotinic acetylcholine receptors. The site of molecular interaction is unknown. Methods The inhibition of alpha7 nicotinic acetylcholine receptors by ketamine was compared to that of 5-hydroxytryptamine-3A (5HT3A) receptors that are resistant to ketamine inhibition in Xenopus laevis oocytes. To determine whether the region of transmembrane segments 2 and 3 is relevant for ketamine inhibition of nicotinic receptors, the authors identified single amino acid residues that differ in the sequence alignment of the two proteins. They created 22 mutant alpha7 nicotinic receptors that contain the single homologous amino acid residue in the 5HT3A sequence. Results Of the 22 mutant alpha7 nicotinic receptors tested, only one (alpha7 A258S) was significantly resistant to 20 microM ketamine. The ketamine concentration response relationship for the alpha7 A258S mutant was shifted to the right with the IC50 for ketamine increased from 17 +/- 2 for wild type to 30 +/- 3 microM in the mutant (P < 0.001). Agonist activation was unchanged by the mutation. The homologous amino acid residue in the 5HT3A receptor was mutated to the alanine that occurs in the wild-type nicotinic receptor. This mutation made the previously insensitive 5HT3A receptor sensitive to ketamine (P < 0.001). Conclusions Conservative mutation of a single amino acid in the extracellular transmembrane segment 2 domain induces resistance to ketamine inhibition in the alpha7 nicotinic receptor and sensitivity to inhibition in the 5HT3A receptor. This region may represent a ketamine binding site in the alpha7 nicotinic receptor, or it may be an important transduction site for ketamine action.

Mice lacking neuronal nicotinic acetylcholine receptor β4-subunit and mice lacking both α5- and β4-subunits are highly resistant to nicotine-induced seizures

2004 ◽  
Vol 17 (2) ◽  
pp. 221-229 ◽  
Author(s):  
Merav Kedmi ◽  
Arthur L. Beaudet ◽  
Avi Orr-Urtreger
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Mutant Mice ◽  
Wild Type ◽  
Nicotinic Acetylcholine ◽  
Nocturnal Frontal Lobe Epilepsy ◽  
Wide Range ◽  
High Doses ◽  
Dose Dependent ◽  
Rate Of Response

Nicotine, the main addictive component of tobacco, evokes a wide range of dose-dependent behaviors in rodents, and when administrated in high doses, it can induce clonic-tonic seizures. Nicotine acts through the nicotinic acetylcholine receptors (nAChRs). Mutations in the human α4- and the β2-nAChR subunit genes cause autosomal dominant nocturnal frontal lobe epilepsy. Using transgenic mice with mutations in nAChR subunits, it was demonstrated previously that the α4-, α5-, and α7-subunits are involved in nicotine-induced seizures. To examine the possibility that the β4-subunit is also involved in this phenotype, we tested mice with homozygous β4-subunit deficiency. The β4 null mice were remarkably resistant to nicotine-induced seizures compared with wild-type and α5 null mice. We also generated mice with double deficiency of both α5- and β4-nAChR subunits and demonstrated that they were more resistant to nicotine’s convulsant effect than either the α5 or the β4 single mutant mice. In addition, the single α5 mutants and the double α5β4-deficient mice exhibited a significantly shorter latency time to seizure than that of the wild-type mice. Our results thus show that β4-containing nAChRs have a crucial role in the pathogenesis of nicotine-induced seizures. Furthermore, by comparing multiple mutant mice with single and double subunit deficiency, we suggest that nicotinic receptors containing either α5- or β4-subunits are involved in nicotine-induced seizures and that receptors containing both subunits are likely to contribute to this phenomena as well. However, the α5-subunit, but not the β4-subunit, regulates the rate of response to high doses of nicotine.

scholarly journals Detection of cotinine in neonate meconium as a marker for nicotine exposure in utero

2004 ◽  
Vol 10 (1-2) ◽  
pp. 96-105
Author(s):  
N. A. Sherif ◽  
S. M. Kamel ◽  
O. S. Al Ashkar ◽  
O. A. Sharaki ◽  
E. A. Seif ◽  
...  
Keyword(s):  
Neonatal Period ◽  
Biological Marker ◽  
Maternity Hospital ◽  
Nicotine Exposure ◽  
Fetal Exposure ◽  
Tobacco Exposure ◽  
Cotinine Level ◽  
Salivary Cotinine ◽  
Pregnancy Urine ◽  
Exposure During Pregnancy

Neonate meconium cotinine level was evaluated as a marker of prenatal exposure to nicotine from tobacco smoking by mothers. Mothers admitted to a maternity hospital in Alexandria, Egypt, were divided into 3 groups:10 active smokers, 10 passive smokers and 10 with no tobacco exposure during pregnancy. Urine and saliva samples were collected from mothers and first-day meconium samples from their neonates. Mean maternal urinary cotinine levels, measured using radioimmunoassay, differed significantly between the 3 groups, as did mean salivary cotinine and mean cotinine levels in meconium. There was a significant positive correlation between cotinine levels in meconium and both maternal urinary and salivary cotinine levels. Meconium is an ideal biological marker for testing direct fetal exposure to tobacco smoke in the neonatal period

Adaptation in the respiratory control system

2003 ◽  
Vol 81 (8) ◽  
pp. 765-773 ◽  
Author(s):  
James Duffin ◽  
Safraaz Mahamed
Keyword(s):  
Experimental Data ◽  
Control System ◽  
Steady State ◽  
Graphical Model ◽  
Respiratory Control ◽  
Ventilatory Responses ◽  
System A ◽  
Hypoxia Adaptation ◽  
Peripheral Chemoreflex

Exposure to hypoxia, whether for short or prolonged periods or for repeated episodes, produces alterations in the ventilatory responses. This review presents evidence that these adaptations are likely to be mediated by adaptations in the respiratory chemoreflexes, particularly the peripheral chemoreflex, and proposes models of respiratory control explaining the observed changes in ventilation. After a brief introduction to the respiratory control system, a graphical model is developed that illustrates the operation of the system in the steady state, which will be used later. Next, the adaptations in ventilatory responses to hypoxia that have been observed are described, and methods of measuring the alterations in the chemoreflexes that might account for them are discussed. Finally, experimental data supporting the view that changes in the activity of the peripheral chemoreflex can account for the ventilatory adaptations to hypoxia are presented and incorporated into models of chemoreflex behaviour during exposures to hypoxia of various durations.Key words: respiration, chemoreflexes, hypoxia, adaptation, models.

Control of ventilation in adult rats hypoxic in the neonatal period

1990 ◽  
Vol 259 (4) ◽  
pp. R836-R841 ◽  
Author(s):  
S. Okubo ◽  
J. P. Mortola
Keyword(s):  
Neonatal Period ◽  
Ventilatory Response ◽  
Acute Hypoxia ◽  
Lower Sensitivity ◽  
Adult Rats ◽  
Genetic Characteristics ◽  
Ventilatory Responses ◽  
Central Inhibition ◽  
Inspiratory Activity ◽  
High Altitude Natives

Three groups of 50-day-old (i.e., postpuberty) rats have been studied: controls, rats exposed to 6 days of hypoxia [inspired fraction of O2 (FIo2) = 10% O2] when newborn (Nb-Hypox), and rats exposed to the same level and duration of hypoxia after weaning (Ad-Hypox). Ventilation during normoxic breathing was higher in Nb-Hypox than in controls or Ad-Hypox. The ventilatory response to acute hypoxia (10 min of 10% O2) was about one-half in Nb-Hypox than in the other two groups. Additional measurements performed on Nb-Hypox and controls showed minimal or no differences between the two groups in the ventilatory responses to hyperoxia and hypercapnia, heart rate and blood pressure at various FIO2, and blood biochemistry. Analysis of the Hering-Breuer reflexes, during barbiturate anesthesia, suggested a decreased central inhibition on inspiratory activity in Nb-Hypox, which with a lower sensitivity to inputs from the peripheral chemoreceptors may contribute to the normoxic hyperventilation and the blunted response to acute hypoxia. The ventilatory patterns of Nb-Hypox rats bear numerous similarities with those of high-altitude natives and could suggest that the highlander's ventilatory responses are not genetic characteristics but relate to chronic hypoxia early in life.

Expression of functional nicotinic acetylcholine receptors in neuroepithelial bodies of neonatal hamster lung

2003 ◽  
Vol 285 (6) ◽  
pp. L1203-L1212 ◽  
Author(s):  
Xiao Wen Fu ◽  
Colin A. Nurse ◽  
Suzanne M. Farragher ◽  
Ernest Cutz
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Respiratory Control ◽  
Hill Coefficient ◽  
Neuroepithelial Bodies ◽  
Patch Clamp Technique ◽  
Nicotinic Acetylcholine ◽  
Whole Cell Patch Clamp ◽  
Inward Currents ◽  
Double Label

Pulmonary neuroepithelial bodies (NEB) are presumed airway chemoreceptors involved in respiratory control, especially in the neonate. Nicotine is known to affect both lung development and control of breathing. We report expression of functional nicotinic acetylcholine receptors (nAChR) in NEB cells of neonatal hamster lung using a combination of morphological and electrophysiological techniques. Nonisotopic in situ hybridization method was used to localize mRNA for the β2-subunit of nAChR in NEB cells. Double-label immunofluorescence confirmed expression of α4-, α7-, and β2-subunits of nAChR in NEB cells. The electrophysiological characteristics of nAChR in NEB cells were studied using the whole cell patch-clamp technique on fresh lung slices. Application of nicotine (∼0.1-100 μM) evoked inward currents that were concentration dependent (EC50 = 3.8 μM; Hill coefficient = 1.1). ACh (100 μM) and nicotine (50 μM) produced two types of currents. In most NEB cells, nicotine-induced currents had a single desensitizing component that was blocked by mecamylamine (50 μM) and dihydro-β-erythroidine (50 μM). In some NEB cells, nicotine-induced current had two components, with fast- and slow-desensitizing kinetics. The fast component was selectively blocked by methyllcaconitine (MLA, 10 nM), whereas both components were inhibited by mecamylamine. Choline (0.5 mM) also induced an inward current that was abolished by 10 nM MLA. These studies suggest that NEB cells in neonatal hamster lung express functional heteromeric α3β2, α4β2, and α7 nAChR and that cholinergic mechanisms could modulate NEB chemoreceptor function under normal and pathological conditions.

scholarly journals Regulation of breathing pattern by IL-10

2019 ◽  
Vol 317 (1) ◽  
pp. R190-R202 ◽  
Author(s):  
Charoula Eleni Giannakopoulou ◽  
Adamantia Sotiriou ◽  
Maria Dettoraki ◽  
Michael Yang ◽  
Fotis Perlikos ◽  
...  
Keyword(s):  
Tidal Volume ◽  
Minute Ventilation ◽  
Control Of Breathing ◽  
Neonatal Rat ◽  
Whole Body ◽  
Wild Type ◽  
Rapid Shallow Breathing Index ◽  
Regulation Of Breathing ◽  
Shallow Breathing

Proinflammatory cytokines like interleukin-1β (IL-1β) affect the control of breathing. Our aim is to determine the effect of the anti-inflammatory cytokine IL-10 οn the control of breathing. IL-10 knockout mice (IL-10−/−, n = 10) and wild-type mice (IL-10+/+, n = 10) were exposed to the following test gases: hyperoxic hypercapnia 7% CO2-93% O2, normoxic hypercapnia 7% CO2-21% O2, hypoxic hypercapnia 7% CO2-10% O2, and hypoxic normocapnia 3% CO2-10% O2. The ventilatory function was assessed using whole body plethysmography. Recombinant mouse IL-10 (rIL-10; 10 μg/kg) was administered intraperitoneally to wild-type mice ( n = 10) 30 min before the onset of gas challenge. IL-10 was administered in neonatal medullary slices (10–30 ng/ml, n = 8). We found that IL-10−/−mice exhibited consistently increased frequency and reduced tidal volume compared with IL-10+/+mice during room air breathing and in all test gases (by 23.62 to 33.2%, P < 0.05 and −36.23 to −41.69%, P < 0.05, respectively). In all inspired gases, the minute ventilation of IL-10−/−mice was lower than IL-10+/+(by −15.67 to −22.74%, P < 0.05). The rapid shallow breathing index was higher in IL-10−/−mice compared with IL-10+/+mice in all inspired gases (by 50.25 to 57.5%, P < 0.05). The intraperitoneal injection of rIL-10 caused reduction of the respiratory rate and augmentation of the tidal volume in room air and also in all inspired gases (by −12.22 to −29.53 and 32.18 to 45.11%, P < 0.05, respectively). IL-10 administration in neonatal rat ( n = 8) in vitro rhythmically active medullary slice preparations did not affect either rhythmicity or peak amplitude of hypoglossal nerve discharge. In conclusion, IL-10 may induce a slower and deeper pattern of breathing.

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