Biomedical subjects

R Monteau

Publications and source records attributed to R Monteau.

At least 19 recordsLinked to original sources

PubMed2001

Perinatal changes of I(h) in phrenic motoneurons.

The hyperpolarization-activated cationic current (I(h)) was characterized and its maturation studied on phrenic motoneurons (PMNs), from reduced preparations of foetal (E18 and E21) and newborn (P0-P3) rats, using the whole-cell patch-clamp technique. In voltage-clamp mode, 2-s hyperpolarizing steps (5-mV, -50 to -110 mV) elicited a noninactivating inward current, blocked by external application of Cs+ or ZD 7288. At -110 mV, Ih current density averaged 0.67 +/- 0.41 pA/pF at E18, reached a transient peak at E21 (1.38 +/- 0.11 pA/pF) and decreased at P0-P3 (0.77 +/- 0.22 pA/pF). V1/2 was similar at E18 and E21 (-79 mV) but was significantly hyperpolarized at P0-P3 (-90 mV). The time constant of activation was voltage-dependent, and significantly faster at E21. Reversal potential was similar at all ages when estimated by extrapolation or tail current procedures. It was positively shifted by 25 +/- 6 mV when external potassium was raised from 3 to 10 m M, suggesting a similar sensitivity to K+ from E18 to P0-3. Cs(+) or ZD 7288 applications on PMNs at rest in current-clamp mode, in a partitioned chamber, induced a 10 +/- 2 mV hyperpolarization at E18 and E21, and an 8 +/- 2 mV hyperpolarization at P0-3. The area of the central respiratory drive potential or current was increased by 33 and 31%, respectively, at E21, but was not significantly modified at E18 and P0-3. Our data suggest a critical period during the perinatal maturation of Ih during which it is transiently upregulated and attenuates the influence of the central respiratory drive on PMNs just prior to birth.

Animals↗

PubMed2000

Abnormal phrenic motoneuron activity and morphology in neonatal monoamine oxidase A-deficient transgenic mice: possible role of a serotonin excess.

In rodent neonates, the neurotransmitter serotonin (5-HT) modulates the activity of both the medullary respiratory rhythm generator and the cervical phrenic motoneurons. To determine whether 5-HT also contributes to the maturation of the respiratory network, experiments were conducted in vitro on the brainstem-spinal cord preparation of neonatal mice originating from the control strain (C3H) and the monoamine oxidase A-deficient strain, which has a brain perinatal 5-HT excess (Tg8). At birth, the Tg8 respiratory network is unable to generate a respiratory pattern as stable as that produced by the C3H network, and the modulation by 5-HT of the network activity present in C3H neonates is lacking in Tg8 neonates. In addition, the morphology of the phrenic motoneurons is altered in Tg8 neonates; the motoneuron dendritic tree loses the C3H bipolar aspect but exhibits an increased number of spines and varicosities. These abnormalities were prevented in Tg8 neonates by treating pregnant Tg8 dams with the 5-HT synthesis inhibitor p-chlorophenylalanine or a 5-HT(2A) receptor antagonist but were induced in wild-type neonates by treating C3H dams with a 5-HT(2A) receptor agonist. We conclude that 5-HT contributes, probably via 5-HT(2A) receptors, to the normal maturation of the respiratory network but alters it when present in excess. Disorders affecting 5-HT metabolism during gestation may therefore have deleterious effects on newborns.

Animals↗

PubMed2000

Substance P and central respiratory activity: a comparative in vitro study in NK1 receptor knockout and wild-type mice.

Neurokinin-1 receptors (NK1) are present within the respiratory medullary network and in the phrenic nucleus, which controls the diaphragm. We compared the efficacy of substance P (SP) at inducing changes in respiratory frequency or the amplitude of the respiratory motor output between NK1 knockout (NK1-/-) and wild-type mice, using the in vitro brainstem-spinal cord preparation. The in vitro respiratory frequency, as well as the variability of the rhythm and the amplitude of the motor output were similar in both lines. In wild-type mice, application of exogenous SP induced either an increase in respiratory frequency (superfusion of the medulla) or an increase of the inspiratory motor output, as defined by the integral of C4 cervical ventral root activity (superfusion of the spinal cord). These two effects were not apparent in NK1-/- mice. In conclusion, NK1 receptors mediate the respiratory responses to SP but the lack of NK1 receptors in newborn NK1-/- mice does not change the respiratory activity.

Action Potentials↗

PubMed2000

Cellular and synaptic effect of substance P on neonatal phrenic motoneurons.

Experiments were carried out on the in vitro brainstem-spinal cord preparation of the newborn rat to analyse the effects of substance P (SP) on phrenic motoneuron (PMN) activity. In current-clamp mode, SP significantly depolarized PMNs, increased their input resistance, decreased the rheobase current and shifted the firing frequency-intensity relationships leftwards, but did not affect spike frequency adaptation or single spike configuration. The neurokinin receptor agonist NK1 had SP-mimetic effects, whereas the NK3 and NK2 receptor agonists were less effective and ineffective, respectively. In a tetrodotoxin-containing aCSF, only SP or the NK1 receptor agonist were still active. No depolarization was observed when the NK1 receptor agonist was applied in the presence of muscarine. In voltage-clamp mode, SP or the NK1 receptor agonist produced an inward current (ISP) which was not significantly reduced by extracellular application of tetraethylammonium, Co2+, 4-aminopyridine or Cs+. In aCSF containing tetrodotoxin, Co2+ and Cs+, ISP was blocked by muscarine. No PMN displayed any M-type potassium current but only a current showing no voltage sensitivity over the range -100 to 0 mV, reversing near the expected EK +, hence consistent with a leak current. SP application to the spinal cord only (using a partitioned chamber) significantly increased the phrenic activity. Pretreatment with the NMDA receptor antagonist DL-2-amino-5-phosphonovaleric acid (AP5) decreased the C4 discharge duration and blocked the effect of SP, thus exhibiting an NMDA potentiation by SP. In conclusion, SP modulates postsynaptically the response of phrenic motoneurons to the inspiratory drive through the reduction of a leak conductance and the potentiation of the NMDA component of the synaptic input.

2-Amino-5-phosphonovalerate↗

PubMed1999

Substance P and central respiratory activity: a comparative in vitro study on foetal and newborn rat.

Experiments were performed in vitro on foetal (embryonic days 18 to 21, E18-21) and newborn rat (postnatal days 0 to 3, P0-3) brainstem spinal cord preparations to analyse the perinatal developmental changes in the effects induced by substance P. Superfusion of the preparations with SP-containing artificial cerebrospinal fluid (aCSF) induced significant increase in the respiratory frequency of newborn rats (10-9 M), whereas concentration up to 10-7 M induced no change in foetal preparations. A whole cell patch clamp approach was used to record intracellularly from phrenic motoneurones. In newborn or E20-21 foetal rats SP-containing aCSF depolarised the phrenic motoneurones, increased their input resistance, reduced the rheobase current and shifted the frequency-intensity curves upward. In E18 foetal rats, no change was evoked by SP. A peptidase inhibitor mixture was used to block the enzymatic degradation of endogenous SP. This mixture was ineffective in changing the respiratory frequency in newborn and foetal preparations. In newborn rat phrenic motoneurones, the peptidase inhibitor mixture induced changes similar to those caused by SP but no change was induced in foetal rats. These results indicate that SP may modulate (i) the activity of the respiratory rhythm generator in newborn but not in foetal rats, and (ii) the activity of phrenic motoneurones at E20, E21 and in newborn rats but not at E18. Results obtained using the peptidase inhibitor mixture suggest that endogenous SP is probably not involved in the control of the respiratory rhythm in the prenatal period, but may influence the activity of the phrenic motoneurones after birth.

Aging↗

PubMed1999

Serotonin levels are abnormally elevated in the fetus of the monoamine oxidase-A-deficient transgenic mouse.

Developmental changes in levels of serotonin, L-tryptophan and 5-hydroxyindol acetic acid (5-HIAA) were measured by high pressure liquid chromatography (HPLC) in the forebrain, brainstem and cervical cord of fetal, neonatal and adult mice from the wild strain C3H and the transgenic strain Tg8, created from the C3H line by the disruption of the gene encoding monoamine oxidase A. The results indicated that the absence of monoamine oxidase A activity in Tg8 mice results in abnormally high 5-hydroxytryptamine (5-HT) levels in all the central nervous structures and at all the studied developmental ages. Since serotonin levels were 4-5 times larger in Tg8 than in C3H mice at gestational day 20, comparing the central network function at birth of C3H and Tg8 neonates should shed some light on the role of serotonin in prenatal network maturation.

Animals↗

PubMed1997

Serotonergic inhibition of phrenic motoneuron activity: an in vitro study in neonatal rat.

In vitro experiments were conducted on neonatal rat brainstem-spinal cord preparations to test the hypothesis of an inhibitory modulation of phrenic activity by serotonin (5-HT) via non-5-HT2A receptors [Lindsay, A.D. and Feldman, J.L., Modulation of respiratory activity of neonatal rat phrenic motoneurones by serotonin, J. Physiol., 461 (1993) 213-233]. The changes induced by 5-HT and related agents on phrenic root discharges and membrane currents in identified phrenic motoneurons were analysed after blockade of spinal 5-HT2A receptors. Spinal application of 5-HT1B (but not 5-HT1A) receptor agonists depressed the phrenic activity and the effect was prevented by pretreatment with 5-HT1B (but not 5-HT1A, 5-HT2A and 5-HT3) receptor antagonists. Results from phrenic motoneuron whole cell recordings do not reject a presynaptic location of the 5-HT receptors responsible for this depression.

Action Potentials↗

PubMed1997

Serotonergic modulation of central respiratory activity in the neonatal mouse: an in vitro study.

In order to determine whether the serotonergic modulation of the central respiratory activity previously reported in neonatal rats occurs in species other than the rat, we performed identical in vitro experiments on the neonatal mouse to those performed on the neonatal rat. The effects of adding serotonin (5-hydroxytryptamine, 5-HT) and related agents to the superfusate suggested that the respiratory rhythm generator undergoes an excitatory modulation via medullary 5-HT1A receptors. Upon applying the drugs to the spinal cord alone, 5-HT was found to have a dual effect on phrenic motoneuron firing: (i) a facilitatory effect mediated by 5-HT2A receptors and (ii) a depressive effect on their inspiratory discharge mediated by non-5-HT1A, non-5-HT2A, non-5-HT3 receptors, possibly of the 5-HT1B subtype. It was therefore concluded that serotonin modulates the neonatal central respiratory activity in mice as well as in rats, and that similar 5-HT receptor subtypes are involved in this process in both species.

Action Potentials↗

PubMed1997

Rostral ventrolateral medulla and respiratory rhythmogenesis in mice.

To compare the mechanisms governing perinatal respiratory rhythmogenesis in mice and rats, we adapted to the neonatal mouse the in vitro brainstem-spinal cord preparation of the neonatal rat. In mouse preparations retaining the pons, phrenic root did not show any rhythmic activity. Elimination of the pons induced phrenic rhythmic bursts which (1) induced respiratory chest movements (rib cage kept attached to the spinal cord), (2) were abolished by spinal cord transection, (3) could be prematurely induced by rostral ventro-lateral medulla (RVLM) stimulation, (4) occurred in phase with the bursting firing of RVLM neurons, and (5) were abolished by RVLM lesion. Then, the RVLM appears crucial for respiratory rhythmogenesis in both species; some results suggest however that vagal and pontine respiratory controls might not be identical in mice and rats.

Animals↗

PubMed1996

Tachykinins and central respiratory activity: an in vitro study on the newborn rat.

The newborn rat brainstem-spinal cord preparation was used to study the effects of tachykinins on the activity of the respiratory rhythm generator in vitro and to characterize the receptors involve. Substance P and tachykinin NK1 and NK3 receptor agonists induced a concentration-dependent increase in the respiratory frequency (10(-9)-10(-7) M), whereas the respiratory frequency was only slightly affected by the tachykinin NK2 receptor agonist. Pre-treatments with tachykinin NK1 receptor antagonists (SR140333, (S)1-¿2-[3-(3.4-dichlorophenyl) -1-(3-isopropoxyphenylacetyl)piperidin-n-3-yl]ethyl¿-4-ph eny l-1-azoniabicyclo [2,2,2]octane chloride; GR82334, pGlu-Ala- Asp-Pro-Asn-Lys-Phe-Tyr-(S-S)Pro-Leu(spiro-gamma-lactam)-Trp-NH2) reduced the substance P-induced increases in the respiratory frequency but the tachykinin NK2 receptor antagonist (SR48968, ((S)-N-methyl-N-[4-4-acetylamino-4-phenylpiperidine)-2-(3,4-dichlorop hen yl) butyl]benzamide); MEN 10376, Asp-Tyr-D-Trp-Val-D-Trp-Lys-NH2) had no effect; the increase in the respiratory frequency induced by the tachykinin NK3 receptor agonist was not affected by a pre-treatment with tachykinin NK1 and NK2 receptor antagonists. These result indicate that tachykinin NK1 and NK3 receptors may be involved in the control of the respiratory frequency.

Animals↗

PubMed1996

Perinatal developmental changes in respiratory activity of medullary and spinal neurons: an in vitro study on fetal and newborn rats.

Experiments were performed in vitro on fetal and newborn rat brainstem-spinal cord preparations to analyse the perinatal developmental changes in inspiratory motor output. The amplitude of the inspiratory bursts of the whole C4 ventral root (global extracellular recording), the firing patterns of 80 medullary inspiratory neurons (unitary extracellular recording) and the firing and membrane properties of 71 respiratory neurons in the C4 ventral horn (whole-cell recording) were analysed at embryonic day 18 (E18), 21 (E21) and post natal days 0 to 3 (P0-3). At E18, the amplitude of the C4 bursts was weak and variable from one respiratory cycle to the next, as well as the discharge pattern of most of the medullary inspiratory neurons. C4 motoneurons were immature, very excitable and displaying variable inspiratory discharges, but already able to deliver sustained bursts of potentials when depolarised. At E21 and P0-3, the amplitude of the C4 bursts was increased and stable, most of the medullary inspiratory neurons already were able to generate a stable firing pattern and C4 motoneurons showed maturational changes in terms of the resting potential, spike amplitude and input membrane resistance. This work suggests that the short period extending from E18 to E21 is a critical maturational period for the medullary respiratory network which becomes able to elaborate a stable respiratory motor output.

Action Potentials↗

PubMed1995

Effects of ethanol on respiratory activity in the neonatal rat brainstem-spinal cord preparation.

Ethanol (1-12 mM) added to the superfusion medium of the isolated brainstem-spinal cords of newborn rats did not affect phrenic activity but significantly reduced hypoglossal activity by 54%, 67% and 55% at 3, 6 and 12 mM, respectively. Although the reasons for the suppression of hypoglossal activity remain unknown, this preparation may be a useful model for determining why cranial motoneurons are more vulnerable than phrenic motoneurons to various agents and, more generally, how ethanol impairs neural function.

Animals↗

PubMed1994

Endogenous serotonin modulates the fetal respiratory rhythm: an in vitro study in the rat.

The aim of the present work was to know whether the excitatory modulation of the central respiratory rhythm generator by serotonin (5-HT) previously found to occur in the newborn rat, is already functional during the fetal life. Experiments were performed at embryonic day 18 (D18) and 20-21 (D20-21; full-term day 21) on the fetal rat brainstem-spinal cord preparation in which the ability to generate central respiratory activity in vitro persists. Replacing the normal medium which bathed the preparation by a medium containing 5-HT increased the respiratory frequency (RF) within 2-3 min in a dose-dependent manner in both D18 and D20-21 fetuses but the effect was particularly drastic at D18. Applying a medium containing the 5-HT antagonist, methysergide, to block the effect of endogenous 5-HT, if any, reduced the RF within 2-3 min and the reduction was especially drastic at D18 where respiratory arrests occurred for several minutes in most of the experiments. Applying a medium containing either the 5-HT reuptake inhibitor fluoxetine to potentiate the effect of endogenous 5-HT or the 5-HT precursor, L-tryptophan, to activate 5-HT biosynthesis mechanisms, increased the RF. To define the type of 5-HT receptors involved in the modulation of the RF, experiments were conducted with specific 5-HT agonists and antagonists. Both 5-HT1 (8-OH-DPAT, buspirone) and 5-HT2 agonists (DOI, alpha-methyl-5-HT) increased the RF but only the 5-HT1A agonist 8-OH-DPAT was efficient at submicromolar concentrations. Applying the 5-HT1A antagonist NAN-190 alone decreased the RF and even elicited respiratory arrests while the 5-HT2 antagonist ketanserin was inefficient. NAN-190 pre-treatment blocked the increase in the RF due to 8-OH-DPAT and 5-HT. Taken as a whole these results clearly indicate that endogenous 5-HT exerts an excitatory modulation on the respiratory rhythm generator via activation of medullary 5-HT1A receptors well before birth, as soon as D18 where the modulation is particularly potent.

Animals↗

PubMed1994

Further evidence that various 5-HT receptor subtypes modulate central respiratory activity: in vitro studies with SR 46349B.

The ability of SR 46349B [trans,4-([3Z)3-(2-dimethylaminoethyl)oxyimino- 3(2-flurophenyl)propen-1-yl]phenol hemifumarate], a 5-HT2 receptor antagonist, to block the changes in respiratory activity induced by serotonin was analysed by using brain stem-spinal cord preparations from newborn rats. The increases in respiratory frequency elicited by serotonin (and 5-HT1A receptor agonist) were not suppressed by SR 46349B. The tonic discharge of cervical motoneurons and the depression of inspiratory hypoglossal activity elicited by serotonin (and 5-HT2 receptor agonist) were reduced in a dose-dependent manner by SR 46349B. These results confirm that activation of 5-HT1A and 5-HT2 receptors influences respiratory frequency and motoneuronal output, respectively.

Animals↗

PubMed1994

Involvement of the rostral ventro-lateral medulla in respiratory rhythm genesis during the peri-natal period: an in vitro study in newborn and fetal rats.

The involvement of the rostral ventro-lateral medulla (RVLM) in respiratory rhythm genesis was analysed on brain stem-spinal cord preparations from newborn and fetal rats in which the ability to generate central respiratory activity in vitro persists. The respiratory rhythm (around 5 per min) was stable in preparations from newborn and pre-term fetal (D20-21) rats but very variable in young fetuses (D18). In newborn and D20-21 fetal rats, RVLM electrical stimulation delivered during mid-expiration initiated premature inspiration while RVLM electrolytic lesions suppressed the respiratory rhythm. In D18 fetuses, RVLM stimulation had no effect and strong stimulations evoked only diffuse activation. Extracellular recordings of the activity of 423 RVLM neurons showed that this area contained numerous inspiratory neurons in all the age groups studied. Low Ca(2+)-high Mg2+ medium bathing (assumed to block synaptic transmission) abolished the inspiratory bursts in the cervical roots and most of the 99 RVLM inspiratory neurons investigated. In newborn and D20-21 rats, however, 7 of the 68 RVLM inspiratory neurons tested behaved like respiratory pacemakers, since they continued to fire with a bursting pattern, while in the D18 preparations, none of 31 did so. These experiments confirm that the RVLM is a crucial site in respiratory rhythm genesis in newborn rats, and suggest that this may also be the case in D20-21 fetuses, but probably not in D18 fetuses.

Aging↗

PubMed1994

Possible involvement of serotonin in obstructive apnea of the newborn.

Experiments were conducted on newborn rats in order to study the serotonergic modulation of the central respiratory activity during the neonatal period. In vitro experiments performed on isolated brainstem spinal cord preparations demonstrated that serotonin exerts a permanent excitatory modulation on the central respiratory rhythm generator but depresses the inspiratory motor output to the genioglossus muscle. In vivo experiments confirmed that increasing endogenous serotonin levels decreases the inspiratory activity of the genioglossus and elicits drastic obstructive apneas.

Animals↗

PubMed1993

Changes in serotonin metabolism may elicit obstructive apnoea in the newborn rat.

1. Experiments were performed on anaesthetized newborn rats (aged 3-10 days) to know whether an increase in central serotonin levels might favour the occurrence of obstructive apnoeas as previously suggested by in vitro results from our group. 2. The levels of serotonin (5-HT), its precursor 5-hydroxytryptophan (5-HTP) and its metabolite, 5-hydroxyindole-acetic acid (5-HIAA), were analysed in cerebrospinal fluid samples collected at the level of the obex prior to and after intraperitoneal injection of L-tryptophan (50 mg kg-1) in sixty-eight anaesthetized newborn rats (control rats prior to injection and injected rats 15, 30 and 45 min after the injection). A significant increase in 5-HT and 5-HTP levels occurred 30 min after the injection, attesting to the activation of 5-HT biosynthesis. 3. The EMG activity of both the genioglossus and the diaphragm was recorded before and after L-tryptophan load (50 mg kg-1) in twenty-two newborn rats. After the injection of L-tryptophan, the amplitude of the integrated genioglossus activity decreased, or was even abolished, either during a few respiratory cycles or for long periods in twenty-one out of twenty-two animals. Recovery of the genioglossus activity occurred within 45-60 min. 4. The thoracic respiratory movements and the resulting upper airway pressure changes were recorded before and after L-tryptophan injection (50 mg kg-1) in sixty-two animals. In some litters (n = 7), most of the animals (21/25) displayed, within 20-40 min of the injection, recurrent episodes of obstructive apnoea often followed by central ones. These respiratory difficulties became severe and drastic, and led in two instances to respiratory distress and death. Lower doses of L-tryptophan (10 mg kg-1) did not induce any respiratory disorders unless these were potentiated by pargyline treatment (50 mg kg-1, n = 7). The obstructive apnoeas liable to occur after an L-tryptophan load (50 mg kg-1) were prevented by blocking the 5-HT receptor with methysergide (50 mg kg-1, n = 5) or by blocking the 5-HT biosynthesis by applying p-chlorophenylalanine (PCPA) pretreatment at birth (300 mg kg-1, n = 7). In other litters (n = 6), none of the eighteen newborn rats tested were affected by L-tryptophan, however, In five young adult rats, L-tryptophan again had no effect.4+ ĕ

5-Hydroxytryptophan↗

PubMed1992

Serotonergic modulation of the respiratory rhythm generator at birth: an in vitro study in the rat.

In order to investigate the mechanisms through which serotonin (5-HT) modulates the activity of the respiratory rhythm generator, respiratory activity was recorded from cervical ventral roots of the superfused isolated brainstem-spinal cord preparation of the newborn rat. Replacing the normal bathing medium by a medium containing 5-HT (30 microM) increased the respiratory frequency by 70% of the control value. Intact pontomedullary structures are necessary for this effect to take place, however, since the 5-HT-induced increases in respiratory frequency were no longer observed after elimination (section and electrolytic lesion) of the caudal ventro-lateral pons containing the A5 areas. Local applications of 5-HT (dual bath, microdialysis and microinjection experiments) revealed, however, that 5-HT acts at the medullary level and that its effects are not due to a diffuse action on all the neurons of the medullary respiratory centers but to a specific action focusing on structures located in the rostral ventro-lateral medulla.

Animals↗