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Biomedical subjects

G Hilaire

Publications and source records attributed to G Hilaire.

At least 37 records · Page 2Linked to original sources
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↗
PubMed1992

In vitro study of central respiratory-like activity of the fetal rat.

A fetal rat brain stem-spinal cord in vitro preparation (15-20 days) which retains for several hours respiratory-like discharges on cervical and cranial ventral roots has been developed for analysing fetal central respiratory activity. Two different patterns of easily distinguishable rhythmic activity were recorded. The first, of spinal origin, appeared every 2-10 min as long bursts of potentials (3-30 s) on cervical, but not hypoglossal, roots. The second pattern corresponded to brief bursts (1 s) of potentials occurring on both cervical and hypoglossal roots at a frequency ranging from 3-4 cycles min-1. The second type of activity was likely to be respiratory since it originated from the medulla, and behaved similarly to the respiratory activity recorded in vitro from newborn rats. The fetal respiratory-like activity was never observed at day 15, appeared at day 16 in 30% of the preparations with fluctuating frequency and amplitude bursts, and stabilised at day 20 where it was usually present and resembled newborn rat respiratory activity: its frequency was stable but was reduced by withdrawal of CO2 and pH stimuli and modulated by a pontine noradrenergic influence. This fetal preparation offers many advantages for studying the ontogeny of the central respiratory activity because of the background knowledge available on the adult and newborn rat respiratory centers and the possibility of performing electrophysiological, morphological and pharmacological fetal studies directly at the central level without any feedback from the periphery.

Animals↗
PubMed1992

Compared effects of serotonin on cervical and hypoglossal inspiratory activities: an in vitro study in the newborn rat.

1. Experiments were performed on the brain stem-spinal cord preparation of newborn rats, in which the phrenic and hypoglossal nerves continue to show rhythmic respiratory activity in vitro, in order to compare the effects of serotonin (5-HT) on both activities and to analyse the mechanisms responsible for the depression by 5-HT of the hypoglossal activity. 2. Under control conditions, simultaneous recordings of the inspiratory discharges of hypoglossal and cervical roots showed that the two bursts did not start simultaneously and had different patterns (time-to-peak and peak values); this suggests that both pools of motoneurons did not share the same central drive(s). 3. Adding 5-HT and related agents to the bathing medium delayed and depressed the hypoglossal inspiratory discharge via activation of 5-HT2 receptors since these effects were elicited by 5-HT2 agonists (alpha-methyl-5-HT and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane-HCl (DOI)) but not by 5-HT1 agonists (RU 24969 and (+/-)-8-hydroxy-2-(di-N-propylamino)tetralin hydrobromide (8-OH-DPAT)). The 5-HT depression of the hypoglossal discharge was prevented by applying a pretreatment with a specific 5-HT2 antagonist (ketanserin). Parallel to the hypoglossal discharge decrease, 5-HT elicited a permanent cervical root discharge along with a persistent inspiratory bursting. Adding the 5-HT precursor L-tryptophan to the bathing medium depressed the hypoglossal (XII) discharge without affecting the cervical one. 4. Local application of 5-HT within the hypoglossal motor nucleus decreased the hypoglossal output, revealing that the 5-HT depression of the hypoglossal discharge was at least partly mediated by the 5-HT effects at the level of the motoneurons. Local application of 5-HT within the cervical motor nucleus elicited a permanent firing in the cervical root with a persistent inspiratory bursting. 5. Intracellular analysis confirmed the existence of differences in central respiratory drive between cervical and hypoglossal motoneurons under control conditions, as well as differences in response to 5-HT. All the hypoglossal motoneurons became silent under 5-HT bathing, and showed no change in the input membrane resistance, a moderate depolarization, and a delayed central respiratory drive with a decreased amplitude. The cervical motoneurons became more active during inspiration, despite a decrease in the amplitude of the central respiratory drive, which was compensated for by a large depolarization and an increased input membrane resistance. Some cervical motoneurons even fired at a low rate during expiration.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

5-Hydroxytryptamine modulates central respiratory activity in the newborn rat: an in vitro study.

Respiratory activity was recorded in cervical ventral roots during in vitro experiments performed on superfused brainstem-cervical cord preparations from newborn rats aged 0-3 days. The effects of 5-HT agents added to the bathing medium on respiratory frequency were analysed. Adding 5-hydroxytryptamine (5-HT, 30 microM) or 5-HT precursors (either L-tryptophane, L-Trp, 50 microM, or 5-hydroxytryptophane, 5-HTP, 50 microM) elicited increases in respiratory frequency. Precursor effects were blocked by a 5-HT antagonist (methysergide, 70 microM) and significantly reduced by pretreatment with a 5-HT synthesis inhibitor (p-chlorophenylalanine, PCPA, i.p. 300 mg/kg at birth). Adding drugs known to block (methysergide, 40 microM) or to potentiate (fluoxetine, 100 microM) any endogenous 5-HT effects decreased or increased respiratory frequency, respectively. These results suggest that the 5-HT biosynthesis mechanisms remain functional in vitro and that a continuous release of endogenous 5-HT exerts excitatory modulation on the respiratory rhythm generator.

Animals↗
PubMed1991

Serotonin and cervical respiratory motoneurones: intracellular study in the newborn rat brainstem-spinal cord preparation.

Previous experiments performed in the in vitro newborn rat brainstem-spinal cord preparation reported that the addition of serotonin (5-HT, 30-50 microM) to the bathing medium induced increases in the respiratory frequency and a large tonic discharge on all the cervical ventral roots. The aim of the present work was to define whether the 5-HT-induced tonic discharge involved respiratory or non-respiratory motoneurones. Intracellular recordings demonstrated that cervical (C2) motoneurones (n = 27) were depolarized by 5-HT but that the 5-HT-induced tonic discharge was mainly due to recruitment of silent motoneurones (n = 18) which fired permanently (15/18; 17 +/- 3 Hz) under 5-HT. The respiratory motoneurones (n = 9) retained a phasic inspiratory discharge (5/9), even if some (4/9) occasionally exhibited a few spikes during expiration. Therefore, it is concluded that the 5-HT-induced tonic discharge is unlikely to have functional significance in respiration.

Animals↗
PubMed1991

Noradrenergic modulation of the medullary respiratory rhythm generator in the newborn rat: an in vitro study.

1. Superfused brain stem-spinal cord preparations of newborn rats, which continue to show a rhythmic respiratory activity in vitro, were used to analyse the mechanisms whereby the A5 noradrenergic area modulates the activity of the medullary respiratory rhythm generator in the newborn. 2. In preparations including the pons (ponto-medullary preparations), noradrenaline (NA, 25-100 microM) added to the bathing medium either increased (n = 29/50) or decreased (n = 21/50) the respiratory frequency and elicited a tonic discharge in the cervical ventral roots in 50% of the experiments. Double-bath experiments showed that the increases in respiratory frequency were due to NA acting on the pons, whereas the decreases in respiratory frequency were due to NA acting on the medulla. The NA-induced increases in respiratory frequency were attributed to inhibition of A5 neurons by NA and therefore to withdrawal of A5 inhibition on the medullary rhythm respiratory generator. The NA-induced decreases in respiratory frequency seemed to mimic the effects of endogenous NA on the A5 medullary targets. 3. Noradrenaline-induced tonic activity (i) could be induced after elimination of the pons but not on isolated spinal cord, (ii) could be elicited by alpha 1- but not alpha 2-agonists, (iii) could be blocked by alpha 1- but not alpha 2-antagonists. The tonic activity therefore originated from activation of alpha 1 receptors located in the medulla but its importance in respiratory function is doubtful. 4. In medullary preparations (elimination of the pons by transection), the effects of NA agonists and antagonists on respiratory frequency were analysed. Significant decreases in respiratory frequency were induced by NA, adrenaline, phenylephrine and alpha-methyl-NA, but not by the agonists classified as alpha 2 (clonidine and guanfacine), alpha 1 (6-fluoro-NA) and beta (isoprenaline). Since yohimbine, idazoxan and piperoxane (alpha 2 antagonists) blocked the NA-induced decreases in respiratory frequency whereas prazosin (alpha 1-antagonist) did not, it is postulated that alpha 2-receptors may be involved in modulating respiratory frequency. 5. Stimulation, lesion and NA microejection experiments showed the complexity of the mechanisms mediating NA-induced changes in respiratory activity but suggested that the main site of NA action is located in the rostral ventrolateral medulla, where electrical stimulations triggered inspiration prematurely, lesions suppressed the NA-induced decrease in respiratory frequency, and localized application of NA led to an immediate decrease in the respiratory frequency.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

Serotonergic influences on central respiratory activity: an in vitro study in the newborn rat.

The in vitro brainstem-spinal cord of the newborn rat has been used to study the central effects of serotonin (5-HT) on the brainstem respiratory motor control system. Brainstem superfusion with a medium containing 5-HT (30 microM) induced a short latency increase of respiratory frequency, often (60% of the experiments) followed by delayed tonic activity. Weaker concentrations of 5-HT (10-20 microM) were ineffective but prior application of drugs limiting 5-HT inactivation (pargyline and fluoxetine) revealed 5-HT effects. Changes in respiratory frequency are: (1) completely antagonized by methysergide; (2) not suppressed by 5-HT2 (ketanserine) and 5-HT3 (zacopride, GR3832F) antagonists; and (3) induced by 5-HT1 agonists (RU24969, buspirone). Since 5-HT2 agonists (DOI, alpha-methyl-5-HT) only evoked minor changes in frequency, the central action of 5-HT on the respiratory rhythm generator seems to depend on activation of 5-HT1 receptors. Tonic activity induced by 5-HT is: (1) antagonized by methysergide or ketanserine but not 5-HT3 antagonists; (2) induced by 5-HT2 but not 5-HT1 agonists; (3) still induced in the isolated spinal cord by 5-HT superfusion or 5-HT microinjection in the cervical ventral horn; and (4) sometimes replaced by rhythmic activity at a frequency different from that of respiration. Tonic activity does not involve the central circuitry responsible for respiration but depends on 5-HT2 receptors linked to spinal networks. These results suggest that 5-HT exerts a facilitory modulation on the respiratory rhythm generator through 5-HT1 medullary receptors and on motoneurons through 5-HT2 spinal receptors.

Animals↗
PubMed1990

Depressant effect of raphe stimulation on inspiratory activity of the hypoglossal nerve: in vitro study in the newborn rat.

Respiratory activity was recorded from the hypoglossal nerve and cervical ventral roots of the superfused isolated brainstem and spinal cord of the newborn rat in order to investigate the effects of serotonin (5-HT). Three experimental procedures were used: (i) brainstem superfusion by exogenous 5-HT (previously reported), (ii) electrical stimulation of pontine midline structures, and (iii) pressure microejection of L-glutamate at the same sites. Each of the experimental procedure increased respiratory frequency and depressed the amplitude of the discharge of the hypoglossal nerve more than that of the cervical roots. These results indicate that 5-HT acts centrally to modulate the activity of the respiratory generator and inhibits the hypoglossal activity. A possible involvement of 5-HT mediated inhibition in obstructive apnea is discussed.

Animals↗
PubMed1990

Differential effects of serotonin on respiratory activity of hypoglossal and cervical motoneurons: an in vitro study on the newborn rat.

Newborn rat respiratory activity was recorded on hypoglossal nerve and ventral cervical roots during in vitro experiments performed on superfused brainstem spinal cord preparations. The addition of serotonin (5-HT) to the bathing medium increased the respiratory frequency and selectively depressed the hypoglossal activity. Any decreases in the amplitude of cervical recordings were always restricted and reversible, whereas the hypoglossal activity was abolished. Furthermore, on cervical roots, 5-HT induced a tonic activity superimposed on the respiratory one, which was never observed with the hypoglossal nerve. When 5-HT was applied on isolated hemispinal cord, a tonic activity could still be elicited. These results indicate that serotonin (i) modulates the activity of neurons involved in the generation of respiratory rhythm, (ii) depresses the activity of hypoglossal motoneurons, and (iii) evokes tonic activity in cervical motoneurons, probably as the result of direct spinal effects.

Action Potentials↗
PubMed1990

Functional significance of the dorsal respiratory group in adult and newborn rats: in vivo and in vitro studies.

The involvement of the dorsal part of the medulla (the so-called dorsal respiratory group: DRG) in the networks participating in respiratory function was investigated in newborn (in vitro) and adult (in vivo) rats. In the dorsal part of the medulla of the isolated brainstem of newborn rats, no respiratory neurons were found and stimulations or lesions neither modified nor suppressed the respiratory output. On the contrary, similar experiments suggest that sites in the ventral medulla have a fundamental importance for respiration. In adult rats, lesion of the DRG areas by electrocoagulation induced transient changes in respiratory timing, and resulted in a significant decrease in the amplitude of the contralateral phrenic output. These results suggest that the dorsal part of the medulla is not involved in controlling respiratory activity in the newborn rat. In adults, no definite conclusion can be reached, but the functional role of the DRG, if any, is probably restricted.

Action Potentials↗
PubMed1990

Effects of N-methyl-D-aspartate (NMDA) antagonist MK-801 on breathing pattern in rats.

In anaesthetized, bivagotomized and artificially ventilated rats, the respiratory effects of systemic injection of MK-801, a non-competitive N-methyl-D-aspartate antagonist, were studied. In all the experiments (n = 11), the injection increased the inspiratory duration and decreased the expiratory duration. In 4 experiments, the inspiratory duration was drastically lengthened, resulting in an apneustic-like breathing pattern. These results demonstrate that apneusis is difficult but possible to induce in rats and suggest that termination of inspiration is controlled via central mechanisms in which NMDA-like receptors are involved.

Action Potentials↗
PubMed1990

Acetylcholine and central chemosensitivity: in vitro study in the newborn rat.

In vitro experiments were performed in the superfused brainstem-spinal cord preparation of newborn rats in order to analyse the central respiratory effects of acetylcholine. The central motor output was assessed from recording electrical activity in nerves supplying respiratory muscles. Acetylcholine added to the bathing medium induced dose-dependent increases in respiratory frequency which were blocked by muscarinic (but not nicotinic) antagonists and enhanced by physostigmine. These effects originated from the medullary ventral surface where chemosensitive structures have been previously located. The respiratory central chemosensitivity of the isolated brainstem was analysed using a CO2 free, pH 7.9 medium instead of the normal medium (bubbled with 5% CO2, pH 7.3). Decreases at the H+ and CO2 stimuli led to decreased inspiratory activity, resulting mainly from a decrease in the amplitude of the motor output. These responses were enhanced by atropine and diminished by physostigmine. These results obtained in vitro on the newborn rat suggest that cholinergic synapses are not directly involved in the genesis of respiratory rhythmicity but confirm previous results obtained in vivo in adult animal revealing that acetylcholine is implicated in the central respiratory chemosensitivity.

Acetylcholine↗