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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)

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

The role of central respiratory drive, muscle spindles and tendon organs in producing respiratory movements has been studied in the cat by recording from motoneurones supplying a set of small axial muscles inserted between each rib and the vertebra immediately rostral, the levatores costae. The levator costae muscles are active during normal inspiration but activity is progressively stronger in the muscles located in more caudal thoracic segments. Intracellular recordings from levator costae motoneurons show a characteristic central respiratory drive potential (c.r.d.p.), comprising phases of depolarization during inspiration alternating with expiratory phased hyperpolarization due to post‐synaptic inhibition. Loading or unloading the levator costae muscles increases and decreases, respectively, their normal inspiratory activity. Electrophysiological and histological analysis of levator costae afferents reveals that each muscle contains three to five spindles and two to three tendon organs. By dissecting the levator costae nerve, afferent discharges from muscle spindle primary and secondary endings and those from tendon organs were recorded ‘in continuity’ and used to trigger an averager for analysing the synaptic potentials they evoke in levator costae motoneurones. Monosynaptic excitation and oligosynaptic inhibition originate from spindle (primary and secondary endings) and from tendon organ afferents respectively. Peculiarly a monosynaptic excitation has been evoked from a tendon organ. The action of the levator costae muscle on the respiratory movements of the ribs in the different thoracic spaces was analysed in relation to their anatomical properties and to the activity of the other respiratory muscles. The levator costae muscles, because of their relatively small size and well‐defined population of proprioceptors, appear to provide a favourable preparation for studying the integrative action of the motoneurone.

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)

1. Respiratory activity was recorded on ventral cervical roots during in vitro experiments performed on superfused newborn rat brain stem‐cervical cord preparations. 2. Eliminating the pontine structures by performing a transection at the level of the ponto‐medullary junction resulted in a sustained increase in respiratory frequency, which suggests the existence of a pontine inhibitory drive impinging on the medullary rhythm generator. 3. Noradrenaline (NA) and drugs affecting NA efficiency were added to the bathing medium and the resulting changes in respiratory frequency were analysed. NA decreased the respiratory frequency, and this effect was potentiated by pargyline (an inhibitor of the NA degradation by monoamine oxidases) and blocked by yohimbine (an alpha 2‐antagonist). 4. Yohimbine or piperoxane (which blocks the alpha 2‐adrenoceptors) increased the resting respiratory frequency to the level reached after ponto‐medullary transection, whereas pargyline or desipramine (which potentiates NA efficiency) decreased the respiratory rate. Since these effects were no longer observed after elimination of the pons, it is suggested that a permanent release of endogenous NA by pontine areas may modulate the activity of the medullary respiratory rhythm generator. 5. When alpha‐methyltyrosine (an inhibitor of NA biosynthesis) was applied to the pons, the respiratory frequency was increased, whereas when tyrosine (a precursor of NA) was applied, the respiratory frequency decreased. This decrease was enhanced by pargyline, suppressed by alpha‐methyltyrosine and blocked by piperoxane. 6. To conclude, it is suggested that the mechanisms underlying NA biosynthesis (i) continue to function under these in vitro experimental conditions and (ii) are responsible for a permanent release of endogenous NA, which slows down the respiratory frequency. These results are discussed as regards the possibility that the medullary respiratory rhythm generator may be modulated via the noradrenergic area A5 in the newborn rat.