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

Abstract

SUMMARY1. 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 (a-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 MS 9503 D. MORIN, R. MONTEA U AND 0. HILAIRE 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.6. Taken as a whole, these results suggest that the hypoglossal depression induced by 5-HT was due to the activation of 5-HT2 receptors located within the hypoglossal nucleus but the exact mechanisms whereby 5-HT modulates the hypoglossal outputs are still open to debate. The functional significance of the effects of 5-HT on hypoglossal inspiratory activity is discussed with reference to the obstructive apno...

5-HT2A/2C Receptor–Mediated Hypopnea in the Newborn Rat: Relationship to Fos Immunoreactivity

“…The former hypothesis is supported by earlier findings that 5-HT 2A/2C receptor activation induced bronchoconstriction in the adult rat (4) and depressed hypoglossal activity in vitro in brain stem preparations from neonatal rats (2). In contrast, spinal motoneurons were excited by 5-HT 2A/2C receptor agonists, which suggested that 5-HT 2A/2C receptor activation might rather contribute to increase tidal volume in the intact animal by reinforcing chest muscle activity (2). The present observation that DOI induced a decrease in tidal volume raised the issue whether increase in airway resistance may prevail over chest muscle activation in the intact newborn rat.…”

“…Both an increase in airway resistance and a depression of "pump" muscle activity could explain this response. The former hypothesis is supported by earlier findings that 5-HT 2A/2C receptor activation induced bronchoconstriction in the adult rat (4) and depressed hypoglossal activity in vitro in brain stem preparations from neonatal rats (2). In contrast, spinal motoneurons were excited by 5-HT 2A/2C receptor agonists, which suggested that 5-HT 2A/2C receptor activation might rather contribute to increase tidal volume in the intact animal by reinforcing chest muscle activity (2).…”

“…5-HT also interferes with breathing control, via central and peripheral 5-HT 2 receptors, and variable responses have been reported. In vitro studies on brain stem-spinal cord preparations isolated from the newborn rat indicated that central 5-HT 2A receptor mechanisms may exert facilitating influences on respiration, by activating spinal respiratory motoneurons (2) and increasing the frequency of rhythmic respiratory discharge (3). In contrast, in adult anesthetized rats, the activation of 5-HT 2 receptors located at the periphery has been involved in decreases in phrenic nerve activity and lung compliance observed during apnea induced by 5-HT (4).…”

“…In decerebrate newborn rats, the application of 5-HT 2A/2C receptor agonists to the floor of the fourth ventricle elicited a bradypnea (5), reminiscent of the decrease in frequency of respiratory-like activity that followed bath application of 5-HT 2C receptor agonists to in vitro preparations (3). Furthermore, the finding that 5-HT 2A/2C receptor agonists inhibit hypoglossal inspiratory activity in isolated brain stemspinal cord preparations led to the hypothesis that 5-HT 2 receptors may be involved in the genesis of obstructive apneas in newborns with increased 5-HT biosynthesis (2,6). Nevertheless, the depressant influence of 5-HT 2 receptor activation on hypoglossal activity has not been confirmed on medullary rhythmic slice (7).…”

5-HT2C-Like Receptors in the Brain of Xenopus laevis Initiate Sex-Typical Fictive Vocalizations

“…All concentrations of drugs and exposure times were determined by consulting the literature. When no previous in vitro use of a drug was reported in literature (i.e., SB 242084, MK-212, and Ro 60 -0175), we selected a minimum dosage in the range of 10 -100 M that consistently blocked or activated behavior based on pilot experiments, a common method used to establish a dose of drugs for selective binding to serotonin receptors in mammalian tissues (Gunther et al 2006;Morin et al 1992;Tryba et al 2006). In cases where agonists and antagonists were previously used only in brain slice preparations (Chen et al 2003;Perrier and Hounsgaard 2003), we selected 10 times the dose for our whole brain preparation so that the drugs penetrated the tissue efficiently.…”