Modulation of respiratory rhythm by 5-HT in the brainstem-spinal cord preparation from newborn rat.
ABSTRACT Effects of 5-hydroxytryptamine (5-HT) on inspiration-related nerve activity and membrane potential of respiratory neurons in the ventrolateral medulla were studied in brainstem-spinal cord preparations isolated from newborn rats. Bath application of 5-100 microM 5-HT induced a biphasic response in inspiratory nerve activity: a transient increase in respiratory frequency followed by a decrease in the rate of discharge. The excitatory effect of 5-HT was particularly prominent in preparations with a respiratory rate of less than 3 min-1, whereas the inhibitory effect was more pronounced in preparations with a higher respiratory rate. In pre-inspiratory (Pre-I) and inspiratory (Insp) neurons, 20 microM 5-HT induced a membrane depolarization of up to 10 mV accompanied by a significant decrease in the input resistance. Membrane depolarization by 5-HT was also evident in the presence of tetrodotoxin. In Pre-I neurons, 5-HT caused an increase in the burst rate, which was followed by a decrease in the intraburst firing frequency and burst amplitude, although the burst rate remained high. The burst rate in Insp neurons first increased and subsequently decreased without significant change in the intraburst firing frequency. Simultaneous intra- and extracellular recordings (in the contralateral medulla) of Pre-I/Pre-I neuron or Pre-I/Insp neuron pairs revealed that 5-HT disturbed the correlation between these neuron bursts. Increase in the respiratory rate induced by 20 microM 5-HT was completely blocked by pretreatment (5-15 min) with 5 microM ketanserin or 1 microM methysergide, but not by 10 microM propranolol. None of these antagonists blocked the inhibitory effects of 5-HT. A 5-HT2 agonist, 1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI, 10-100 microM) increased the respiratory rate. Perfusion with a 5-HT1A agonist, 8-hydroxy-dipropylaminotetralin hydrobromide (8-OH-DPAT, 20-100 microM) induced an increase or a decrease in the respiratory rate. A 5-HT2C agonist, 1-(3-chlorophenyl)piperazine (m-CPP, 2-10 microM) induced an initial decrease in the respiratory rate followed by a further long- lasting decrease. Burst activity of Pre-I neurons was suppressed upon administration of 10 microM m-CPP and enhanced with 20 microM DOI. The results suggest that changes in the bursting properties of Pre-I and Insp neurons induced by 5-HT lead to modulation of the respiratory network, thus causing biphasic modulation of the respiratory rhythm. In addition to effects via 5-HT1A receptors, activation of 5-HT2A and 5-HT2C receptor subtypes might be involved in excitatory effects and inhibitory effects of 5-HT respectively.
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ABSTRACT: In addition to evidence supporting serotonergic modulation of respiratory rhythmogenesis, serotonergic mechanisms play a role in central respiratory chemoreception. We examined the role of serotonin 5HT1A receptors in respiratory rhythmicity and central respiratory chemosensitivity in in vitro brainstem preparations of the bullfrog tadpole, Rana catesbeiana. Spontaneous respiratory motor output was recorded from cranial nerve 7 at control bath pH (7.8) and hypercapnic bath pH (7.4) as bath concentrations of a 5HT1A receptor agonist were steadily increased from 0.5 to 25 microM. Activation of the 5HT1A receptor significantly altered the respiratory burst cycle. Significant increases in both gill and lung burst cycle were observed in response to bath application of 8-OH-DPAT; gill burst cycle in response to 8-OH-DPAT was influenced by bath pH, as gill burst cycle at bath pH 7.8 was not significantly increased at 0.5 or 5.0 microM 8-OH-DPAT. However, when the pH was reduced to 7.4 gill burst cycle was significantly increased at these same bath concentrations of 8-OH-DPAT. Gill burst amplitude was not altered in response to bath application of 8-OH-DPAT; however, lung burst amplitude was significantly decreased at 25.0 microM 8-OH-DPAT at bath pH 7.8. These data indicate that 5HT1A receptors are involved in neural respiratory rhythmogenic and chemoreceptive circuits in the bullfrog tadpole, and support the hypothesis that abnormalities in serotonergic systems may be an underlying component of Sudden Infant Death Syndrome.Ethnicity & disease 01/2010; 20(1 Suppl 1):S1-39-44. · 0.90 Impact Factor
Article: Expression and function of serotonin 2A and 2B receptors in the mammalian respiratory network.[show abstract] [hide abstract]
ABSTRACT: Neurons of the respiratory network in the lower brainstem express a variety of serotonin receptors (5-HTRs) that act primarily through adenylyl cyclase. However, there is one receptor family including 5-HT(2A), 5-HT(2B), and 5-HT(2C) receptors that are directed towards protein kinase C (PKC). In contrast to 5-HT(2A)Rs, expression and function of 5-HT(2B)Rs within the respiratory network are still unclear. 5-HT(2B)R utilizes a Gq-mediated signaling cascade involving calcium and leading to activation of phospholipase C and IP3/DAG pathways. Based on previous studies, this signal pathway appears to mediate excitatory actions on respiration. In the present study, we analyzed receptor expression in pontine and medullary regions of the respiratory network both at the transcriptional and translational level using quantitative RT-PCR and self-made as well as commercially available antibodies, respectively. In addition we measured effects of selective agonists and antagonists for 5-HT(2A)Rs and 5-HT(2B)Rs given intra-arterially on phrenic nerve discharges in juvenile rats using the perfused brainstem preparation. The drugs caused significant changes in discharge activity. Co-administration of both agonists revealed a dominance of the 5-HT(2B)R. Given the nature of the signaling pathways, we investigated whether intracellular calcium may explain effects observed in the respiratory network. Taken together, the results of this study suggest a significant role of both receptors in respiratory network modulation.PLoS ONE 01/2011; 6(7):e21395. · 4.09 Impact Factor