title: Endogenous activation of serotonin-2A receptors is required for respiratory rhythm generation in vitro.
abstract: Endogenous amines and peptides continuously modulate the activity of neuronal networks and are required even for their normal operation. The respiratory rhythm generator, localized in the pre-Bötzinger complex, is not an exception. This network is modulated by various neurotransmitters, including serotonin (5-HT). In this study, we isolated the respiratory network in brainstem slices and demonstrate that the endogenous activation of 5-HT(2A) is required for the generation of the respiratory rhythm in vitro. At the network level, activation of 5-HT(2A) receptors with 4-iodo-2,5-dimethoxyamphetamine or the 5-HT uptake blocker alaproclate increased the frequency of respiratory activity. Blockade of endogenously activated 5-HT(2A) receptors with three different antagonists decreased the frequency, amplitude, and regularity of respiratory population activity, an effect that was blocked by protein kinase C (PKC) activators. At the cellular level, blockade of 5-HT(2A) receptors reduced the action potential discharge in all examined respiratory neurons, which was associated with a reduction in the fast and the persistent sodium current. Continuous application of 5-HT(2A)-receptor antagonists differentially affected pacemaker neurons. Pacemaker activity was eliminated in cadmium-insensitive pacemaker neurons. In cadmium-sensitive pacemaker neurons, the frequency of pacemaker activity was unaffected and the amplitude of pacemaker bursts was enhanced. It is assumed that cadmium-insensitive pacemakers rely on the persistent sodium current, whereas cadmium-sensitive pacemakers depend on the activation of calcium currents. We conclude that endogenously activated 5-HT(2A) receptors are required for maintaining fictive respiratory activity in the brainstem slice by modulating sodium conductances via a PKC pathway.
authors.affiliation: Committee on Computational Neurobiology, Committee on Neurobiology, and Department of Organismal Biology and Anatomy, University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Fernando
authors.initials: F
authors.lastname: Peña
authors.forename: Jan-Marino
authors.initials: JM
authors.lastname: Ramirez
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001933:Brain Stem / Q000502:physiology; D002104:Cadmium / Q000494:pharmacology; D002478:Cells, Cultured; D004553:Electric Conductivity; D005260:Female; D007700:Kinetics; D008297:Male; D051379:Mice; D009415:Nerve Net; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010507:Periodicity; D011493:Protein Kinase C / Q000378:metabolism; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000378:metabolism* / Q000502:physiology; D015656:Respiratory Mechanics / Q000502:physiology*; D012137:Respiratory System / Q000294:innervation*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D015222:Sodium Channels / Q000502:physiology
chemical_list: D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D015222:Sodium Channels; D002104:Cadmium; D011493:Protein Kinase C