title: Dual effects of 5-HT(1a) receptor activation on breathing in neonatal mice.
abstract: Inhibitory 5-HT(1a) receptors are located on serotonin (5-HT) neurons (autoreceptors) as well as neurons of the respiratory network (heteroreceptors). Thus, effects on breathing of 5-HT(1a) agonists, such as (R)-(+)-8-hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT), could either be due to decreased firing of 5-HT neurons or direct effects on the respiratory network. Mice in which the transcription factor LMX1B is genetically deleted selectively in Pet1-1-expressing cells (Lmx1b(f/f/p)) essentially have complete absence of central 5-HT neurons, providing a unique opportunity to separate the effect of activation of downstream 5-HT(1a) heteroreceptors from that of autoreceptors. We used rhythmically active medullary slices from wild-type (WT) and Lmx1b(f/f/p) neonatal mice to differentiate autoreceptor versus heteroreceptor effects of 8-OH-DPAT on hypoglossal nerve respiratory output. 8-OH-DPAT transiently increased respiratory burst frequency in Lmx1b(f/f/p) preparations, but not in WT slices. This excitation was abolished when synaptic inhibition was blocked by GABAergic/glycinergic receptor antagonists. Conversely, after 10 min of application, frequency in Lmx1b(f/f/p) slices was not different from baseline, whereas it was significantly depressed in WT slices. In WT mice in vivo, subcutaneous injection of 8-OH-DPAT produced similar biphasic respiratory effects as in Lmx1b(f/f/p) mice. We conclude that 5-HT1a receptor agonists have two competing effects: rapid stimulation of breathing due to excitation of the respiratory network, and delayed inhibition of breathing due to autoreceptor inhibition of 5-HT neurons. The former effect is presumably due to inhibition of inhibitory interneurons embedded in the respiratory network.
authors.affiliation: Department of Biology and Wildlife, University of Alaska Fairbanks, Fairbanks, Alaska 99775, Departments of Neurology and Cellular and Molecular Physiology, Yale University, New Haven, Connecticut 06520, Department of Physiology and Neurobiology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire 03756, Department of Anesthesia, Perioperative and Pain Medicine, Boston Children's Hospital, Boston, Massachusetts 02115, Cellular and Systems Neurobiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, Veteran's Affairs Medical Center, Iowa City, Iowa 52242, and Departments of Neurology, and Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa 52242.
authors.forename: Andrea E
authors.initials: AE
authors.lastname: Corcoran
authors.forename: Kathryn G
authors.initials: KG
authors.lastname: Commons
authors.forename: Yuanming
authors.initials: Y
authors.lastname: Wu
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Smith
authors.forename: Michael B
authors.initials: MB
authors.lastname: Harris
authors.forename: George B
authors.initials: GB
authors.lastname: Richerson
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D011485:Protein Binding / Q000502:physiology; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D012119:Respiration / Q000187:drug effects; D012125:Respiratory Center / Q000187:drug effects / Q000502:physiology; D015656:Respiratory Mechanics / Q000187:drug effects / Q000502:physiology*; D059326:Serotonergic Neurons / Q000187:drug effects / Q000502:physiology; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology*
chemical_list: D058825:Serotonin 5-HT1 Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A
keywords: 8-OH-DPAT; Lmx1b; serotonin