NDLI: A selective 5-HT1a receptor agonist improves respiration in a mouse model of Rett syndrome.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Levitt, Erica S. Hunnicutt, Barbara J. Knopp, Sharon J. Williams, John T. Bissonnette, John M.
Description	Author Affiliation: Levitt ES ( Vollum Institute, Oregon Health and Science University, Portland, Oregon)
Abstract	Rett syndrome is a neurological disorder caused by loss of function mutations in the gene that encodes the DNA binding protein methyl-CpG-binding protein 2 (Mecp2). A prominent feature of the syndrome is disturbances in respiration characterized by frequent apnea and an irregular interbreath cycle. 8-Hydroxy-2-dipropylaminotetralin has been shown to positively modulate these disturbances (Abdala AP, Dutschmann M, Bissonnette JM, Paton JF, Proc Natl Acad Sci U S A 107: 18208-18213, 2010), but the mode of action is not understood. Here we show that the selective 5-HT1a biased agonist 3-chloro-4-fluorophenyl-(4-fluoro-4-{[(5-methylpyrimidin-2-ylmethyl)-amino]-methyl}-piperidin-1-yl)-methanone (F15599) decreases apnea and corrects irregularity in both heterozygous Mecp2-deficient female and in Mecp2 null male mice. In whole cell voltage-clamp recordings from dorsal raphe neurons, F15599 potently induced an outward current, which was blocked by barium, reversed at the potassium equilibrium potential, and was antagonized by the 5-HT1a antagonist WAY100135. This is consistent with somatodendritic 5-HT1a receptor-mediated activation of G protein-coupled inwardly rectifying potassium channels (GIRK). In contrast, F15599 did not activate 5-HT1b/d receptors that mediate inhibition of glutamate release from terminals in the nucleus accumbens by a presynaptic mechanism. Thus F15599 activated somatodendritic 5-HT1a autoreceptors, but not axonal 5-HT1b/d receptors. In unanesthetized Mecp2-deficient heterozygous female mice, F15599 reduced apnea in a dose-dependent manner with maximal effect of 74.5 ± 6.9% at 0.1 mg/kg and improved breath irrregularity. Similarly, in Mecp2 null male mice, apnea was reduced by 62 ± 6.6% at 0.25 mg/kg, and breathing became regular. The results indicate respiration is improved with a 5-HT1a agonist that activates GIRK channels without affecting neurotransmitter release.
File Format	HTM / HTML
ISSN	87507587
e-ISSN	15221601
DOI	10.1152/japplphysiol.00889.2013
Journal	Journal of Applied Physiology
Issue Number	11
Volume Number	115
Language	English
Publisher	American Physiological Society
Publisher Date	2013-12-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Discipline Physiology Receptor, Serotonin, 5-ht1a Metabolism Respiration Drug Effects Rett Syndrome Drug Therapy Serotonin 5-ht1 Receptor Agonists Pharmacology Action Potentials Animals Apnea Physiopathology Brain Disease Models, Animal G Protein-coupled Inwardly-rectifying Potassium Channels Glutamic Acid Methyl-cpg-binding Protein 2 Mice Mice, Inbred C57bl Piperidines Potassium Pyrimidines Raphe Nuclei Serotonin Serotonin 5-ht1 Receptor Antagonists Synaptic Transmission Research Support, N.i.h., Extramural Research Support, Non-u.s. Gov't
Content Type	Text
Resource Type	Article
Subject	Physiology Physiology (medical) Sports Science

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