{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T14:52:06Z","timestamp":1790779926893,"version":"4.1.0"},"reference-count":36,"publisher":"American Physiological Society","issue":"11","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal of Applied Physiology"],"published-print":{"date-parts":[[2013,12,1]]},"abstract":"<jats:p>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\u201318213, 2010), but the mode of action is not understood. Here we show that the selective 5-HT<jats:sub>1a<\/jats:sub>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-HT<jats:sub>1a<\/jats:sub>antagonist WAY100135. This is consistent with somatodendritic 5-HT<jats:sub>1a<\/jats:sub>receptor-mediated activation of G protein-coupled inwardly rectifying potassium channels (GIRK). In contrast, F15599 did not activate 5-HT<jats:sub>1b\/d<\/jats:sub>receptors that mediate inhibition of glutamate release from terminals in the nucleus accumbens by a presynaptic mechanism. Thus F15599 activated somatodendritic 5-HT<jats:sub>1a<\/jats:sub>autoreceptors, but not axonal 5-HT<jats:sub>1b\/d<\/jats:sub>receptors. In unanesthetized Mecp2-deficient heterozygous female mice, F15599 reduced apnea in a dose-dependent manner with maximal effect of 74.5 \u00b1 6.9% at 0.1 mg\/kg and improved breath irrregularity. Similarly, in Mecp2 null male mice, apnea was reduced by 62 \u00b1 6.6% at 0.25 mg\/kg, and breathing became regular. The results indicate respiration is improved with a 5-HT<jats:sub>1a<\/jats:sub>agonist that activates GIRK channels without affecting neurotransmitter release.<\/jats:p>","DOI":"10.1152\/japplphysiol.00889.2013","type":"journal-article","created":{"date-parts":[[2013,10,4]],"date-time":"2013-10-04T03:28:19Z","timestamp":1380857299000},"page":"1626-1633","source":"Crossref","is-referenced-by-count":51,"title":["A selective 5-HT<sub>1a<\/sub>receptor agonist improves respiration in a mouse model of Rett syndrome"],"prefix":"10.1152","volume":"115","author":[{"given":"Erica S.","family":"Levitt","sequence":"first","affiliation":[{"name":"Vollum Institute, Oregon Health and Science University, Portland, Oregon;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara J.","family":"Hunnicutt","sequence":"additional","affiliation":[{"name":"Vollum Institute, Oregon Health and Science University, Portland, Oregon;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon J.","family":"Knopp","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, Oregon; 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