SPINAL 5-HT7 RECEPTORS AND PROTEIN KINASE A CONSTRAIN INTERMITTENT HYPDXIA-INDUCED PHRENIC LONG-TERM FACILITATION

Phrenic long-term facilitation (pLTF) is a form of serotonin-dependent respiratory plasticity induced by acute intermittent hypoxia (AIH). pLTF requires spinal Gq proteincoupled serotonin-2 receptor (5-HT2) activation, new synthesis of brain-derived neurotrophic factor (BDNF) and activation of its high-affinity receptor, TrkB. Intrathecal injections of selective agonists for Gs protein-coupled receptors (adenosine 2A and serotonin-7; 5-HT7) also induce long-lasting phrenic motor facilitation via TrkB trans-activation. Since serotonin released near phrenic motor neurons may activate multiple serotonin receptor subtypes, we tested the hypothesis that 5-HT7 receptor activation contributes to AIH-induced pLTF. A selective 5-HT7 receptor antagonist (SB-269970, 5 mu M, 12 mu l) was administered intrathecally at C4 to anesthetized, vagotomized and ventilated rats prior to AIH (3, 5-min episodes, 11% 02). Contrary to predictions, pLTF was greater in SB-269970 treated versus control rats (80 +/- 11% versus 45 6% 60 min postAIH; p < 0.05). Hypoglossal LTF was unaffected by spinal 5-HT7 receptor inhibition, suggesting that drug effects were localized to the spinal cord. Since 5-HT7 receptors are coupled to protein kinase A (PKA), we tested the hypothesis that PKA inhibits AIH-induced pLTF. Similar to 5-HT7 receptor inhibition, spinal PKA inhibition (KT-5720, 100 mu M, 15 mu l) enhanced pLTF (99 +/- 15% 60 min post-AIH; p < 0.05). Conversely, PKA activation (8-br-cAMP, 100 mu M, 15 mu l) blunted pLTF versus control rats (16 +/- 5% versus 45 +/- 6% 60 min post-AIH; p < 0.05). These findings suggest a novel mechanism whereby spinal Gs protein-coupled 5-HT7 receptors constrain AIH-induced pLTF via PKA activity. (C) 2013 IBRO. Published by Elsevier Ltd. All rights reserved.