title: 5-HT induces enhanced phrenic nerve activity via 5-HT(2A) receptor/PKC mechanism in anesthetized rats.
abstract: Respiratory behavior expresses diverse forms of plasticity by altering breathing patterns. Failure of respiratory neuroplasticity often leads to malfunctions. Long-term facilitation (LTF), the most frequently studied model induced by episodic hypoxia to produce long-lasting enhancement of phrenic motor output, is thought to be serotonin 2A (5-HT(2A)) receptor-dependent. Previous studies have described 5-HT-induced prompt apnea in intact animals. However, the role of exogenous 5-HT in mediating respiratory neuroplasticity is less attended in vivo study. We hypothesized that an in vivo 5-HT challenge contributes to respiratory neuroplasticity. Here, we found that systemic bolus administration of 5-HT exerted an initial transient inhibition followed by marked facilitation, forming a biphasic pattern of phrenic nerve activity in artificially ventilated, midcervically vagotomized, and anesthetized adult rats. The facilitatory phase corresponded to the enhanced phrenic nerve activity that lasted for at least one hour after drug exposure, characterized as phrenic LTF (pLTF). The 5-HT-induced biphasic pattern and pLTF were 5-HT(2A) receptor-dependent and coupled to protein kinase C (PKC) activation. The initial inhibition of phrenic nerve activity was found to be nodose ganglion-associated, whereas the subsequent facilitation was carotid body-associated, establishing a peripheral inhibitory-facilitatory afferent balance. Immunoreactive expressions of 5-HT/5-HT(2A) receptors and phospho-PKC isoforms/PKC substrate provide morphological evidence of existence of a 5-HT/5-HT(2A) receptor/PKC mechanism in the nodose ganglion and the carotid body. We speculate that 5-HT challenge in vivo may contribute to respiratory neuroplasticity, to yield pLTF or augmented pLTF in animals with reduced or absent peripheral inhibitory inputs.
authors.affiliation: Institute of Neurosciences, The Fourth Military Medical University, Xi'an, PR China. yingyliu@fmmu.edu.cn
authors.forename: Jinping
authors.initials: J
authors.lastname: Liu
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wei
authors.forename: Caihong
authors.initials: C
authors.lastname: Zhao
authors.forename: Sanjue
authors.initials: S
authors.lastname: Hu
authors.forename: Jianhong
authors.initials: J
authors.lastname: Duan
authors.forename: Gong
authors.initials: G
authors.lastname: Ju
authors.forename: Margaret T T
authors.initials: MT
authors.lastname: Wong-Riley
authors.forename: Yingying
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000758:Anesthesia; D000818:Animals; D002344:Carotid Body / Q000166:cytology / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007527:Isoenzymes / Q000378:metabolism; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D009473:Neuronal Plasticity / Q000187:drug effects; D009620:Nodose Ganglion / Q000187:drug effects / Q000502:physiology; D010750:Phosphoproteins / Q000378:metabolism; D010791:Phrenic Nerve / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D012137:Respiratory System / Q000187:drug effects; D012701:Serotonin / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D019311:Staurosporine / Q000494:pharmacology
chemical_list: D007527:Isoenzymes; D010750:Phosphoproteins; D044402:Receptor, Serotonin, 5-HT2A; D012702:Serotonin Antagonists; D012701:Serotonin; D007650:Ketanserin; D011493:Protein Kinase C; D019311:Staurosporine