Ivana Dodig Pavlinac
dr. sc. PAVLINAC DODIG IVANA dr. med.
„THE ROLE OF SEROTONIN 5-HT1A RECEPTORS IN LONG-TERM PHRENIC NERVE FACILITATION CAUSED BY REPETITIVE ACUTE HYPOXIA IN RAT“
: prof. dr.sc. VALIĆ MAJA
Qualifying research publications:
Ivana Pavlinac, Renata Pecotic, Zoran Dogas, Maja Valic. Role of 5-HT1A receptors in induction and preservation of phrenic long-term facilitation in rats. Respir Physiol Neurobiol 2011;175:146-152.
IF (JCR 2011) 2.242
IVANA P. DODIG, RENATA PECOTIC, MAJA VALIC and ZORAN DOGAS.
Acute intermittent hypoxia induces phrenic long-term facilitation which is modulated by 5-HT1A receptor in the caudalraphe region of the rat. J Sleep Res. 2012;21(2):195-203.
IF (JCR 2012) 3.043
Obstructive sleep apnea (OSA) is characterized by periods of upper airway collapse accompanied by repeated episodes of hypoxia. In experimental animals acute repeated bouts of hypoxia (AIH) may evoke sustained augmentation of phrenic nerve activity, known as phrenic long-term facilitation (pLTF). This form of physiological compensation might contribute to stable breathing, minimizing the occurrence of apneas and/or hypopneas during sleep in patients with OSA. Serotonin has been shown to modulate respiratory neuronal activity, possibly via projections originating in the raphe nuclei. The aim of this dissertation was to investigate the role of 5-HT1A receptor activation in induction and preservation of pLTF at two different time points, before exposures to AIH and after pLTF was induced. Moreover, the focus was set on the effects of 5-HT1A receptors blockade by selective antagonist WAY-100635 into the caudal raphe region on pLTF after exposure to AIH episodes. To investigate the role of 5-HT1A receptor activation in induction and preservation of pLTF, adult, male, urethane anesthetized, vagotomized, paralyzed, and mechanically ventilated Sprague–Dawley rats were exposed to an AIH protocol. Experimental groups of animals received an intravenous injection of WAY-100635, before the onset of the first hypoxic stimulus (WAY0, n=7), and after pLTF was induced (WAY60, n=7). Control group of animals (n=7) did not received WAY-100635, but was exposed to AIH protocol. Peak phrenic nerve activity (pPNA), burst frequency, and respiratory rhythm parameters were analyzed during the five hypoxic exposures, as well as at 15, 30, and 60 min after the end of the last hypoxic episode.
In the control group, pPNA was elevated from baseline (121.6±7.3%, P<0.001) at 60 min after episodic hypoxia indicating pLTF. Administration of WAY-100635 prior to hypoxic stimulation prevented the induction of pLTF. Additionally, administration of WAY-100635 after pLTF developed impaired preservation of pLTF. To investigate the effects of 5-HT1A receptors in the caudal raphe region on pLTF, adult, male, urethane anesthetized, vagotomized, paralyzed and mechanically ventilated Sprague–Dawley rats were exposed to AIH protocol. Experimental group (WAY group, n=7) received microinjection of WAY-100635 into the caudal raphe nucleus, whereas the control group (n=7) received saline into the same site. In the control group, 1 h post-hypoxia pLTF was developed. Microinjections of selective 5-HT1A receptor antagonist WAY-100635 into the raphe nuclei prior to the AIH protocol prevented induction of pLTF. In conclusion, there is an important role for 5-HT1A receptors in induction as well as in preservation of pLTF in urethane anesthetized rats. Moreover, the obtained results suggest that 5-HT1A receptor activation at supraspinal level is important for induction of pLTF, which is suggested to be an important respiratory neuroplasticity model in animal studies that possibly correlates with OSA in humans.