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1 Division of Sleep Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
Exposure to episodic hypoxia induces a persistent augmentation of respiratory activity, known as long-term facilitation (LTF). LTF of phrenic nerve activity has been reported to require serotonin receptor activation and protein syntheses. However, the underlying cellular mechanism still remains poorly understood. NMDA receptors play key roles in synaptic plasticity (e.g. some forms of hippocampal long-term potentiation). The present study was designed to examine the role of NMDA receptors in phrenic LTF and test if the relevant receptors are located in the phrenic motonucleus. Integrated phrenic nerve activity was measured in anaesthetized, vagotomized, neuromuscularly blocked and artificially ventilated rats before, during and after three episodes of 5 min isocapnic hypoxia (Pa,O2= 30–45 mmHg), separated by 5 min hyperoxia (50% O2). Either saline (as control) or the NMDA receptor antagonist MK-801 (0.2 mg kg–1, I.P.) was systemically injected 
1 h before hypoxia. Phrenic LTF was eliminated by the MK-801 injection (vehicle, 32.8 ± 3.7% above baseline in phrenic amplitude at 60 min post-hypoxia; MK-801, –0.5 ± 4.1%, means ±S.E.M.), with little change in both the CO2-apnoeic threshold and the hypoxic phrenic response (HPR). Vehicle (saline, 5 x 100 nl) or MK-801 (10 µM; 5 x 100 nl) was also microinjected into the phrenic motonucleus region in other groups. Phrenic LTF was eliminated by the MK-801 microinjection (vehicle, 34.2 ± 3.4%; MK-801, –2.5 ± 2.8%), with minimal change in HPR. Collectively, these results suggest that the activation of NMDA receptors in the phrenic motonucleus is required for the episodic hypoxia-induced phrenic LTF.
(Received 29 March 2005;
accepted after revision 1 June 2005;
first published online 2 June 2005)
Corresponding author L. Ling: Division of Sleep Medicine @ BIDMC, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA. Email: lling{at}partners.org
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 S. R. Reeves, G. S. Mitchell, and D. Gozal Early postnatal chronic intermittent hypoxia modifies hypoxic respiratory responses and long-term phrenic facilitation in adult rats Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2006; 290(6): R1664 - R1671. [Abstract] [Full Text] [PDF]
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