N-methyl-d-aspartate (
NMDA) receptor antagonism in the phrenic motonucleus area eliminates phrenic long-term facilitation (pLTF; a persistent augmentation of phrenic nerve activity after episodic
hypoxia) in anesthetized rats. However, whether
NMDA antagonism can eliminate ventilatory LTF (vLTF) in awake rats is unclear. The role of non-
NMDA receptors in LTF is also unknown.
Serotonin receptor antagonism before, but not after, episodic
hypoxia eliminates pLTF, suggesting that
serotonin receptors are required for induction, but not maintenance, of pLTF. However, because
NMDA and non-
NMDA ionotropic glutamate receptors are directly involved in mediating the inspiratory drive to phrenic, hypoglossal, and intercostal motoneurons, we hypothesized that these receptors are required for both formation and maintenance of vLTF. vLTF, induced by five episodes of 5-min poikilocapnic
hypoxia (10% O(2)) with 5-min normoxia intervals, was measured with plethysmography in conscious adult male Sprague-Dawley rats. Either (+/-)-
2-amino-5-phosphonovaleric acid (APV;
NMDA antagonist, 1.5 mg/kg) or
6-cyano-7-nitroquinoxaline-2,3-dione (
CNQX; non-
NMDA antagonist, 10 mg/kg) was systemically (ip) injected approximately 30 min before
hypoxia. APV was also injected immediately after or 20 min after episodic
hypoxia in additional groups. As control, vehicle was similarly injected in each rat 1-2 days before. Regardless of being injected before or after episodic
hypoxia, vehicle did not alter vLTF ( approximately 23%), whereas APV eliminated vLTF while having little effect on baseline ventilation or hypoxic ventilatory response. In contrast,
CNQX enhanced vLTF ( approximately 34%) while decreasing baseline ventilation. Collectively, these results suggest that activation of
NMDA but not non-
NMDA receptors is necessary for formation and maintenance of vLTF in awake rats.