Serotonin receptor subtypes involved in vagus nerve stimulation-induced phrenic long-term facilitation in rats

Episodic vagus nerve stimulation (VNS) induces phrenic long-term facilitation (LTF, a persistent augmentation of phrenic nerve activity after the stimulation ends), sensitive to the serotonin 5-HT(1,2,5,6,7) receptor antagonist methysergide and similar to that elicited by episodic hypoxia or carotid sinus nerve stimulation. This study examined the effect of ketanserin (5-HT(2) antagonist) or clozapine (5-HT(2,6,7) antagonist) on VNS-induced LTF in anesthetized, vagotomized, paralyzed and ventilated rats to determine which receptor subtype(s) is involved. Three episodes of 5 min VNS (50 Hz, 0.1 ms, approximately 500 microA) with 5 min intervals elicited phrenic LTF in control (amplitude: 38% above baseline at 60 min post-VNS) and ketanserin (2 mg x kg(-1), i.p.) pre-treated rats (45%), but not clozapine (3 mg x kg(-1)) rats (8%). These data suggest that unlike hypoxia-induced LTF (5-HT(2) receptor-dependent), VNS-induced LTF requires non-5-HT(2) serotonin receptors, perhaps 5-HT(6) and/or 5-HT(7) subtype(s).