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Am J Physiol Regul Integr Comp Physiol (October 9, 2003). doi:10.1152/ajpregu.00463.2003
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Submitted on August 14, 2003
Accepted on October 6, 2003

Serotonin Receptor Subtypes Required for Ventilatory Long-Term Facilitation and Its Enhancement after Chronic Intermittent Hypoxia in Awake Rats

Michelle McGuire1, Yi Zhang1, David P White1, and Liming Ling1*

1 Division of Sleep Medicine, Brigham & Women's Hospital/Harvard Medical School, Boston, MA, USA

* To whom correspondence should be addressed. E-mail: lling{at}partners.org.

Respiratory long-term facilitation (LTF), a serotonin-dependent, persistent augmentation of respiratory activity after episodic hypoxia, is enhanced by pre-treatment of chronic intermittent hypoxia (CIH: 5-min 11-12% O2/5-min air, 12 h/night for 7 nights). The present study examined the effects of methysergide (serotonin 5-HT1,2,5,6,7 receptor antagonist), ketanserin (5-HT2 antagonist) or clozapine (5-HT2,6,7 antagonist) on both ventilatory LTF and the CIH effect on ventilatory LTF in conscious male adult rats to determine which specific receptor subtype(s) is involved. In untreated rats (i.e., animals not exposed to CIH), LTF, induced by 5 episodes of 5-min poikilocapnic hypoxia (10% O2) separated by 5-min normoxic intervals, was measured twice by plethysmography. Thus, the measurement was conducted 1-2 days before (as control) and ~1 h after systemic injection of methysergide (1 mg.kg-1, i.p.), ketanserin (1 mg.kg-1), or clozapine (1.5 mg.kg-1). Resting ventilation, metabolic rate and hypoxic ventilatory response (HVR) were unchanged, but LTF (~18% above baseline) was eliminated by each drug. In CIH-treated rats, LTF was also measured twice, before and ~8 h after CIH. Vehicle, methysergide, ketanserin or clozapine was injected ~1 h before the second measurement. Neither resting ventilation nor metabolic rate was changed after CIH and/or any drug. HVR was unchanged after methysergide and ketanserin but reduced in 4/7 clozapine rats. The CIH-enhanced LTF (~28%) was abolished by methysergide and clozapine but only attenuated by ketanserin (to ~10%). Collectively, these data suggest that ventilatory LTF requires 5-HT2 receptors and that the CIH effect on LTF requires non-5-HT2 serotonin receptors, probably 5-HT6 and/or 5-HT7 subtype(s).




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