Serotonin receptor activation is necessary for phrenic long‐term facilitation following sustained hypoxia with spinal protein phosphatase inhibition

Abstract

Phrenic long-term facilitation (pLTF) is a form of pattern-sensitive respiratory plasticity elicited by intermittent (IH), but not sustained hypoxia (SH). While the mechanism of pLTF pattern-sensitivity is unknown, the lack of pLTF expression following SH may relate to protein phosphatase activity, as spinal inhibition of serine/threonine protein phosphatases with okadaic acid (OA) reveals pLTF following SH (Wilkerson et al., FASEB J, 2006). Since spinal protein phosphatase inhibition alone does not elicit pLTF, hypoxia is also required. IH-induced pLTF requires spinal serotonin (5HT) receptor activation; we tested the hypothesis that spinal 5HT receptor activation and protein phosphatase inhibition are both necessary to induce pLTF following SH with OA. Methysergide maleate (4 mg/kg), a broad-spectrum 5HT receptor antagonist, was administered intravenously prior to an intrathecal OA application (25nM, n=6) over the C4 spinal cord in anesthetized, vagotomized, paralyzed and ventilated male Sprague-Dawley rats. Baseline conditions were established and the rats were exposed to 25 min SH (11±1%O2). 60 min post-SH, integrated phrenic burst amplitude was increased in control versus methysergide-treated rats (52±21% and -3±13% baseline, respectively; p < 0.05). Thus, 5HT receptor activation is necessary to reveal pLTF during/following both IH and SH with spinal protein phosphatase inhibition, suggesting a common mechanism. Spinal phosphatase inhibition is permissive, but not sufficient to induce pLTF. Supported by NIH HL89209 and HL07654.