Intermittent hypercapnia enhances CO2 responsiveness and overcomes serotonergic dysfunction

Abstract

Serotonergic dysfunction compromises ventilatory chemosensitivity and may enhance vulnerability to pathologies such as the Sudden Infant Death Syndrome (SIDS). We have shown raphé contributions to central chemosensitivity involving serotonin (5-HT)-and γ-aminobutyric acid (GABA)-mediated mechanisms. We tested the hypothesis that mild intermittent hypercapnia (IHc) induces respiratory plasticity, due in part to strengthening of GABA mechanisms. Rat pups were IHc-pretreated (8 consecutive cycles; 5 min 5 % CO2 - air, 10 min air) or constant normocapnia-pretreated as a control, each day for 5 consecutive days beginning at P12. We subsequently assessed CO2 responsiveness using the in situ perfused brainstem preparation. Hypercapnic responses were determined with and without pharmacological manipulation. Results show IHc-pretreatment induces plasticity sufficient for responsiveness despite removal of otherwise critical ketanserin-sensitive mechanisms. Responsiveness following IHc-pretreatment was absent if ketanserin was combined with GABAergic antagonism, indicating that plasticity depends on GABAergic mechanisms. We propose that IHc-induced plasticity could reduce the severity of reflex dysfunctions underlying pathologies such as SIDS.

CO2-inhibited neurons in the medullary raphé are GABAergic

“…Experiments were conducted in preparations derived from juvenile (P20–P30; 60–150g) male Simonsen albino rats; (n=105; Sprague-Dawley derived; Simonsen Laboratories) in situ using the perfused decerebrate juvenile rat brainstem preparation, as per published methods (Corcoran et al, 2013; Mosher et al, 2014). Briefly, animals were heparinized (0.3 mL of 1,000 i.u./mL; i.p.…”