Role of Serotonin (5-HT) in Hypoxic and Hypercapnic Ventilatory Responses
Bale, Tejus A.
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Breathing is fundamental to life, and responding appropriately to hypercapnic and hypoxic conditions is essential to survival. Abberant respiratory behavior is a feature of a wide variety of clinical conditions, and appears to be central and causative to the progression and outcome of some diseases, including Sudden Infant Death Syndrome (SIDS). Evidence of serotonergic (5-HT) abnormalities within the medulla are amongst the most robust and consistent pathological findings in SIDS victims. It is hypothesized that these underlying brainstem abnormalities precipitate the failure of normal, protective homeostatic responses to physiological stressors. Understanding the mechanisms by which 5-HT modulates the responses to hypoxia and hypercapnia, two potential stressors, is of paramount importance. It has been established that 5-HT exerts a strong, primarily excitatory, neuromodulatory effect on breathing, which may be accounted for by activation of the 5-HT<sub>2A</sub> receptor. Recent studies have begun to examine the role of 5-HT<sub>2A</sub> receptor activation on eupnea and gasping; however, our understanding of this role is far from complete. Moreover, very little is known about the role of 5-HT<sub>2A</sub> receptor-mediated modulation of the hypercapnic ventilatory response although considerable evidence supports a role for 5-HT neurons functioning as central CO<sub>2</sub> chemosensors. Furthermore, in our previous studies, we have found evidence to support an important role for gap junctions in CO<sub>2</sub> chemosensitivity, including the observation that mice deficient in gap junction protein connexin32 (Cx32) display an abnormal hypercapnic ventilatory response in vivo. While we have characterized and identified the presence of gap junction proteins in medullary raphe 5-HT neurons, their functional role is yet to be ascribed. This thesis research was designed to (1) evaluate the influence of 5-HT<sub>2A</sub> receptor activation and blockade on phrenic nerve discharge under eupneic and hypoxic conditions using an arterially-perfused adult rat preparation, (2) examine the role of endogenous 5-HT2A receptor activation in the hypercapnic ventilatory response using an arterially-perfused adult rat preparation, and (3) study the effects of chronic elevation of endogenous 5-HT on the hypercapnic ventilatory response in wildtype C57BL/6 and Cx32-deficient mice in vivo.