DEVELOPMENTAL REGULATION OF HYPERCAPNIC RESPONSES

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DESCRIPTION (provided by applicant): Apnea of prematurity, which is a manifestation of immature centrally mediated respiratory control mechanisms, remains a troublesome problem in low birth weight infants. As a consequence large numbers of preterm infants receive therapy with xanthines, although their precise mechanism of action is not clearly understood. In the prior funding cycle of this proposal, we have demonstrated that ?-aminobutyric acid (GABA)-ergic pathways contribute greatly to the inhibition of respiratory timing that characterizes respiratory reflex responses in the newborn. As a natural continuation of this work, we now focus on the role of GABA in mediating the effects of adenosine on neonatal respiratory control. Our most recent preliminary data provide evidence in rat pups that adenosine A2A receptors are prominent in respiratory related areas of the brainstem, and present on GABA containing neurons. Furthermore, administration of A2A receptor agonists induces inspiratory inhibition, which is greatest in the youngest animals, and this effect is blocked by the GABAA receptor antagonist bicuculline. In this proposal we therefore seek to test the hypothesis that adenosine elicits inspiratory inhibition via activation of A2A receptors on GABA containing neurons, and that inhibition of inspiratory related neurons is secondary to increased GABAergic influences. In Aim 1 we hypothesize that these adenosine A2A/GABAergic interactions are greatest in early postnatal life. In Aim 2 we hypothesize that exposure to repetitive hypoxia and/or hypercapnia increases centrally mediated respiratory inhibition by increasing A2A receptor expression on GABAergic neurons and GABAA receptor expression on inspiratory related neurons at the medullary rhythm-generating site (preBtzinger complex, pBc). In both aims we will use neuroanatomic and physiologic studies, with which we have expertise, in maturing rats. The neuroanatomic studies will employ immunohistochemical and molecular techniques combined with retrograde tracers to identify the presence of A(2A) receptor at message and protein levels on respiratory related GABAergic neurons, and GABA(A) receptors at the medullary rhythm generating site (pBc). The physiologic studies will employ whole animals and in vitro medullary slices to measure phrenic and hypoglossal neural output, in addition to single unit recording, in response to application of adenosine receptor agonists with and without GABA(A) receptor blockade at targeted sites. These studies should shed new light on interaction between key inhibitory neurotransmitters during maturation of respiratory control, their role in the pathogenesis of neonatal apnea and our understanding of how a common pharmacologic strategy modulates these phenomena.