Our goal during the next funding period is to concentrate on the important role that CNS excitatory amino acids (EAAs) have in the control of breathing. This goal will be pursued by: (1) determining the respiratory effects of pharmacologically interfering with CNS EAA neurotransmission by systemic administration of drugs that block NMDA receptors, block the glycine-site NMDA receptor, block non-NMDA receptors, and block the release of glutamate; (2) determine the CNS site of action whereby systemically administered EAA antagonists act to disrupt respiratory activity; and (3) study the effect of EAA antagonists, and other drugs that alter EAA neurotransmission on individual neurons within the ventrolateral subnucleus of the tractus solitarius (VLNTS. The experimental approaches that will be used for these studies include monitoring phrenic nerve activity in decerebrate, vagotomized, and paralyzed animals during drug administration; microinjecting drugs into specific brain sites, particularly into the VLNTS while monitoring phrenic nerve activity; lesioning the VLNTS and evaluating IV administered drugs for phrenic nerve effects under this condition; unit recording of VLNTS neurons in vivo and noting effects of drugs iontopheresed onto these neurons; and using the whole cell patch- clamp recording of single VLNTS neurons in the in vitro brain slice preparation (rat) to study the role of EAAs. In addition, our plan is to use immunohistochemical techniques involving antibodies to specific subtypes of EAA receptors to elucidate which EAA receptors are present on respiratory (inspiratory) neurons. Data obtained from these studies should provide new information on the role of CNS EAAs in controlling breathing. Our data should also provide new insights on how the CNS regulates respiratory activity. Finally, our findings will advance current knowledge on the safety of using EAA antagonists to treat CNS disorders, and may provide a basis for preventing potential deleterious effects of these agents on the respiratory system.
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