The overall goal of this proposal is to characterize the actions of the potent, volatile anesthetics on specific synaptic events within the spontaneously active mammalian respiratory system, in vivo. The findings of the proposed research will result in new knowledge that will increase our understanding of the mechanisms by which volatile anesthetics alter neuronal function in the intact central nervous system. This proposal is unique because we propose studies that focus on specific respiratory neurons of known function in an intact neuronal network under in vivo conditions. In our experimental paradigm synaptic neurotransmitters are released at levels that are present during normal function of the respiratory centers. Our overall hypothesis is that the effects of volatile anesthetics on central respiratory output are mainly due to depression of excitatory rather than enhancement of inhibitory synaptic neurotransmission. Recordings of action potentials from premotor neurons in conjunction with localized pressure microejection of neurotransmitter agonists and antagonists will be used to examine the relative importance of anesthetic-induced alterations on excitatory and inhibitory neurotransmission, and on presynaptic vs. postsynaptic mechanisms.
Three specific aims have been developed to test our hypothesis.
In specific aim 1, we will determine the amount of overall anesthetic-induced alterations of glutamatergic excitation and GABAergic inhibition of inspiratory and expiratory premotor neurons in a decerebrate canine model.
In specific aim 2, we will determine the relative contribution of anesthetic-induced presynaptic and postsynaptic effects to the overall depression of these premotor neurons.
In specific aim 3, we will characterize and contrast the differential agent-and site-specific effects of halothane, isoflurane, and sevoflurane on the synaptic mechanisms of these premotor neurons. Our model will serve as a paradigm to explore other neuronal circuits in vivo. Furthermore, the insights that will be gained from our proposed studies will allow us to develop rational mechanism- based therapeutic strategies that will minimize the serious side- effects of these agents, such as depression of the cardiorespiratory centers. Such mechanistic knowledge could also help in the design of safer anesthetic agents with the least deleterious effects on respiration.
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