NEUROACTIVE AGENTS AND HYPOXIC EXCITATION OF BREATHING

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A number of neuroactive substances have been implicated in the regulation of breathing. Two classes of putative neurotransmitters, the tachykinins (particularly substance P and neurokinin A) and catecholamines (especially dopamine) seem to be critically involved at several levels of the neuraxis (the carotid body, the petrosal ganglion, and the medulla) in mediating the hypoxic response. At the carotid body, for instance, substance P (SP) and neurokinin A (NKA) have excitatory effects while dopamine (DA) usually inhibits. Although a similar kind of regulation may occur at other sites, the precise interaction depends on the immediate biochemical environment (including the presence of other transmitters) and local anatomic connections. In addition, the interplay among SP, NKA and DA may vary as hypoxic stimulation is maintained. The proposed research uses cross-disciplinary approaches to define how tachykinins and dopamine participate in shaping the respiratory increase caused by hypoxia. This study has as its goals: (a) To determine the interplay of tachykinins and dopaminergic elements in the carotid body in modulating the afferent activity of single fibers and in causing the release of tachykinins and dopamine. Both in vivo and in vitro preparations of the cat will be used. (b) To define the expression and regulation of peptidergic and dopaminergic phenotypic traits in chemoreceptor afferent neurons. Combined retrograde tracing and immunochemistry will be used to delineate precisely the localization of tachykinins and peptides within carotid body afferents and to define the relationship of peptidergic and dopaminergic expression in vivo. In addition, cultured rat petrosal ganglion neurons will be used as a model system to elucidate the regulation and plasticity of peptidergic and dopaminergic traits of carotid body afferents in vitro. (c) To examine in cats the role of tachykinins and dopamine in the processing of chemoreceptor signals in the nucleus tractus solitarius and nucleus paragigantocellularis using anatomic and electrophysiologic techniques, as well as by measuring the release of tachykinins and dopamine. By defining transmitter interaction in these chemoreceptor pathways the proposed research may shed light on fundamental principles of biochemical organization, applicable to the nervous system as a whole.