SEROTONIN AT THE PHRENIC MOTOR NECLEUS AND RESPIRATION

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We have shown that serotonin is present at the phrenic motor nucleus (PMN) in neurons that appear to originate from the brainstem raphe nuclei. The overall objectives of this research proposal are to confirm by neurochemical techniques that the raphe nuclei are the primary source of serotonin at the PMN and to evaluate by physiological techniques what the function of this neurotransmitter is at this spinal cord respiratory nucleus. The specific aims are to: 1) confirm that the raphe nuclei are the primary source(s) of the serotonin at the PMN and how much of the serotonergic innervation each of these nuclei contributes; 2) determine what alterations in serotonergic activity at the PMN do to normal respiratory activity; 3) determine what alterations in serotonergic activity at the PMN do to the respiratory responses elicited by the physiological stimuli of hypercapnia and hypoxia and 4) determine what alterations in serotonergic activity at the PMN do to stimulation of the raphe nuclei and known brainstem respiratory nuclei. Methods to be used include: 1) chemical lesioning of the raphe nuclei and measurement of serotonin at the PMN by high pressure liquid chromatography; 2) measurement of several indices of respiratory activity (tidal volume, respiratory rate, minute volume, trachael pressure, end tidal CO2 and blood gases) in anesthetized and decerebrated cats fitted with a pneumotachograph; 3) intrathecal administration of drugs to alter serotonergic activity at the PMN and 4) electrical and chemical (glutamate microinjection) stimulation of brain stem nuclei. These studies are important since they will provide information about the neuropathways and neurotransmitters controlling PMN activity. This information is important for understanding normal breathing but is critical for understanding CNS respiratory disorders. Possible respiratory disorders involving the PMN and its central inputs include Sudden Infant Death Syndrome and Sleep Apnea. Knowledge of the role of the neurotransmitters and neuropathways involved in the central control of respiration will further our understanding of these respiratory disorders, and may provide a rational basis for the treatment of these disorders.