Breathing is significantly depressed during the loss of wakefulness. This form of respiratory depression is referred to as state-dependent since normal breathing typically returns with the resumption of waking consciousness. Clinical data emphasize that the occurrence of state- dependent respiratory depression is epidemiologically significant. Three examples include: (l) sleep apnea, the periodic cessation of breathing during sleep, which is estimated to affect 4% of male and 2% of female adults. (2) Sudden infant death syndrome (SIDS), the most common cause of death in infants between l month and l year of age. A leading hypothesis about one cause of SIDS is related to brain stem dysfunction in the control of sleep and breathing. (3) In the U.S., 19 million patients are anesthetized each year. Maintaining normal breathing is a key concern during every general anesthesia. This application is motivated by the fact that for each of these three examples the exact cause of respiratory depression is unknown. One overall theory is that brain stem cholinergic neurotransmission plays a key role in the regulation of sleep and breathing. During the past six years this research program has identified new groups of cholinergic and cholinoceptive pontine neurons that cause state-dependent respiratory depression. The long-term goal of this application is to begin to understand the cellular mechanisms through which pontine cholinergic neurotransmission regulates sleep and breathing. This application proposes 5 specific aims.
Aims 1 and 2 use in vivo brain microdialysis and high performance liquid chromatography (HPLC) to test the hypothesis that nitric oxide contributes to state-dependent respiratory depression by regulating ACh release from pontine cholinergic neurons.
Aim 3 uses microdialysis and HPLC to determine whether n-methyl- D-Aspartate (NMDA) receptor mechanisms modulate ACh release in the pons via nitric oxide.
Aim 4 uses brain microinjection techniques to test the hypothesis that pertussis toxin sensitive guanine nucleotide binding proteins (G proteins) and other second messenger systems contribute to state-dependent respiratory depression known to be caused by pontine cholinergic mechanisms.
Aim 5 uses recently developed techniques for selectively labeling muscarinic receptor subtypes in order to localize the distribution of M l, M2, M3, and M4 receptors within brain stem respiratory nuclei. These 5 aims are unified and conceptually related to the long-term goal by their ability to specify the presynaptic, neuronal, and postsynaptic mechanisms through which pontine cholinergic neurotransmission influences sleep and breathing. Together, the 5 specific aims will provide information essential for rational drug development and for other important adjuncts to the clinical management of state-dependent respiratory depression.
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