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Mechanisms underlying modulations of respiration by nicotine

Institution: University of California, Los Angeles
Investigator(s): Xuesi Shao, M.D.
Award Cycle: 2001 (Cycle 10) Grant #: 10RT-0241 Award: $330,458
Subject Area: Pulmonary Disease
Award Type: Research Project Awards

Initial Award Abstract
Smoking have been associated with some prevalent disorders of respiratory control such as sudden infant death syndrome (SIDS) and sleep-disordered breathing (sleep apnea). SIDS is the second-ranking cause of infant death between one month and one year of age. Impaired control of breathing and arousal responsiveness are believed to be the underlying mechanisms. The incidence of SIDS is known to correlate to maternal smoking, but how it causes SIDS is unknown. About 6 to 7 percent of the U. S. population have sleep apnea, i.e., frequent episodes of limited or no ventilation during sleep. The public health burden attributable to sleep apnea is substantial because sleep apnea can cause high blood pressure and other cardiovascular disease, memory problems and lack of sleep leading to job impairment and motor vehicle crashes. Nicotine from cigarette smoking acts on nicotinic acetylcholine receptors in the brain affecting respiratory pattern. The goal of this project is to understand the cellular and synaptic mechanisms underlying modulation of breathing by nicotine and to identify the pharmacology subtypes of nicotinic receptors mediating the effects. Respiratory rhythm is believed to be generated in the preBötzinger Complex (preBötC) in the brainstem in mammals. The concentration of nicotine equivalent to the blood nicotine concentration when a cigarette is smoked will be applied and the nicotine effects on respiratory neurons and neurotransmission in preBötC will be determined. The pre- and/or postsynaptic mechanisms and the receptor subtypes mediating the nicotine effects will be established. The necessity of cholinergic neurotransmission in respiratory rhythm generation will also be examined. Insight into these cellular processes will provide a rational basis for prevention, diagnosis and treatment of SIDS, sleep apnea and respiratory failure during organophosphorus poisoning. Establishing the pre- or postsynaptic mechanisms and identifying the subtypes of nicotinic receptors mediating the cholinergic modulation of breathing will lead to more effective treatments and will help also in the design of drugs more specific to target receptor subtypes with fewer side effects.

Pharmacology of nicotinic receptors in preBotzinger complex that mediate modulation of respiratory pattern.
Periodical: Journal of Neurophysiology Index Medicus:
Authors: Shao XM, and Feldman JL ART
Yr: 2002 Vol: 88 Nbr: Abs: Pg: 1851-1858

Agonist profile of nicotinic receptors that mediate modulation of respiratory pattern by nicotine in preBotzinger complex.
Periodical: Society for Neuroscience Abstracts Index Medicus:
Authors: Shao XM, and Feldman ABS
Yr: 2001 Vol: Nbr: Abs: V27 Pg:

Modulation of AMPA receptors by cAMP-dependent protein kinase (PKA) in PreBotzinger complex inspiratory neurons regulates respiratury rhythm in the rat.
Periodical: Journal of Physiology Index Medicus:
Authors: Shao XM, Ge Q, Feldman JL ART
Yr: 2003 Vol: 547 Nbr: Abs: Pg: 543-553

Muscarinic receptors expression in neurokinin-1 receptor-expressing (NK1R) neurons in preBotzinger complex (preBotC) in adult rats.
Periodical: Society for Neuroscience Abstracts Index Medicus:
Authors: Shao X, Feldmen J ABS
Yr: 2002 Vol: 28 Nbr: Abs: Pg: