Neuronal nicotinic acetylcholine receptors (nAchR) are targets for the neurotransmitter acetylcholine and exogenous cholinergic ligands such as nicotine from cigarette smoke. Nicotinic receptors are expressed on peripheral (carotid body) and central (brainstem neurons) structures that are involved in mediating the respiratory responses to hypoxia. Prenatal nicotine destabilizes breathing, diminishes the compensatory respiratory response to hypoxic stress and contributes to sudden infant death syndrome (SIDS). One aspect of the maladaptive respiratory response to nicotine exposure appears to be mediated by a reduction in central GABAergic regulation of respiratory rhythm formation. This results, in part, from the """"""""loss-of-function"""""""" of nAchR subunits. The overall goal of this proposal is to develop a novel imaging system which combines atomic force microscopy (AFM) and high-speed optical imaging to investigate the effect of nicotine on the development and stability of breathing rhythms in response to hypoxia. We propose to use this hybrid imaging system to determine whether prenatal nicotine alters synaptic transmission in central respiratory circuits responsible for generating breathing rhythms.
The specific aims are: 1. Identify nicotine-induced changes the spatiotemporal patterns of central respiratory network activity using optical imaging. Based on Preliminary studies, we hypothesize that prenatal exposure to nicotine will alter the spatial and temporal patterns of central respiratory activity during hypoxic stimulation and will reduce the ability to autoresuscitate. 2. Evaluate the effect of nicotine on the binding properties of 17 and 14 nAchRs using atomic force microscopy. Based on Preliminary studies, we hypothesize that prenatal nicotine will reduce the binding probability of 17 and 14 subunit containing nAchR expressed on central respiratory neurons. Results obtained from this proposal are significant because they will be the first to directly visualize nicotine-induced changes in the spatiotemporal patterns of neuronal activity in key populations of central respiratory neurons using a preparation that preserves pontomedullary respiratory circuitry. Experiments outlined in this proposal will also provide new insight to the deleterious affects of prenatal nicotine on the functional binding properties of nAchRs. These new findings may aid in developing clinical recommendations to alleviate hypoxic-induced respiratory depression associated with the incidence of SIDS and other prenatal respiratory disorders.

Public Health Relevance

Prenatal exposure to nicotine from cigarette smoke predisposes infants to sudden infant death syndrome (SIDS). Recent scientific evidence strongly suggests that nicotine may predispose infants to SIDS by causing excessive activation of nicotinic receptors on brain cells that control breathing. The goal of this proposal is to determine the effect of prenatal nicotine exposure on the control of breathing by the brain. Knowledge of the effects of nicotine on respiratory neurons is important since the pathogenesis of SIDS remains incompletely understood, and thus, severely limits potential pharmacological targets and treatment strategies. It is also of clinical significance since nicotine replacement therapy for pregnant women is often regarded as a safe alternative in smoking cessation programs.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Small Research Grants (R03)
Project #
3R03DA022355-01A2S1
Application #
7847043
Study Section
Special Emphasis Panel (ZDA1-MXS-M (03))
Program Officer
Aigner, Thomas G
Project Start
2008-09-30
Project End
2010-10-31
Budget Start
2009-06-01
Budget End
2010-10-31
Support Year
1
Fiscal Year
2009
Total Cost
$26,680
Indirect Cost
Name
University of North Texas
Department
Physiology
Type
Other Domestic Higher Education
DUNS #
110091808
City
Fort Worth
State
TX
Country
United States
Zip Code
76107