(Scanned from the applicant's description): Nicotine, a major component of tobacco smoke, is a neuroteratogen that binds to nicotinic cholinergic receptors on catecholamine-containing neurons and induces neuroplasticity. Catecholaminergic systems are vulnerable to the effects of prenatal exposure to nicotine since these systems develop early in ontogeny and have trophic influences on the development of multiple neuronal networks. Perturbations in neurotransmission in dopaminergic and noradrenergic neurons in the central nervous system induced by nicotine exposure are associated with postnatal morbidities which include, impaired cognitive function, attention deficit disorders and abnormalities in locomotion. Prenatal nicotine exposure also affects maturation of adrenal chromaffin cells resulting in altered stress responses. We present data that prenatal nicotine exposure increases catecholaminergic traits in peripheral arterial chemoreceptors that are involved in cardiorespiratory control. An increase in inhibitory catecholaminergic traits in peripheral arterial chemoreceptors may in part account for the striking epidemologic association between prenatal exposure to tobacco smoke and sudden infant death syndrome (SIDS). Infants born to smoking mothers have depressed hypoxic arousal responses, reduced respiratory drive, and blunted ventilatory responses to hypoxia. Similarly, animals exposed prenatally to nicotine have abnormalities in hypoxic ventilation, delayed autoresuscitation and increased mortality with exposure to hypoxia. Comparable to nigrostriatal neurons and adrenal chromaffin cells, peripheral arterial chemoreceptors are rich in catecholamines and express nicotinic receptors. Plasticity of neurons in the central nervous system induced by nicotine exposure involves regulation of catecholaminergic traits mediated by cAMP/calcium and the neurotrophins, basic fibroblast growth factor (bFGF) and brain-derived nerve growth factor (BDNF). Our preliminary data show that prenatal nicotine increases tyrosine hydroxylase (TH) mRNA expression, the rate-limiting enzyme for catecholamine synthesis, in peripheral arterial chemoreceptors. However, the mechanism for this effect is unknown. Yet, it is known that the expression of catecholaminergic traits in peripheral arterial chemoreceptors during development is neurotrophin dependent. In the current proposal, we hypothesize that nicotine exposure during development up-regulates catecholaminergic systems in peripheral arterial chemoreceptors via cAMP/calcium mechanisms and the induction of neurotrophins. Thus, using an in vitro rat model of peripheral arterial chemoreceptors, the goals of this proposal are to 1) determine the plasticity of peripheral arterial chemoreceptors induced by late fetal and early postnatal nicotine exposure and 2), elucidate the cellular and molecular mechanisms involved in this plasticity.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA013940-02
Application #
6497839
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Thadani, Pushpa
Project Start
2001-04-01
Project End
2005-01-31
Budget Start
2002-02-01
Budget End
2003-01-31
Support Year
2
Fiscal Year
2002
Total Cost
$322,876
Indirect Cost
Name
Johns Hopkins University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Richardson, Kimberlei A; Yohay, Anne-Lise J; Gauda, Estelle B et al. (2006) Neonatal animal models of opiate withdrawal. ILAR J 47:39-48
Kwak, Daniel J; Kwak, Spencer D; Gauda, Estelle B (2006) The effect of hyperoxia on reactive oxygen species (ROS) in rat petrosal ganglion neurons during development using organotypic slices. Pediatr Res 60:371-6
Kwak, D J; Kwak, S D; Gauda, E B (2006) The effect of hyperoxia on reactive oxygen species (ROS) in petrosal and nodose ganglion neurons during development (using organotypic slices). Adv Exp Med Biol 580:111-4; discussion 351-9
Gauda, Estelle B; Cooper, Reed Z; Donnelly, David F et al. (2006) The effect of development on the pattern of A1 and A2a-adenosine receptor gene and protein expression in rat peripheral arterial chemoreceptors. Adv Exp Med Biol 580:121-9; discussion 351-9
Tolosa, Jose N; Cooper, Reed; Myers, Allen C et al. (2005) Ontogeny of retrograde labeled chemoafferent neurons in the newborn rat nodose-petrosal ganglion complex: an ex vivo preparation. Neurosci Lett 384:48-53
McLemore, Gabrielle L; Cooper, Reed Z B; Richardson, Kimberlei A et al. (2004) Cannabinoid receptor expression in peripheral arterial chemoreceptors during postnatal development. J Appl Physiol 97:1486-95
Gauda, Estelle B; McLemore, Gabrielle L; Tolosa, Jose et al. (2004) Maturation of peripheral arterial chemoreceptors in relation to neonatal apnoea. Semin Neonatol 9:181-94
Gauda, Estelle B; Cooper, Reed; Johnson, Sheree M et al. (2004) Autonomic microganglion cells: a source of acetylcholine in the rat carotid body. J Appl Physiol 96:384-91
Gauda, Estelle B; Cooper, Reed; Johnson, Sheree M (2003) Autonomic ganglion cells: likely source of acetylcholine in the rat carotid body. Adv Exp Med Biol 536:505-15
Gauda, Estelle B (2002) Gene expression in peripheral arterial chemoreceptors. Microsc Res Tech 59:153-67

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