With recent data indicating an increased incidence of cigarette use among young women, the potential consequences of maternal smoking on fetal outcome is an issue of increasing clinical significance. In vivo data indicate that prenatal nicotine exposure has significant effects on the development of brain catecholamine (CA) systems, and that this may underlie some observed behavioral deficits. However, the exact mechanism by which nicotine affects central CA development is unclear. The purpose of the present application is to determine whether brain CA neurons are directly regulated by nicotinic receptors (nAChRS) during early brain development. Unlike the majority of previous studies, we propose to use in vitro methodologies so that experimental variables can be better controlled and indirect effects minimized. Quantitative anatomical techniques will be used to examine the developmental expression of nAChR mRNA and high affinity binding sites within developing norepinephrine (NE) and dopamine (DA) cells of the locus coeruleus (LC) and substantia nigra/ventral tegmental area (SN/VTA), respectively. Combined isotopic and non-isotopic in situ hybridization will be used to quantitate the developmental expression of nAChR subunit mRNAs within cells which also express the CA synthetic enzyme, tyrosine hydroxylase. High affinity nAChR binding in these developing cell groups will also be examined using [3H]cytisine and [3H]epibatidine as radioligands. Animals to be used for the study will be analyzed by age and sex, and will encompass the full range of CA development from embryonic day 15 through adult. The functional role of nAChRs in controlling NE and DA release in developing brain will be evaluated using transmitter release assays. Using brain slices, the effects of nicotine will be examined on NE and DA release from selected terminal fields of the LC and SN/VTA. The age of onset of nAChR regulation will be examined, as will the pharmacological characteristics of the receptor in immature brain. In particular, we will evaluate the hypothesis that the properties of nAChRs regulating LC function change with age. A primary neuronal cell culture model will also be used to analyze the properties of nAChRs on developing LC neurons, and to examine the developmental consequences of chronic nAChR activation. It is anticipated that the proposed in vitro analysis will provide a substantial framework for interpreting data on the effects of chronic perinatal nicotine administration in vivo.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA010612-03
Application #
2898077
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Hoffman, Allison
Project Start
1997-05-01
Project End
2001-03-31
Budget Start
1999-05-01
Budget End
2001-03-31
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of California Irvine
Department
Pharmacology
Type
Schools of Medicine
DUNS #
161202122
City
Irvine
State
CA
Country
United States
Zip Code
92697
Cao, Junran; Dwyer, Jennifer B; Mangold, Jamie E et al. (2011) Modulation of cell adhesion systems by prenatal nicotine exposure in limbic brain regions of adolescent female rats. Int J Neuropsychopharmacol 14:157-74
Dwyer, Jennifer B; McQuown, Susan C; Leslie, Frances M (2009) The dynamic effects of nicotine on the developing brain. Pharmacol Ther 122:125-39
Franke, Ryan M; Park, Minjung; Belluzzi, James D et al. (2008) Prenatal nicotine exposure changes natural and drug-induced reinforcement in adolescent male rats. Eur J Neurosci 27:2952-61
Dwyer, Jennifer B; Broide, Ron S; Leslie, Frances M (2008) Nicotine and brain development. Birth Defects Res C Embryo Today 84:30-44
O'Leary, Kathryn T; Loughlin, Sandra E; Chen, Yiling et al. (2008) Nicotinic acetylcholine receptor subunit mRNA expression in adult and developing rat medullary catecholamine neurons. J Comp Neurol 510:655-72
Azam, L; Chen, Y; Leslie, F M (2007) Developmental regulation of nicotinic acetylcholine receptors within midbrain dopamine neurons. Neuroscience 144:1347-60
O'Leary, K T; Leslie, F M (2006) Enhanced nicotinic acetylcholine receptor-mediated [3H]norepinephrine release from neonatal rat hypothalamus. Neuropharmacology 50:81-8
Park, Minjung K; Loughlin, Sandra E; Leslie, Frances M (2006) Gestational nicotine-induced changes in adolescent neuronal activity. Brain Res 1094:119-26
Loughlin, Sandra E; Islas, Michelle I; Cheng, Michelle Y et al. (2006) Nicotine modulation of stress-related peptide neurons. J Comp Neurol 497:575-88
Liang, Kevin; Poytress, Bonnie Sue; Chen, Yiling et al. (2006) Neonatal nicotine exposure impairs nicotinic enhancement of central auditory processing and auditory learning in adult rats. Eur J Neurosci 24:857-66

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