The outcome of pregnancy is adversely affected by maternal use of tobacco products. Aberrations produced by in utero exposure to cigarette smoke range from a reduction in birth weight to an increased incidence of sudden infant death syndrome. Neuropsychological disorders including attention deficit disorder and hyperkinesis are also more prevalent in children whose mothers smoked cigarettes during pregnancy. Although tobacco smoke contains many compounds, nicotine is considered the primary teratogen. Nicotine administration to pregnant rodents causes developmental and behavioral disorders that are similar to those reported for human smokers. Nicotinic cholinergic receptors (nAChr) in the central nervous system mediate the behavioral and physiological effects of nicotine. These receptors are present at early stages of embryonic development and may modulate the maturation of the brain. The proposed research will identify the developmental pattern of nAChr binding in mouse brain using quantitative autoradiography. Nicotine and alpha-bungarotoxin binding will be measured in discrete brain loci, using animals of various gestational and postnatal ages. Messenger RNA's that encode for brain nAChr will be examined on adjacent brain sections using quantitative in situ hybridization histochemistry. The effects of in utero nicotine exposure on the developmental incidence of the receptors and mRNA will also be investigated. Nicotine will be chronically administered to female mice via the drinking solution. This method produces little stress and results in significant changes in behavior as well as brain biochemistry. The effects of prenatal nicotine exposure on sensitivity to nicotine will be tested in the offspring using a battery of tests that includes acoustic startle response, open field activity and body temperature regulation. It is predicted that prenatal nicotine exposure will alter the number of brain nAChr in the progeny; therefore the functional status of these receptors must be addressed. Ion flux assays have recently been developed to assess responsiveness to nicotinic stimulation at the biochemical level. Striatal tissue will be used to measure nicotine-stimulated dopamine release; rubidium (a tracer for K+) flux will be used to measure functional responses of nAChr in other brain regions. These experiments will provide important information concerning the effects of prenatal nicotine exposure on the development of brain nicotinic cholinergic systems and responsiveness to nicotine.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
1R29DA008443-01
Application #
3461411
Study Section
Drug Abuse Biomedical Research Review Committee (DABR)
Project Start
1993-09-01
Project End
1998-08-31
Budget Start
1993-09-01
Budget End
1994-08-31
Support Year
1
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Medical College of Georgia (MCG)
Department
Type
Schools of Medicine
DUNS #
City
Augusta
State
GA
Country
United States
Zip Code
30912
Pauly, James R; Sparks, Jae A; Hauser, Kurt F et al. (2004) In utero nicotine exposure causes persistent, gender-dependant changes in locomotor activity and sensitivity to nicotine in C57Bl/6 mice. Int J Dev Neurosci 22:329-37
Hauser, Kurt F; Khurdayan, Valeriya K; Goody, Robin J et al. (2003) Selective vulnerability of cerebellar granule neuroblasts and their progeny to drugs with abuse liability. Cerebellum 2:184-95
Opanashuk, L A; Pauly, J R; Hauser, K F (2001) Effect of nicotine on cerebellar granule neuron development. Eur J Neurosci 13:48-56
Sparks, J A; Pauly, J R (1999) Effects of continuous oral nicotine administration on brain nicotinic receptors and responsiveness to nicotine in C57Bl/6 mice. Psychopharmacology (Berl) 141:145-53
Barman, S A; Pauly, J R; Isales, C M (1997) Canine pulmonary vasoreactivity to serotonin: role of protein kinase C and tyrosine kinase. Am J Physiol 272:H740-7
Kapasi, A A; Kumar, R; Pauly, J R et al. (1996) Differential expression and autoradiographic localization of atrial natriuretic peptide receptor in spontaneously hypertensive and normotensive rat testes: diminution of testosterone in hypertension. Hypertension 28:847-53
Barman, S A; Pauly, J R (1995) Mechanism of action of endothelin-1 in the canine pulmonary circulation. J Appl Physiol 79:2014-20
Yang, X; Buccafusco, J J; Pauly, J R (1994) Pharmacological evaluation of methylcarbamylcholine-induced drinking behavior in rats. Pharmacol Biochem Behav 49:1-6