The CNS effects of nicotine are mediated by multiple subtypes of neuronal nicotinic cholinergic receptors (nAChRs). The effects of nicotine after chronic administration differ from those after acute administration, and nicotine effects also vary at different stages of development. Our previous work characterized the effects of chronic nicotine on expression and function of different subtypes of nAChRs. Knowledge of the shifting expression pattern of these receptors during nicotine use is critical for understanding cholinergic neurophysiology as well as nicotine pharmacology. Chronic nicotine is associated with dependence, changes in gene expression and behavior, and altered neural development. This latter effect is of critical importance given the widespread exposure to nicotine that occurs during periods of critical neural development, particularly due to prenatal exposure from mothers who smoke or use NRT products, and adolescents who are beginning to experiment with tobacco. Prenatal nicotine exposure can have profound effects upon subsequent development and behavior of offspring. Adolescent exposure to nicotine is associated with higher rates of adult dependence, both to nicotine and to other drugs of abuse. Thus these represent uniquely vulnerable periods for nicotine exposure. The overarching goal of the present proposal is to compare the effects of chronic nicotine exposure at three critical ages: prenatal, adolescence and adult. We will employ rat models to study the overlapping effects of chronic nicotine exposure on nAChR expression and function, neuronal morphology and gene expression;we will focus on receptors, genes and brain regions associated with nicotine dependence. In particular, we will examine for persistent effects of nicotine exposure on these parameters. These studies will test the general hypothesis that nicotine's effects on these parameters differ at different developmental stages of exposure. In particular, Aim 4 will test the hypothesis that prenatal nicotine exposure inhibits the response of adolescents to subsequent nicotine challenge, increasing the number of cigarettes smoked and thus the likelihood of subsequent dependence. For each of the following Specific Aims, we will test for both the short-term and persistent effects of chronic nicotine exposure on expression (using autoradiography and immunoprecipitation) and function (using rubidium efflux and neurotransmitter release) of nAChR subtypes, alteration of neuronal morphology (measuring dendritic length and spine density), and changes in global gene expression (using microarrays and rtPCR) in brain regions associated with nicotine dependence. Differential developmental effects will be determined by comparison across aims.
SPECIFIC AIMS 1. Determine the immediate and the persistent direct effects of prenatal chronic nicotine exposure. 2. Determine the immediate and the persistent direct effects of adolescent chronic nicotine exposure. 3. Determine the immediate and the persistent direct effects of adult nicotine exposure. 4. Determine the persistent indirect effects of prenatal nicotine exposure by determining how prenatal nicotine exposure alters the ability of the adolescent to respond to a new nicotine exposure

Public Health Relevance

This work will address hypotheses critical for understanding how chronic exposure to nicotine, such as occurs in tobacco smokers and NRT users, can alter receptor expression and function, neuronal structure, and gene expression. The work will measure nicotine's effects on these parameters caused by prenatal exposure in rats, and compare them to those effects from exposure during adolescence and adulthood. These studies should help to better understand the unique age-specific effects underlying vulnerability to nicotine's effects at these younger ages.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Molecular Neuropharmacology and Signaling Study Section (MNPS)
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Pollock, Jonathan D
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George Washington University
Schools of Medicine
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Hoegberg, Bethany G; Lomazzo, Ermelinda; Lee, Norman H et al. (2015) Regulation of ?4?2?5 nicotinic acetylcholinergic receptors in rat cerebral cortex in early and late adolescence: Sex differences in response to chronic nicotine. Neuropharmacology 99:347-55
Hussmann, G Patrick; Turner, Jill R; Lomazzo, Ermelinda et al. (2012) Chronic sazetidine-A at behaviorally active doses does not increase nicotinic cholinergic receptors in rodent brain. J Pharmacol Exp Ther 343:441-50
Lomazzo, Ermelinda; Hussmann, Gregory P; Wolfe, Barry B et al. (2011) Effects of chronic nicotine on heteromeric neuronal nicotinic receptors in rat primary cultured neurons. J Neurochem 119:153-64
Doura, M B; Luu, T V; Lee, N H et al. (2010) Persistent gene expression changes in ventral tegmental area of adolescent but not adult rats in response to chronic nicotine. Neuroscience 170:503-13
Gold, Allison B; Keller, Ashleigh B; Perry, David C (2009) Prenatal exposure of rats to nicotine causes persistent alterations of nicotinic cholinergic receptors. Brain Res 1250:88-100
Doura, Menahem B; Gold, Allison B; Keller, Ashleigh B et al. (2008) Adult and periadolescent rats differ in expression of nicotinic cholinergic receptor subtypes and in the response of these subtypes to chronic nicotine exposure. Brain Res 1215:40-52
Rasmussen, Bruce A; Perry, David C; O'Neil, Jahn et al. (2008) Effects of nicotine on sensorimotor gating impairment induced by long-term treatment with neurotoxic NMDA antagonism. Neurotox Res 13:151-61
Cox, Brandon C; Marritt, Andrea M; Perry, David C et al. (2008) Transport of multiple nicotinic acetylcholine receptors in the rat optic nerve: high densities of receptors containing alpha6 and beta3 subunits. J Neurochem 105:1924-38
Mao, Danyan; Perry, David C; Yasuda, Robert P et al. (2008) The alpha4beta2alpha5 nicotinic cholinergic receptor in rat brain is resistant to up-regulation by nicotine in vivo. J Neurochem 104:446-56
Perry, David C; Mao, Danyan; Gold, Allison B et al. (2007) Chronic nicotine differentially regulates alpha6- and beta3-containing nicotinic cholinergic receptors in rat brain. J Pharmacol Exp Ther 322:306-15

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