Review
Nicotine-induced plasticity during development: Modulation of the cholinergic system and long-term consequences for circuits involved in attention and sensory processing

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Abstract

Despite a great deal of progress, more than 10% of pregnant women in the USA smoke. Epidemiological studies have demonstrated correlations between developmental tobacco smoke exposure and sensory processing deficits, as well as a number of neuropsychiatric conditions, including attention deficit hyperactivity disorder. Significantly, data from animal models of developmental nicotine exposure have suggested that the nicotine in tobacco contributes significantly to the effects of developmental smoke exposure. Consequently, we hypothesize that nicotinic acetylcholine receptors (nAChRs) are important for setting and refining the strength of corticothalamic-thalamocortical loops during critical periods of development and that disruption of this process by developmental nicotine exposure can result in long-lasting dysregulation of sensory processing. The ability of nAChR activation to modulate synaptic plasticity is likely to underlie the effects of both endogenous cholinergic signaling and pharmacologically administered nicotine to alter cellular, physiological and behavioral processes during critical periods of development.

Introduction

Tobacco use causes more than 440,000 deaths and $75 billion in direct health care expenses annually in the USA alone (USDHHS, 2004). Despite considerable public awareness, 20.8% of American adults are currently smokers (CDC, 2007, USDHHS, 2004). In addition, in 2005, between 10.7% and 12.4% of pregnant women in the USA were smokers (Martin et al., 2007). Gestational tobacco exposure has numerous consequences, including intrauterine growth retardation, reduced birthweight and an increased risk for both preterm delivery and still birth (Salihu and Wilson, 2007). During infancy, exposed individuals also exhibit a generalized increased risk of morbidity and mortality, including an increased risk of sudden infant death syndrome (Salihu and Wilson, 2007).

Children exposed to tobacco smoke in utero also show increased risk for psychological disorders including a 2–4 fold increased risk of attention deficit hyperactivity disorder (ADHD) (Button et al., 2007, Ernst et al., 2001, Linnet et al., 2003), conduct disorder, antisocial behavior and substance abuse (Brennan et al., 2002, Button et al., 2007, Ernst et al., 2001).

Developmental tobacco smoke exposure also has persistent effects on cognitive processes, with evidence of impairments in the verbal learning and design memory subscales of the Wide Range Assessment of Learning and Memory battery and increased perseverative responding in the Wisconsin Card Sorting Task (Cornelius et al., 2001). These observations suggest deficits in learning from auditory stimuli, impaired recall of visual stimuli and potentially impaired cognitive flexibility, an inability to learn from feedback, or a failure of attentional control in developmentally exposed 10 year olds (Cornelius et al., 2001).

Further, there is evidence of impairments in basic visuospatial function, as assessed by the Test of Visual–Perceptual Skills (TVPS) in 9–12 year old, prenatally exposed children (Fried and Watkinson, 2000) and impairments in both immediate and delayed visuospatial memory, as assessed by the Brief Visuospatial Memory Test-Revised, in gestationally exposed adolescents (Jacobsen et al., 2006). A subsequent study in adolescents identified sex differences in the sensitivity of different sensory modalities to developmental tobacco exposure, with females exhibiting impairments in tasks dependent on visual or auditory attention, while auditory dependent attention appears to be most prominently impaired in males (Jacobsen et al., 2007).

Critically, numerous studies have demonstrated impaired auditory processing in children exposed to tobacco smoke in utero (Fried and Makin, 1987, Picone et al., 1982, Saxton, 1978). Indeed, evidence from the Ottawa Prenatal Prospective Study has indicated deficits in the cognitive and attentional performance of tobacco exposed children which persist to 16 years of age, with particular disruptions in auditory and language related abilities (Fried and Makin, 1987, Fried et al., 1992a, Fried et al., 1992b, Fried et al., 1997, Fried et al., 1998, Fried et al., 2003, Fried and Watkinson, 1988, Fried and Watkinson, 1990, Fried and Watkinson, 2001, Kristjansson et al., 1989, McCartney et al., 1994). It is likely that stimulus processing, rather than detection, is affected in these individuals, since there is no evidence of disrupted hearing or auditory brainstem responses in tobacco exposed neonates (Trammer et al., 1992).

Based on these human studies, it appears that developmental tobacco exposure can have deleterious effects on cognitive and attentional processes. While direct effects of developmental exposure on the higher cortical areas responsible for attentional and cognitive control cannot be excluded, it is also possible that developmental tobacco exposure may preferentially affect the neuronal circuitry responsible for the early stages of sensory processing, such as the thalamocortical neurons responsible for the gating and relay of sensory information from the thalamus to the corresponding regions of primary sensory cortex. By altering this critical cortical input, altered sensory representations could be provided to higher cortical areas, and therefore induce altered performance in tasks which rely on the detection and use of external stimuli.

Clearly, understanding the neurobiological mechanism underlying these deleterious consequences of early tobacco exposure is of great importance from a clinical and therapeutic perspective. For this, the use of animal models of developmental exposure is critical, not only to eliminate the potential confounds relating to maternal IQ, mental health, socio-economic status and education, the home environment, and the genetic susceptibility of both mother and child to psychiatric illness inherent in human studies (Shenassa et al., 2003, Winzer-Serhan, 2008), but also to determine which of the more than 4000 constituents in tobacco smoke (Smith et al., 2003) are responsible for the effects of developmental tobacco exposure on the nervous system at a molecular and cellular level. Of these, nicotine is one of the most likely candidates, not only because it is the main psychoactive component in tobacco, but also because the fetal brain expresses nicotinic acetylcholine receptors (nAChRs), the primary targets for nicotine in the brain, at a very early stage (Cairns and Wonnacott, 1988, Larsson et al., 1985, Navarro et al., 1989, Slotkin, 1998, Sugiyama et al., 1985, Zoli et al., 1995), providing a window of vulnerability to developmental nicotine exposure in many critical neurodevelopmental processes. We will therefore review studies conducted in animal models suggesting that developmental nicotine exposure is a critical determinant of the psychiatric and behavioral effects observed in tobacco exposed human children, and we will summarize the evidence that nicotine-mediated alterations to neuronal ensembles responsible for the processing of sensory stimuli, and in particular the relays between the sensory thalamus and cortex, are an essential underlying factor for these effects.

Section snippets

Rodent models of developmental nicotine exposure

Rodent exposure models typically involve maternal nicotine administration via repeated injection, osmotic mini-pump, drinking water, intravenous infusion, or inhalation to simulate in utero exposure in the first two human trimesters (Carmines et al., 2003, Gaworski et al., 2004, LeSage et al., 2006, Winzer-Serhan, 2008). Due to developmental differences, the first three postnatal weeks in the rodent appear to correspond to the third trimester of human pregnancy, particularly for thalamic and

Behavioral consequences of developmental nicotine exposure in rodents

As noted previously, one of the most prominent co-morbidities with maternal smoking is an increased risk of attention deficit hyperactivity disorder (ADHD) in the offspring (Button et al., 2007). With the widespread use of psychostimulants to control ADHD symptoms in children (Olfson et al., 2003), it is important to understand how developmental nicotine exposure may induce this disorder. This may help elucidate the etiology of ADHD and lead to the development of non-psychostimulant based

Neurobiological consequences of developmental nicotine exposure

Based on observations in both developmentally exposed and genetically modified rodents, it seems clear that nicotine, acting via nAChRs, modulates the development of neuronal ensembles underlying the processing of sensory input, which may underlie the behavioral alterations observed in both rodents and humans. The mechanisms by which nicotine exerts these effects are largely unclear, in part due to the wide variety of effects developmental nicotine administration can have at the molecular and

Conclusions

From the evidence presented here, developmental nicotine exposure can clearly exert a variety of effects on the developing nervous system. These alterations, which encompass changes at all levels of analysis, from individual molecules to neuronal structure, can persist into adulthood and may underlie the behavioral, cognitive and attentional differences observed in developmentally exposed humans and animals.

In particular, a strong case can be made for nicotine-induced alterations in the

Acknowledgements

The authors were supported by grants DA00436 and DA10455 from the National Institute on Drug Abuse.

References (116)

  • P. Fried et al.

    Visuoperceptual functioning differs in 9- to 12-year olds prenatally exposed to cigarettes and marihuana

    Neurotoxicol. Teratol.

    (2000)
  • P. Fried et al.

    Differential effects on facets of attention in adolescents prenatally exposed to cigarettes and marihuana

    Neurotoxicol. Teratol.

    (2001)
  • P. Fried et al.

    A follow-up study of attentional behavior in 6-year-old children exposed prenatally to marihuana, cigarettes, and alcohol

    Neurotoxicol. Teratol.

    (1992)
  • P. Fried et al.

    Reading and language in 9- to 12-year olds prenatally exposed to cigarettes and marijuana

    Neurotoxicol. Teratol.

    (1997)
  • P. Fried et al.

    Differential effects on cognitive functioning in 9- to 12-year olds prenatally exposed to cigarettes and marihuana

    Neurotoxicol. Teratol.

    (1998)
  • P. Fried et al.

    Differential effects on cognitive functioning in 13- to 16-year-olds prenatally exposed to cigarettes and marihuana

    Neurotoxicol. Teratol.

    (2003)
  • Y. Fung et al.

    Effects of prenatal nicotine exposure on rat striatal dopaminergic and nicotinic systems

    Pharmacol. Biochem. Behav.

    (1989)
  • R. Guillery et al.

    Thalamic relay functions and their role in corticocortical communication: generalizations from the visual system

    Neuron

    (2002)
  • N. Hagino et al.

    Effect of maternal nicotine on the development of sites for [3H]nicotine binding in the fetal brain

    Int. J. Develop. Neurosci.

    (1985)
  • C. Hsieh et al.

    Nicotine exposure during a postnatal critical period alters NR2A and NR2B mRNA expression in rat auditory forebrain

    Brain Res. Dev. Brain Res.

    (2002)
  • L. Huang et al.

    Chronic neonatal nicotine upregulates heteromeric nicotinic acetylcholine receptor binding without change in subunit mRNA expression

    Brain Res.

    (2006)
  • E. Kristjansson et al.

    Maternal smoking during pregnancy affects children's vigilance performance

    Drug Alcohol Depend.

    (1989)
  • C. Larsson et al.

    Regional [3H]acetylcholine and [3H]nicotine binding in developing mouse brain

    Int. J. Develop. Neurosci.

    (1985)
  • M. LeSage et al.

    Effects of maternal intravenous nicotine administration on locomotor behavior in pre-weanling rats

    Pharmacol. Biochem. Behav.

    (2006)
  • E. Levin et al.

    Prenatal nicotine exposure and cognitive performance in rats

    Neurotoxicol. Teratol.

    (1993)
  • E. Levin et al.

    Prenatal nicotine effects on memory in rats: pharmacological and behavioral challenges

    Brain Res. Dev. Brain Res.

    (1996)
  • Z. Liu et al.

    Role of endogenous nicotinic signaling in guiding neuronal development

    Biochem. Pharmacol.

    (2007)
  • J. McCartney et al.

    Central auditory processing in school-age children prenatally exposed to cigarette smoke

    Neurotoxicol. Teratol.

    (1994)
  • K. Muneoka et al.

    Prenatal nicotine exposure affects the development of the central serotonergic system as well as the dopaminergic system in rat offspring: involvement of route of drug administrations

    Brain Res. Dev. Brain Res.

    (1997)
  • K. Muneoka et al.

    Prenatal administration of nicotine results in dopaminergic alterations in the neocortex

    Neurotoxicol. Teratol.

    (1999)
  • K. Muneoka et al.

    Nicotine exposure during pregnancy is a factor which influences serotonin transporter density in the rat brain

    Eur. J. Pharmacol.

    (2001)
  • L. Murrin et al.

    Nicotine administration to rats: methodological considerations

    Life Sci.

    (1987)
  • H. Navarro et al.

    Prenatal exposure to nicotine impairs nervous system development at a dose which does not affect viability or growth

    Brain Res. Bull.

    (1989)
  • R. Paulson et al.

    Behavioral effects of prenatally administered smokeless tobacco on rat offspring

    Neurotoxicol. Teratol.

    (1993)
  • J. Pauly et al.

    In utero nicotine exposure causes persistent, gender-dependant changes in locomotor activity and sensitivity to nicotine in C57Bl/6 mice

    Int. J. Dev. Neurosci.

    (2004)
  • D. Peters et al.

    Sex-dependent biological changes following prenatal nicotine exposure in the rat

    Pharmacol. Biochem. Behav.

    (1982)
  • T. Picone et al.

    Pregnancy outcome in North American women. II. Effects of diet, cigarette smoking, stress, and weight gain on placentas, and on neonatal physical and behavioral characteristics

    Am. J. Clin. Nutr.

    (1982)
  • E. Popke et al.

    Prenatal exposure to nicotine: effects on prepulse inhibition and central nicotinic receptors

    Pharmacol. Biochem. Behav.

    (1997)
  • A. Potter et al.

    Central nicotinic cholinergic systems: a role in the cognitive dysfunction in attention-deficit/hyperactivity disorder?

    Behav. Brain Res.

    (2006)
  • D. Rasmusson

    The role of acetylcholine in cortical synaptic plasticity

    Behav. Brain Res.

    (2000)
  • A. Represa et al.

    Trophic actions of GABA on neuronal development

    Trends Neurosci.

    (2005)
  • S. Richardson et al.

    Hyperactivity in the offspring of nicotine-treated rats: role of the mesolimbic and nigrostriatal dopaminergic pathways

    Pharmacol. Biochem. Behav.

    (1994)
  • R. Romero et al.

    Gender-related response in open-field activity following developmental nicotine exposure in rats

    Pharmacol. Biochem. Behav.

    (2004)
  • P. Rowell et al.

    Oral administration of nicotine: its uptake and distribution after chronic administration to mice

    J. Pharmacol. Methods

    (1983)
  • T. Roy et al.

    Effects of prenatal nicotine exposure on the morphogenesis of somatosensory cortex

    Neurotoxicol. Teratol.

    (1994)
  • T. Roy et al.

    Effects of gestational nicotine exposure on hippocampal morphology

    Neurotoxicol. Teratol.

    (1998)
  • H. Salihu et al.

    Epidemiology of prenatal smoking and perinatal outcomes

    Early Hum. Dev.

    (2007)
  • D. Saxton

    The behaviour of infants whose mothers smoke in pregnancy

    Early Hum. Dev.

    (1978)
  • J. Shacka et al.

    Prenatal nicotine sex-dependently alters agonist-induced locomotion and stereotypy

    Neurotoxicol. Teratol.

    (1997)
  • C. Slawecki et al.

    Neonatal nicotine exposure alters hippocampal EEG and event-related potentials (ERPs) in rats

    Pharmacol. Biochem. Behav.

    (2000)
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