Preclinical Data Elucidate Molecular and Neural Mechanisms
of Perinatal Nicotine Effects on Neurodevelopment and
Behavior: Translational Opportunities and Implications
1Department of Psychiatry and Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA
Neuropsychopharmacology (2010) 35, 2322–2323; doi:10.1038/npp.2010.147
Developmental exposure to nicotine, the addictive consti-
tuent in tobacco, alters early brain development, leading to
defects in sensory and cognitive processing. In this issue of
Neuropsychopharmacology, Heath et al (2010) utilize a novel
mouse model of developmental nicotine exposure to clarify
the molecular and neural mechanisms underlying the effects
of perinatal nicotine on the developing brain and behavior.
The authors show that mice exposed to nicotine during a
critical period for corticothalamic development exhibit
increased sensitivity to passive avoidance behavior, char-
acterized by a longer latency to enter a chamber in which
mild footshock was administered. Further, they provide
compelling evidence that this neurobehavioral effect of
developmental nicotine is mediated by a4b2a5 nicotinic
acetylcholine receptors (nAChRs) expressed in the corti-
cothalamic pathway. These preclinical findings are novel
and important, informing human neuropsychopharmacol-
ogy investigations that may lead to improved prevention
and treatment of nicotine addiction and its consequences.
On the basis of their experiments and prior data, the
authors suggest that the passive avoidance phenotype
reflects altered sensory processing, which heightens the
aversive effects of the mild footshock administered. As they
point out, humans exposed to tobacco smoke in utero
exhibit a range of processing deficits in both sensory and
cognitive domains (Jacobsen et al, 2007). In contrast,
however, nicotine exposure in adult animals and humans
can enhance sensory processing and cognitive function
(Evans and Drobes, 2009). Taken together, these data may
support a translational hypothesis that the increased
incidence of smoking among persons exposed to tobacco
smoke in utero (Buka et al, 2003) reflects ‘self-medication’
with nicotine to reverse sensory and cognitive deficits.
Preclinical investigations can define, under controlled
experimental conditions, the specific cognitive and sensory
domains altered by perinatal tobacco exposure, thereby
informing clinical investigations to better characterize
nicotine dependence phenotypes in this subgroup of
The mouse model of developmental nicotine exposure
could also be used to screen nicotine dependence medica-
tions. On the basis of the paucity of data on the efficacy and
safety of existing pharmacotherapies for pregnant smokers,
nonpharmacological (behavioral) cessation interventions
are recommended as first-line treatment despite their
relatively lower efficacy in the general population of
smokers (Oncken and Kranzler, 2009). Thus, by elucidating
the molecular and neurobehavioral effects of perinatal
exposure to cessation medications, preclinical studies can
inform the clinical treatment of pregnant smokers.
Data presented by Heath et al (2010) also suggest novel
molecular mechanisms important in the neurodevelopmen-
tal effects of nicotine exposure. They find that the a5
nAChR subunit expressed with a4b2 nAChRs on corti-
cothalamic neurons has an important modulatory role in
developmental cholinergic function and sensory processing.
Interestingly, a common polymorphism in the a5 nAChR
subunit (CHRNA5) gene has been associated with persis-
tence of smoking during pregnancy (Freathy et al, 2009)
and with the subjective effects of the initial smoking
experience (Sherva et al, 2008). The current preclinical
findings (Heath et al, 2010) suggest the hypothesis that
altered sensory processing is an intermediate mechanism
linking CHRNA5 with nicotine dependence.
Lastly, data pointing to the corticothalamic circuit as
important in nicotine’s developmental effects helps to
advance human neuroimaging research aimed at elucidating
the functional neurocircuitry underlying nicotine depen-
dence phenotypes. In humans, genetic variation at CHRNA5
and the severity of nicotine dependence have both been
associated with reduced resting functional connectivity in a
dorsal cingulate cortical circuit (Hong et al, 2010). Thus,
parallel preclinical and human studies lend support to the
premise that assessment of functional cortical connectivity
Received 3 August 2010; accepted 3 August 2010
*Correspondence: Dr C Lerman, Department of Psychiatry and
Abramson Cancer Center, University of Pennsylvania, 3535 Market
Street, Suite 4100, Philadelphia, PA 19104, USA, Tel: +2 15 746 7141,
Fax: +2 15 746 7140, E-mail: firstname.lastname@example.org
Neuropsychopharmacology (2010) 35, 2322–2323
& 2010 Nature Publishing GroupAll rights reserved 0893-133X/10 $32.00
may be a useful translational biomarker of nicotine’s effects.
The preclinical data by Heath et al (2010) suggest the value
of examining corticothalamic connectivity in future clinical
investigations of developmental nicotine effects.
Thus, the paper by Heath et al (2010) provides an excellent
example of the value of preclinical research for informing
clinical research and practice. Not only does it suggest
directions for human neuropsychopharmacology studies of
the adverse effects of developmental nicotine, but it also
highlights important translational opportunities to elucidate
the functional neurobiology of nicotine addiction and develop
better treatments for nicotine-addicted smokers.
This work was supported by NIH grants P50CA143187,
U01DA020830 and R01DA026849.
Dr Lerman has served as a consultant and/or has received
research funding from GlaxoSmithKline, AstraZeneca,
Pfizer and Targacept. In the past 3 years, she has also
received compensation for professional services from the
National Institutes of Health, University of North Carolina,
American Association of Cancer Research, the Cancer
Prevention Research Institute of Texas, Moffitt Cancer Cen-
ter, University of New Mexico, Memorial Sloan Kettering
Cancer Center, University of Virginia, University of Illinois,
Washington University in St Louis, Northwestern Univer-
sity and Rutgers University.
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