title: Mode of action: disruption of brain cell replication, second messenger, and neurotransmitter systems during development leading to cognitive dysfunction--developmental neurotoxicity of nicotine.
abstract: Developmental exposure to nicotine in rats results in neurobehavioral effects such as reduced locomotor and cognitive function. Key events in the animal mode of action (MOA) include binding to the nicotinic cholinergic receptor during prenatal and/or early postnatal development. This leads to premature onset of cell differentiation at the expense of cell replication, which leads to brain cell death or structural alterations in regional brain areas. Other events include an initial increase followed by a decrease in adenyl cyclase activity, as well as effects on the noradrenergic, dopaminergic, and serotonergic neurotransmitter systems. Because the nicotine receptor is also present in the developing human brain and the underlying biology for DNA synthesis and cell signaling is comparable, this MOA is likely to be relevant for humans. Although the effects of nicotine exposure in developing humans is not well documented, nicotine exposure as a result of cigarette smoking during pregnancy is associated with several physiological and behavioral outcomes that are reminiscent of the effects of nicotine alone in animal models. As data become available with the advent of the use of the nicotine patch in pregnant humans, the question as to the relative importance of smoking per se versus nicotine alone may be determined.
authors.affiliation: Division of Neurotoxicology, NCTR/FDA, Jefferson, Arkansas 72079, USA. wslikker@nctr.fda.gov
authors.forename: William
authors.initials: W
authors.lastname: Slikker
authors.forename: Z Alex
authors.initials: ZA
authors.lastname: Xu
authors.forename: Edward D
authors.initials: ED
authors.lastname: Levin
authors.forename: Theodore A
authors.initials: TA
authors.lastname: Slotkin
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D003072:Cognition Disorders / Q000139:chemically induced* / Q000473:pathology* / Q000523:psychology; D005260:Female; D006801:Humans; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000473:pathology / Q000523:psychology; D018377:Neurotransmitter Agents; D009538:Nicotine / Q000493:pharmacokinetics / Q000633:toxicity*; D018722:Nicotinic Agonists / Q000493:pharmacokinetics / Q000633:toxicity*; D011247:Pregnancy; D051381:Rats; D015290:Second Messenger Systems / Q000502:physiology*
chemical_list: D018377:Neurotransmitter Agents; D018722:Nicotinic Agonists; D009538:Nicotine