Mode of Action: Disruption of Brain Cell Replication, Second Messenger, and Neurotransmitter Systems During Development Leading to Cognitive Dysfunction-Developmental Neurotoxicity of Nicotine

• Published in: Critical reviews in toxicology Vol. 35; no. 8-9; pp. 703 - 711
• Main Authors: Slikker, William, Xu, Z. Alex, Levin, Edward D., Slotkin, Theodore A.
• Format: Journal Article
• Language: English
• Published: England Informa UK Ltd 01.10.2005; Taylor & Francis; Taylor & Francis Ltd
• Subjects: Animals; Brain - drug effects; Brain - pathology; Cell Division - drug effects; Cell Signaling; Cognition Disorders - chemically induced; Cognition Disorders - pathology; Cognition Disorders - psychology; Female; Human Relevance; Humans; Nervous System Diseases - chemically induced; Nervous System Diseases - pathology; Nervous System Diseases - psychology; Neurobehavioral Dysfunction; Neuroteratogen; Neurotransmission; Neurotransmitter Agents; Nicotine; Nicotine - pharmacokinetics; Nicotine - toxicity; Nicotinic Agonists - pharmacokinetics; Nicotinic Agonists - toxicity; Nicotinic Cholinergic Receptor; Pregnancy; Rats; Second Messenger Systems - physiology
• ISSN: 1040-8444; 1547-6898
• DOI: 10.1080/10408440591007421

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.