Associate editor: S. AndersenThe dynamic effects of nicotine on the developing brain
Introduction
Tobacco is one of the most heavily abused drugs in the world, with an estimated 21% of adults in the US identifying themselves as regular smokers (CDC, 2006). Smoking is highly addicting, with a nearly 97% relapse rate for unaided quit attempts (Hughes et al., 1992), and may cause one out of every five deaths each year (CDC, Health effects of smoking, 2008). Tobacco exposure is not only a health concern for adults, however. It has also been shown to exert deleterious effects on the health of the fetus, newborn, child, and adolescent (Prokhorov et al., 2006, Kum-Nji et al., 2006, Mathers et al., 2006, Rogers, 2008). Indeed, the long-term effects of tobacco exposure may be more profound at these younger ages, since maturation of neural circuitry is not yet complete and the inherent plasticity of the developing brain makes it particularly vulnerable to drug-induced alteration.
Whereas tobacco smoke contains over four thousand chemicals (U.S. Department of Health and Human Services, 1989), there is substantial evidence that nicotine, the main psychoactive ingredient, exerts neurotoxic effects on developing brain. Nicotine can both activate and desensitize neuronal nicotinic acetylcholine receptors (nAChRs), which are ligand gated ion channels that mediate the physiological effects of the neurotransmitter, acetylcholine (ACh) (Dani, 2001). nAChRs are expressed by the first trimester in human brain and exhibit a complex pattern of developmental expression that is both region-specific and temporally regulated. In many brain areas there is a transient appearance of nAChRs during critical phases of development. Such findings suggest that acetylcholine, acting through nAChRs, may have an important functional role in modulating brain development, particularly during critical periods when brain maturation is most sensitive to perturbation.
The present review will discuss what is known of the complex roles of nAChRs in regulating brain development and will provide a conceptual framework for understanding the developmental consequences of clinical nicotine exposure, through smoking, second-hand smoke, or nicotine replacement therapy. Substantial emphasis will be placed on rodent models that provide valuable insight into the mechanisms underlying nicotine-induced pathophysiology. Although the rate of maturation of human and rodent nervous systems are vastly different, the brain contains core elements and developmental patterns that are universally shared across mammalian species, giving rise to strong parallels in their morphological development. Anatomical studies have correlated periods of rodent neural development to corresponding phases of human development, and have validated use of animal models to study human brain maturation (Bayer et al., 1993, Quinn, 2005). As is described below, there is substantial comparability in patterns of nAChR expression in developing human and rodent brain, and increasing evidence of convergence in the findings of the effects of nicotine on developmental outcomes in the clinical and animal literature. This body of work shows that the effects of nicotine are highly dependent on the timing of exposure, with specific neural vulnerabilities at each developmental phase. Furthermore, there is ample evidence that prenatal, early postnatal, and adolescent brain maturation is physiologically regulated by ACh via activation of nAChRs, and that exogenous nicotine produces marked and unique long-term deficits in developing structures by interfering with these cholinergic regulatory processes.
Section snippets
Pharmacology of nAChRs
nAChRs are pentameric ligand-gated cation channels that are widely distributed throughout human and rodent brain during all phases of development (Zoli et al., 1995, Broide and Leslie, 1999, Hellström-Lindahl and Court, 2000, Pentel et al., 2006). Depending on their subunit composition, nAChRs can gate both Na+ and Ca++, and exist in one of three conformational states: open, closed at rest, and desensitized, in which ligand binding cannot induce channel opening (Dani & Bertrand, 2007). There
Prenatal morphological development
Rats and mice are altricial animals that are born at a stage of brain development that is considerably more immature than that of humans. The gestational period of the rat spans only 22 days, which is roughly equivalent to the first 2 trimesters of human brain development. During this prenatal period, in both humans and rodents, most neuronal cell groups are born and early synaptogenesis occurs (Bayer et al., 1993). In the rat, the central nervous system begins to form around gestational day
Early postnatal morphological development
The first 12 days of life in the rat are approximately comparable to the third trimester of human gestation (Dobbing, 1971, Quinn, 2005). This period is characterized by rapid brain growth including dendritic arborization, axonal growth, peak synaptogenesis, gliogenesis, and maturation of neurotransmission (Dobbing, 1971, Dobbing and Sands, 1979). During this time, neurogenesis of the olfactory bulb, hippocampus and cerebellum is just beginning (Bayer et al., 1993). For example, the hippocampus
Adolescent morphological development
Adolescence, which is conservatively defined as approximately 12–20 years in humans and P28–42 in rats, is the final developmental epoch leading to adulthood (Spear, 2000). This maturational period is defined by characteristic behaviors such as risk-taking, novelty-seeking, high play and increased social interactions, features that are conserved across species (Spear, 2000). Another hallmark feature of this period is the development of executive functions such as decision-making and impulse
Conclusion
nAChRs are present in the brain from the earliest phases of neural development through childhood and adolescence, and into adulthood. However, their patterns of expression are regionally and temporally heterogeneous and, in many cases, unique to the developmental period. The multitude of nAChR subunits, and the resulting range of pharmacological and physiological properties of the nAChR, allows the cholinergic system immense flexibility to regulate many aspects of brain development. The
Acknowledgments
This work was supported by U.S. Public Health Service grants DA 10612, DA 19138 and GM 08620 and TRDRP fellowship 16DT-0189.
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