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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction
the mouth (Armitage et al., 1978; Gori et al., 1986). Nicotine constitutes about 95% of the total alkaloid content of commercial cigarette tobacco (Gorrod and Jenner, 1975).
The mechanisms by which nicotine exerts its actions at a molecular level are complex. Dale (Dale, 1914) noticed the structural similarity between nicotine and acetylcholine (Ach) and the resemblance of the effects of nicotine in vivo to those of Ach after pretreatment with the muscarinic antagonist atropine. The muscarinic effects of Ach are now recognized to be mediated via one of the five heptahelical muscarinic receptors (M1-M5). Ligation of these receptors may activate downstream signaling pathways via their interaction with diverse G proteins. Nicotinic receptors (nAchRs), by contrast, are ligand gated ion channels (Domino, 1999; Lena and Changeux, 1998). These pentamers are comprised of various combinations of α, β, γ, and δ subunits. Recent studies have demonstrated that specific configurations of these subunits mediate the diverse effects of nicotine. Although this area of research is evolving, the neuronal subunits that appear to be primarily responsible for the effects of nicotine contain α3,4,7 and β2 and 4 subunits. The α4β2 subtype is particularly prevalent in the brain and may be responsible for the self-administration of nicotine. Mice deficient in the β2 subunit do not self-administer nicotine (Cordero-Erausquin et al., 2000), suggesting that this subunit in particular may be important in reinforcing the effects of nicotine. In addition, some preliminary evidence suggests that the α7 subunit may play a significant role in withdrawal and sensory gating functions of schizophrenics (Adler et al., 1998; Nomikos et al., 2000; Panagis et al., 2000). Localization studies have identified nAchRs in the brain, neuromuscular junctions, autonomic ganglia, and adrenal medulla (Gundisch, 2000). Ligation of nAchRs by nicotine opens the channel, and the ionic influx activates signal transduction pathways, culminating in release of a number of different neurotransmitters, which have been related to nicotine’s pharmacodynamic effects. These include dopamine (pleasure and appetite suppression), serotonin (appetite suppression and mood modulation), epinephrine and norepinephrine (arousal and appetite suppression), Ach (arousal and cognitive enhancement), vasopressin (memory improvement), glutamate (improvement in learning), β-endorphin (mood modulation and analgesia), and δ-aminobutyric acid. Nicotine also increases nAchR expression. For example, prenatal nicotine exposure upregulates the pulmonary expression of the α7 receptor subunit and consequently affects fetal lung development in monkeys (Sekhon et al., 1999). Nicotine caused lung hypoplasia and reduced surface complexity of developing alveoli in this model. Collagen surrounding the large airways and vessels was increased, as was the number of type II cells and neuroendocrine cells in neuropepithelial