Chapter 18. Neurobiology of Nicotine and Tobacco

Nicotine is found in the leaves of plants in the Solanaceae family and acts as a natural insecticide. Among plants in this family, the tobacco plant ( Nicotiana tabacum ) contains the highest concentrations of nicotine; however, significantly lower levels of nicotine are also found in other members of the Solanaceae family, including tomatoes, potatoes, and eggplants. Use of tobacco by humans dates back at least 2,500 years to the Mayans, with its introduction to Europe occurring in the early 1500s. Snuff and pipe tobacco were the most prevalent early forms used, followed by cigars in the 1800s. The first commercially available cigarettes were produced in the mid-1800s, and they became the most prevalent form used. There are currently an estimated 1 billion smokers worldwide. Smoking remains one of the leading preventable causes of death in the world. There are over 7,000 different compounds found in tobacco smoke, some of which (in addition to nicotine) are psychoactive (Margolis et al. 2017). These include compounds such as minor tobacco alkaloids, monoamine oxidase (MAO) inhibitors, and acetaldehyde. Nicotine accounts for approximately 95% of the alkaloid content found in tobacco, with the primary minor alkaloids being anatabine, anabasine, and norcotinine (von Weymarn et al. 2016). The pharmacological actions of nicotine have the largest role in contributing to tobacco addiction (Figure 18–1 ). Nicotine can exist in two stereoisomeric forms (the same atoms arranged in differing spatial arrangements): R-nicotine and S-nicotine. In the tobacco plant, nicotine is produced primarily (~ 90%) in the S (versus the R) isomeric form, whereas synthesized formulations of nicotine contain similar proportions of both stereoisomers. The stereoisomers of nicotine differ in their receptor-binding properties and psychoactive effects; the S isomer is more biologically active, and the R form is a weaker agonist. Biobehavioral model showing factors and processes that contribute to nicotine/tobacco dependence. Nicotine acts on nicotinic cholinergic receptors, triggering the release of neurotransmitters that produce psychoactive effects that are rewarding. With repeated exposure, tolerance develops to many of the effects of nicotine, thereby reducing its primary reinforcing effects and inducing physical dependence (i.e., withdrawal symptoms in the absence of nicotine). Smoking behavior is influenced by pharmacological feedback and by environmental factors such as smoking cues, friends who smoke, stress, and product advertising. Levels of nicotine in the body in relation to a particular level of nicotine intake from smoking are modulated by the rate of nicotine metabolism, which occurs in the liver largely by means of the enzyme CYP2A6. Other factors that influence smoking behavior include age, sex, genetics, mental illness, and substance abuse. Source. Reprinted from Figure 1 (“The Biology of Nicotine Addiction”) in Benowitz NL: “Nicotine Addiction.” New England Journal of Medicine 362(24):2295–2303, 2010. Copyright 2010, Massachusetts Medical Society. Used with permission. As a tertiary amine, nicotine can exist in both a charged and an uncharged form (i.e., ionized and un-ionized). The ratio of ionized to un-ionized nicotine is altered by pH, with the majority of nicotine molecules being ionized in more acidic conditions (e.g., a pH of ≤ 5.5) and un-ionized in more alkaline conditions (e.g., a pH of ≥ 6.5). Charged and uncharged nicotine molecules differ in their membrane permeability. Un-ionized nicotine is lipophilic and can be absorbed through the skin and buccal membrane, whereas ionized nicotine cannot (Benowitz et al. 2009). The pH of tobacco smoke influences nicotine absorption and behavior among users. Cigarette smoke and cigar smoke differ in pH, with smoke from cigars being alkaline and smoke from most cigarettes being acidic. These differences between cigars and cigarettes are due to the type of tobacco used, the method for curing after harvesting, and the addition of chemicals during processing and formulation. In cigar smoke, a higher proportion of the nicotine molecules are un-ionized and can be absorbed in the mouth through the buccal membrane, allowing for nicotine absorption without inhalation. In contrast, cigarette smoke has a higher proportion of ionized nicotine molecules, which are lipophobic and not readily absorbed through the buccal membrane, resulting in limited absorption in the mouth without inhalation. In smokeless tobacco, the pH is adjusted to be more alkaline, resulting in a high proportion of un-ionized nicotine and more rapid buccal absorption of nicotine. Tobacco can be smoked or chewed, and nicotine can be ingested in the form of gum, a lozenge, or spray; applied as a dermal patch; or inhaled as an aerosol through an electronic cigarette device or inhaler. Electronic cigarette devices heat a solution of nicotine and flavorant mixed with propylene glycol and/or glycerin into an aerosol, which is inhaled by the user. There are multiple types of electronic cigarette devices, which differ in design, formulations dispensed, and efficacy of nicotine delivery. Nicotine from cigarette smoke is rapidly absorbed in the small airways and alveoli of the lung. Smoking one cigarette results in absorption of approximately 1–1.5 mg of nicotine systemically, depending on the smoking pattern and nicotine concentration in the cigarette (Benowitz and Jacob 1984). Nicotine from cigarette smoke is rapidly delivered to the brain within 15 seconds after inhalation (Berridge et al. 2010). The swift delivery of nicotine to the brain from smoking a cigarette contributes to the increased abuse liability of cigarettes compared with other routes of nicotine administration (Benowitz 2010; Benowitz et al. 1988). Nicotine has a half-life of approximately 2 hours in humans, although genetic and other factors (e.g., medications, diet, sex, estrogen, use of menthol cigarettes, compounds in tobacco smoke) contribute to individual differences in the rate of nicotine metabolism (Benowitz et al. 2009). With regular smoking, nicotine levels build up throughout the day, plateauing at 4–6 hours and then decreasing slowly overnight, but with significant levels still present first thing in the morning. Thus, nicotine is present in the brain 24 hours a day, facilitating the development of tolerance and dependence, as discussed in the section “Individual Vulnerability to Nicotine Dependence.” Tolerance also develops throughout each day, with the greatest effects being experienced from the first cigarette of the day and subsequent cigarette craving and smoking being triggered at least in part by the need to relieve or avoid withdrawal symptoms.