Tls Smoke Lesson 2 18
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Tobacco addiction remains a substantial problem in the United States and worldwide. Of those individuals who have ever tried smoking, about one-third become daily smokers (USDHHS 1994, p. 67). Of those smokers who try to quit, less than 5 percent are successful at any one time (Centers for Disease Control and Prevention [CDC] 2002, 2004). Although not all smokers become nicotine dependent, the prevalence of individuals diagnosed as nicotine dependent is higher than that for any other substance abuse disorder (Anthony et al. 1994; CDC 1995b; Kandel et al. 1997). Any efforts to reduce tobacco-related disease must take into account the addiction potential of a tobacco product.
Earlier studies that examined a wide range of animal species have shown that nicotine alone can lead to self-administration in preference to an inert control substance (Henningfield and Goldberg 1983; USDHHS 1988; Swedberg et al. 1990; Rose and Corrigall 1997; Royal College of Physicians of London 2000). Humans have also demonstrated a preference for nicotine over a control substance in studies examining intravenous administration (Henningfield and Goldberg 1983; Harvey et al. 2004), nasal administration (Perkins et al. 1996a), and use of medicinal gum (Hughes et al. 1990a). Furthermore, if levels of nicotine in the body are altered, smokers tend to compensate or titrate their dose by (1) smoking more if the levels of nicotine are reduced or blocked by a nicotinic receptor antagonist or (2) smoking less if exogenous nicotine or higher levels of nicotine are administered (USDHHS 1988; NCI 1996, 2001). Titration of the level of nicotine in the body during smoking involves adjusting smoking behaviors by changing the (1) number of puffs on a cigarette, (2) duration of the puffs, (3) interpuff intervals, and/or (4) number of cigarettes smoked (Griffiths et al. 1982). For example, researchers observed this compensatory smoking behavior in smokers who had either switched from cigarettes with a high machine-determined yield of nicotine to cigarettes with a low yield (Scherer 1999; NCI 2001) or reduced the number of cigarettes smoked (Fagerström and Hughes 2002; Hecht et al. 2004). The resulting levels of cotinine and other biochemical indicators of exposure to tobacco were proportionately lower than expected, considering the reduction in the nicotine yield of the cigarette or the number of cigarettes smoked.
Acetaldehyde, a constituent in tobacco smoke that results from burning sugars and other materials in the tobacco leaf, may play a role in increasing the reinforcing effects of nicotine (DeNoble and Mele 1983). In a later study, acetaldehyde enhanced the acquisition of nicotine self-administration among adolescent rats but not among adult rats (Belluzzi et al. 2005). The authors point out that adolescence may be a time of particular sensitivity to the effects of nicotine. This observation is supported by the fact that even a limited exposure to nicotine during adolescence may lead to symptoms of dependence (Kandel and Chen 2000; DiFranza et al. 2002b). In animals, nicotine treatment during adolescence leads to neurochemical changes in the brain that differ from those observed in adults (Adriani et al. 2002; Slotkin 2002). Furthermore, studies show an increased sensitivity to the rewarding effects of nicotine in adolescent compared with adult rodents (Adriani et al. 2002; Levin et al. 2003; Belluzzi et al. 2004). Further research is needed to understand the mechanism(s) by which acetaldehyde enhances the reinforcing effects and other effects of nicotine.
Fowler and colleagues (2003) point out that compared with nonsmokers and former smokers, current smokers had lower levels of MAOA, which preferentially oxidizes norepinephrine and serotonin, and of MAOB, which preferentially oxidizes phenethylamine. Both forms of MAO also oxidize dopamine, tyramine, and octopamine. Because former smokers showed normal MAO levels, the low levels in smokers appear to result from the pharmacologic effects of tobacco use, rather than from an inherent characteristic of smokers. Low levels of MAO may contribute to the reinforcing effects of tobacco use, because of the resulting higher levels of catecholamines. Nicotine does not appear to be responsible for this effect. Rather, the responsible constituents appear to be extracts (2,3,6- dimethyl-benzoquinone and 2-naphthylamine) from flue-cured tobacco leaves (Khalil et al. 2000; Hauptmann and Shih 2001). Animal studies with rats and mice have also shown that cigarette smoke and solutions of cigarette smoke (Yu and Boulton 1987; Carr and Basham 1991), as well as cigarette tobacco extract (Yu and Boulton 1987), inhibit MAO activity in the brain. The MAO inhibition in smokers is partial, with reductions at about 30 and 40 percent for MAOA and MAOB, respectively (Fowler et al. 2003). The reduction in MAOB levels does not appear to be rapidly reversible, as demonstrated by a study that showed no difference in MAOB levels when smokers were scanned by positron emission tomography (PET) at 10 minutes or 11 hours after smoking a cigarette (Fowler et al. 2000). One study found that the intensity of the withdrawal symptoms was inversely related to platelet MAO activity (Rose et al. 2001a); that is, smokers with low platelet activity at baseline experienced the most severe withdrawal symptoms.
Nonetheless, although the pharmacokinetics of some smokeless tobacco products may overlap with those of medicinal nicotine products, medicinal products tend to have a slower rate and a lower amount of nicotine absorption than do the most popular brands of conventional smokeless tobacco products (Kotlyar et al. 2007). Among the medicinal nicotine products, nicotine nasal spray has the fastest rate of nicotine absorption, followed by nicotine gum, the nicotine lozenge, and the nico- tine patch.
Chronic tolerance to nicotine or to most drugs is difficult to examine in clinical studies for practical and ethical reasons. The time required for the onset of chronic tolerance generally precludes longitudinal studies of changes in tolerance. Thus, the study of chronic tolerance usually requires cross-sectional comparisons between groups that differ in past histories of smoking, which can require administering nicotine to nonsmokers. Such comparisons may also introduce potential bias due to self-selection of drug history and because smoking history may covary with many other important differences that affect responses to nicotine, such as history of other drug use and psychiatric history (Hughes et al. 2000; Richter et al. 2002).
Chronic tolerance to some effects of nicotine develops after long-term smoking. However, tolerance appears to be a nonsensitive marker for dependence among those with any history of extensive smoking (Perkins 2002). Per-kins hypothesized that if a close association exists between tolerance and the level of dependence, then (1) more dependent smokers would show tolerance greater than that of less dependent smokers, (2) tolerance to nicotine before smoking cessation would predict the success of a subsequent attempt to stop smoking, and (3) tolerance would decrease with a longer duration of abstinence after cessation, indicating loss of dependence. However, the limited evidence suggests no such links between tolerance and dependence (Perkins 2002).
Other effects of nicotine may also reinforce its use, but their links with self-administration have not been clearly established. These effects include modulating negative affect (e.g., reducing fatigue, anxiety, or sadness) (Kassel et al. 2003), enhancing attention and concentration during cognitively demanding tasks (Heishman et al. 1994), and perhaps preventing hunger and maintaining a lower body weight (Perkins 1993). Evidence suggests that these effects are observed largely in abstinent smokers experiencing withdrawal and are thus examples of negative rather than positive reinforcement.
Reinforcement is often assessed in basic research studies by analyzing regular, or extent of, smoking behavior over a period of time. This is usually determined by the number of cigarettes smoked per day but occasionally by microtopographic measures of puffing behaviors, blood nicotine levels, or the percentage of carbon monoxide in expired air (Lee et al. 2003), a biochemical index of acute smoking exposure. Smoking behavior in such short-term studies has been sensitive to a variety of manipulations of nicotine exposure, demonstrating the reinforcing effects of nicotine. For example, the intensity of acute smoking behavior increases when the nicotine yield of the cigarette is lowered, which is a compensation to maintain nicotine intake (Zacny and Stitzer 1988). The increase in plasma concentrations of nicotine from smoking is greater after pretreatment with mecamylamine, a nicotine receptor antagonist. The increase is probably a result of more intense puffing in an attempt to overcome the blockade of nicotine receptors (Rose et al. 2001b). Factors have been observed to moderate the reinforcing effects of tobacco. Some studies have shown increased smoking reinforcement after pretreatment with alcohol (Nil et al. 1984; Mitchell et al. 1995) or with stimulant drugs such as d-amphetamine (Tidey et al. 2000), methylphenidate (Rush et al. 2005), or cocaine (Roll et al. 1997), but not with other stimulants such as caffeine (Nil et al. 1984; Lane and Rose 1995). The increase in smoking reinforcement from acute pretreatment with drugs may help to explain the association between a history of drug use and nicotine dependence (Richter et al. 2002).
Nevertheless, some of the manipulations that alter smoking behavior also alter the self-administration of novel nicotine formulations. Nicotine alone, isolated from tobacco smoke, is reinforcing in humans (Perkins et al. 1996a; Harvey et al. 2004). The choice of nicotine nasal spray instead of a placebo nasal spray increases with smoking abstinence (Perkins et al. 1996b) and subsequently predicts a more severe withdrawal and a faster relapse during an attempt to stop smoking without medication (Perkins et al. 2002a). Blocking the effects of nicotine with mecamylamine pretreatment increases the intravenous self-administration of nicotine (Rose et al. 2003a). Also, under the same conditions of assessment, the amount of nicotine spray used voluntarily is correlated with the amount of voluntary smoking (Perkins et al. 1997). This finding indicates a generalizability between nicotine reinforcement through smoking and reinforcement through at least one novel form of nicotine delivery. 2b1af7f3a8