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Clinical Pharmacology of Nicotine: Implications for Understanding, Preventing, and Treating Tobacco Addiction

Department of Medicine, University of California, San Francisco, California, USA.
Clinical Pharmacology &#38 Therapeutics (Impact Factor: 7.39). 05/2008; 83(4):531-41. DOI: 10.1038/clpt.2008.3
Source: PubMed

ABSTRACT Understanding the basic and clinical pharmacology of nicotine provides a basis for improved prevention and treatment of tobacco addiction. Nicotine acts on nicotinic cholinergic receptors in the brain to release dopamine and other neurotransmitters that sustain addiction. Neuroadaptation and tolerance involve changes in both nicotinic receptors and neural plasticity. Nicotine addiction can occur in the context of physical dependence characterized by self-medication to modulate negative affect and/or to relieve withdrawal symptoms, as well as, in light or occasional smokers, primarily for positive reinforcement in specific situations. Nicotine is metabolized primarily by CYP2A6. Its clearance exhibits considerable individual variability that is determined by genetic, racial, and hormonal (sex) factors. Genetically slow metabolism of nicotine appears to be associated with a lower level of dependence. Nicotine dependence is highly heritable and appears to be influenced by genes coding for some nicotine receptor subtypes, some neurotransmitter genes, and genes involved in neural connectivity. Novel pharmacotherapies for nicotine dependence include partial agonists for nicotinic receptors and nicotine vaccines. Pharmacogenetic studies suggest various candidate genes and a nicotine metabolism phenotype that influence outcome. Human pharmacology studies of nicotine and smoking behavior also provide a basis for assessing the benefits and risks of long-term nicotine use for harm reduction and for a potential cigarette regulatory strategy that includes reducing nicotine content of cigarettes to nonaddictive levels.

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    • "However, because NRTs appear to be more effective in suppressing tonic or background craving as opposed to phasic or peaks in craving (Ferguson and Shiffman, 2009; Schlagintweit et al., 2014), one might expect that NRTs would be most effective when smoking opportunities are not perceived to be imminently available. NRT effects are generally attributed to the pharmacological properties of nicotine M a n u s c r i p t 6 (e.g., Benowitz, 2008; Stead et al., 2012); however, there is growing evidence that suggests that non-pharmacological factors make a substantial contribution (Caggiula et al., 2001; Dar and Barrett, 2014). Balanced placebo research, which crosses instructions regarding nicotine content (told nicotine-containing vs. told nicotine-free) with actual nicotine content (contains nicotine vs. no nicotine) suggests that the belief that nicotine has been consumed reduces cigarette craving and withdrawal regardless of whether or not nicotine was actually consumed (Dar and Barrett, 2014; Darredeau and Barrett, 2010; Gottlieb et al., 1987; Schlagintweit et al., 2014). "
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    ABSTRACT: Background: Perceptions regarding the availability of smoking opportunities are known to affect cigarette craving; however, whether they impact actual smoking or how smokers respond to acute nicotine replacement therapy (NRT) administration is not known. This study examined the impact of pharmacological and expectancy components of NRT administration on craving and smoking in smokers anticipating or not anticipating an imminent smoking opportunity. Methods: 154 smokers (84 male) completed an experimental session in which instructions regarding the nicotine content of a lozenge (4mg vs. no nicotine) and regarding the availability of a future smoking opportunity were manipulated. Cigarette craving was assessed before and after manipulations and lozenge administration. All participants were then allotted one hour to self-administer as many cigarette puffs as they wished. Results: Unanticipated smoking opportunities reduced latency to self-administration (p<0.001), regardless of nicotine expectancy or pharmacology. When analyses included all participants, nicotine reduced intentions to smoke (p=0.016) and withdrawal-related craving (p=0.043) regardless of expectancy. Conversely, analyses using only “believers” of the nicotine content instructions revealed that nicotine expectancy reduced intentions to smoke (p=0.034) and withdrawal-related craving (p=0.047) regardless of actual nicotine administration. “Believers” also reported increased withdrawal-related craving when a smoking opportunity was perceived to be imminent (p=0.041). These effects were not significant when analyses included all participants. Conclusions: Findings suggest that unexpected smoking opportunities may be more appealing than expected ones regardless of perceived or actual acute NRT use. They also highlight the importance of reporting balanced placebo findings using all participants as well as “believers” only.
    Drug and alcohol dependence 02/2015; 147. DOI:10.1016/j.drugalcdep.2014.12.012 · 3.28 Impact Factor
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    • "Current models of drug dependence propose that the failure to control or inhibit prepotent urges and responses to drug stimuli become heightened with increased periods of abstinence, with subsequent failings of IC promoting continued drug use (Goldstein and Volkow, 2002; Lubman et al., 2004; Goldstein and Volkow, 2011). Interestingly, unlike other drugs, a typical pattern of nicotine use results in cumulative, 24-h a day nicotine exposure (Benowitz, 2008), meaning that unlike some forms of dependence, the contribution of IC dysfunction to nicotine dependence may not be of clinical significance until the decision to quit or abstain from nicotine. Hence focusing on the interaction between IC and abstinence may be critical to improving clinical outcomes within this population. "
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    ABSTRACT: Background Although the majority of substance use disorders depict reliable deficits in inhibitory control (IC), similar deficits are not consistently found in nicotine dependence. The mixed results of past research may have been due to confounding variables known to independently influence IC function, including age, concurrent drug use and particularly, length of nicotine abstinence. Methods A Stop Signal Task was used to examine Stop Signal Reaction Time (SSRT), a typical measure of IC, in nicotine dependence across two studies that attempted to closely control for IC confounds. Study 1 compared the SSRT of 37 dependent cigarette smokers (11 female) to 36 non-smokers (13 female), following 3-hours of nicotine abstinence. Study 2 compared 22 dependent cigarette smokers’ (11 female) SSRT scores when satiated on nicotine to their performance following 10-hours of nicotine abstinence. Results Nicotine dependent individuals did not differ from controls in SSRT performance following 3-hr abstinence, but showed a significant decline in performance following 10-hr abstinence, when compared to nicotine satiation. Conclusions During shorter abstinence periods, the acute benefits of nicotine satiation appear to facilitate inhibitory control, however IC was poorer during extended periods of nicotine abstinence. In turn, this suggests that the reliability of IC dysfunction in nicotine dependence varies according to abstinence length and needs to be carefully considered for future behavioural and neuroimaging examination of IC within this population.
    Drug and Alcohol Dependence 10/2014; 143. DOI:10.1016/j.drugalcdep.2014.07.008 · 3.28 Impact Factor
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    • "Smokers usually maintain a continuous supply of nicotine daytime that induces tolerance, while at night, the first prodromal symptoms of the withdrawal syndrome begin. Indeed, the first cigarette of the day restores the effectiveness of nicotine to such an extent that smokers defined it as " the most rewarding one of the day " [5] [7]. "
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    ABSTRACT: Nicotine is one of the drugs of abuse that frequently causes addiction and relapse during abstinence. Nicotine's strong addicting properties reside in its ability to enhance dopamine transmission, and to induce specific changes in synaptic plasticity. Currently, approved therapies for smoking cessation increase the chances of remaining abstinent, but lack high levels of efficacy and are associated with significant adverse side effects. As a result, there is an urgent need for more effective antismoking medications. Studies have revealed that drugs targeting the peroxisome proliferator-activated-receptor-α (PPARα) show promise for the treatment of nicotine addiction. These drugs include synthetic PPARα ligands, such as the clinically available hypolipidemic fibrates, and drugs that increase levels of endogenous endocannabinoid-like fatty acid ethanolamides (FAEs) that act as PPARα agonists.In this review, we will discuss the specific interaction between PPARα and nicotine, and the molecular mechanisms whereby these intracellular receptors regulate nicotinic acetylcholine receptor functions in neurons. Modulation of neurophysiological, neurochemical and behavioral effects of nicotine by PPARα will be also reviewed. Indeed, a picture is emerging where FAEs are endogenous regulators of acetylcholine transmission. Notably, the implications of this specific cross talk extend beyond nicotine addiction, and might bear relevance for psychiatric disorders and epilepsy.
    Pharmacological Research 04/2014; 86. DOI:10.1016/j.phrs.2014.03.009 · 3.98 Impact Factor
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