NICOTINE ADDICTION

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Nicotine is central to maintaining tobacco use. Understanding how nicotine sustains smoking provides a necessary basis for optimal smoking cessation therapy. This article updates several earlier reviews on the pharmacology of nicotine addiction.5, 7, 8

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WHAT IS ADDICTION?

Approximately 45 million Americans currently smoke tobacco products. Seventy percent of smokers state they would like to quit, and 30% make a serious attempt to quit each year,1 that is, they quit for at least 1 day. Only 3% of smokers, however, successfully quit each year. Unfortunately, the rate of appearance of new daily smokers, primarily among children or adolescents, matches the quit rate, so the prevalence of cigarette smoking has not declined for many years.38

The key concept in

EVIDENCE THAT NICOTINE IS ADDICTING

Loss of control of tobacco use is evident to most health care professionals who have tried to get patients with smoking-related diseases to quit. However, it is worthwhile to review the various lines of evidence for tobacco addiction, and the role of nicotine in sustaining tobacco addiction. The first line of evidence for tobacco addiction is that most smokers state they would like to quit smoking, and many have made several quit attempts that have failed. Most studies indicate that smokers on

CENTRAL NERVOUS SYSTEM MECHANISMS OF NICOTINE ADDICTION

(S)-Nicotine binds stereoselectively to nicotinic cholinergic receptors that are present in the brain, autonomic ganglia, the medulla, and neuromuscular junctions. Most relevant to nicotine addiction are the neuronal nicotinic cholinergic receptors. These are found throughout the brain, with the greatest number of binding sites in the cortex, thalamus, and interpeduncular nucleus, and substantial binding in the amygdala, septum, brain stem motor nuclei, and locus coeruleus.24 The nicotinic

PHARMACODYNAMICS OF NICOTINE ADDICTION

The release of various neurotransmitters results in behavioral arousal, sympathetic neural activation, and a number of other effects that are believed to be rewarding.5 The release of specific neurotransmitters has been speculatively linked to the reported reinforcing effects of nicotine (Fig. 1). For example, enhanced release of dopamine and norepinephrine may be associated with both pleasure and appetite suppression, the latter of which may contribute to lower body weight. Release of

ABSORPTION OF NICOTINE FROM TOBACCO

Nicotine is distilled from burning tobacco and carried proximally on tar droplets that are inhaled and deposited in the small airways and alveoli. The absorption of nicotine across biologic membranes depends on pH. The pH of smoke from the flue-cured tobaccos found in most cigarettes is acidic (pH 5.5 to 6.5). At this pH, the nicotine is primarily ionized. In the ionized state, it does not cross cell membranes rapidly. Consequently, there is little buccal absorption of nicotine from cigarette

NICOTINE KINETICS AND ADDICTION: THE CIGARETTE IS AN OPTIMAL DRUG DELIVERY SYSTEM

Smoking is a unique form of systemic drug administration, because nicotine is delivered to the pulmonary rather than to the portal or systemic venous circulations. It takes 10 to 19 seconds for nicotine to pass from the cigarette to the brain.6 The lag time between smoking and the entry of nicotine into the brain is shorter than that observed when nicotine is injected intravenously. Nicotine enters the brain quickly, but the brain levels decline rapidly thereafter as the drug is distributed to

REGULATION OF NICOTINE INTAKE

That smokers regulate their intake of nicotine has been clearly demonstrated. Smokers change the way they puff a cigarette depending on nicotine yield, as determined by the cigarette smoking machine.46, 74 They puff lower yield cigarettes more frequently or more intensely than higher yield cigarettes, presumably to obtain more nicotine. Smokers who switch from higher yield to lower yield cigarettes consume more nicotine from the lower yield cigarettes than is predicted by smoking machine tests.

ASSESSING NICOTINE ADDICTION

The first section of this article discussed the definitions of addiction and the criteria developed by the Surgeon General and the American Psychiatric Association to determine addiction. Translating definitions of addiction to practical criteria that can be used to assess addiction at the bedside has been problematic. The most widely used assessment tool has been the Fagerström Tolerance Questionnaire (Table 4).33 These questions were developed to assess the level of tolerance to nicotine, but

ACKNOWLEDGMENT

The author would like to thank Kaye Welch for editorial assistance.

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      Citation Excerpt :

      Nicotine binds to nicotinic acetylcholine receptors (nAChRs), a group of cationic ligand-gated ion channels found in both the peripheral nervous system (PNS) and CNS.17–20 There are three nAChR subtypes in the mammalian brain (α4β2-, α3β4- and α7-nAChRs); the most predominant subtype in humans, α4β2-nAChR, is where nicotine displays the highest binding affinity (Ki < 1 nM), and is a full agonist at this site.17–20 The binding affinity for nicotine at the α3β4-nAChR (Ki = 530 nM) and the α7-nAChR (Ki = 6290 nM) are much weaker than at the α4β2-nAChR.20

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    Address reprint requests to Neal L. Benowitz, MD, University of California, San Francisco, Box 1220, San Francisco, California 94143-1220, e-mail: [email protected]

    This work was supported by Grants No. DA02277 and DA01696 from the National Institutes of Health.

    *

    Departments of Medicine, Psychiatry, and Biopharmaceutical Sciences, University of California, San Francisco; and the Division of Clinical Pharmacology and Experimental Therapeutics, Medical Service, San Francisco General Hospital Medical Center, San Francisco, California

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