A neurobiological basis for nicotine withdrawal
Tobacco products have been used for >1,000 years, and the key active psychopharmacological ingredient, nicotine, has been studied for almost 200 years (1, 2). The health hazards of tobacco use have been studied and documented extensively in dozens of reports from U.S. Surgeons General, the Centers for Disease Control and Prevention, the World Health Organization, and other government offices, as well by not-for-profit organizations, epidemiologists, physicians, psychologists, nurses, and others. Nicotine also has received an extraordinary amount of research attention for its role in tobacco use and as a possible treatment for physical and mental health disorders. Therefore, it is noteworthy and impressive when a new investigation of nicotine makes a meaningful contribution to the research literature. The article by George et al. (3) in a recent issue of PNAS does just that. These investigators address the critical, and poorly understood, biological mechanism for the nicotine abstinence syndrome (or nicotine “withdrawal”). They make a sound argument that corticotropin-releasing factor (CRF)–CRF1 system activation underlies nicotine withdrawal. They also suggest that this system is the biological basis of negative reinforcement that plays a key role in difficulty abstaining from tobacco and in relapsing to tobacco use. If correct, then this article is a watershed paper in the science of nicotine addiction and suggests new pharmaceutical directions to help tobacco users abstain.
Arguably, nicotine is the most important drug of addiction in history. Alcohol, opiates, caffeine, cocaine, amphetamines, and other drugs certainly are important, but nicotine has the distinction of wreaking more havoc through tobacco use and offering more hope as a medicine than all of the other drugs. Tobacco-related illnesses cause more deaths each year (440,000 per year in the United States and 5 million per year worldwide) than do all other drugs plus homicides, suicides, motor vehicle accidents, HIV/AIDS, and fires. Cigarette smoking causes approximately one in every five deaths in the United States, and 1,200 Americans die each day from tobacco use. Put even more starkly, tobacco use has a death toll equivalent to that of the 9/11 tragedy but occurring two to three times per week, all year round. Nicotine is the primary drug of addiction in tobacco, and it maintains a powerful hold on its user, despite knowledge about the deadly effects of tobacco. Yet nicotine also offers promise as a treatment for obesity, attention disorders, depression, Parkinson's disease, Alzheimer's disease, senile dementia, and pain.
Arguably, nicotine is also the most interesting drug of addiction in history. Certainly, all of the drugs of addiction are fascinating, and each has biological and psychological actions and mechanisms that are well worth studying. However, only nicotine can bring us up when we are down and calm us down when we are up. Nicotine can have a mild euphoric effect, control hunger, focus attention, attenuate pain, relieve anxiety and depression, and help us cope with stress. Other addictive drugs are either CNS stimulants (e.g., cocaine, amphetamines, caffeine) or CNS depressants (e.g., alcohol, opiates, barbiturates). Although nicotine is categorized as a CNS stimulant, its effects seem to depend on the state or needs of its user (animal or human) and have earned it the nickname of a “paradoxical” drug (4).
Tobacco and Nicotine Research
Understanding the importance of George et al.'s article (3) requires a perspective on what has been studied about nicotine and what is missing. Historically, the study of tobacco and the study of nicotine were on separate tracks. Tobacco has played, and continues to play, a monumental role in the U.S. economy, and centuries of study focused on issues related to agriculture, manufacturing, production, marketing, and so on. Tobacco science has a long and sophisticated history within and outside the tobacco industry. Separately, nicotine—isolated, identified, and synthesized in the 19th century—became a valuable tool in pharmacology and played a key role in the discovery of neurotransmission and receptor biology (2). In the 20th century, investigators began to consider and study whether nicotine was the key ingredient responsible for many of the effects of tobacco (5). In the 1960s, a few investigators outside the tobacco industry focused on nicotine's role in tobacco use (6–9). By the late 20th century, dozens of laboratories were studying nicotine as it related to tobacco use. Their collective findings were summarized in the U.S. Surgeon General's Report, The Health Consequences of Smoking: Nicotine Addiction (2), which concluded that
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Cigarettes and other forms of tobacco are addicting.
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Nicotine is the drug in tobacco that causes addiction.
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The pharmacologic and behavioral processes that determine tobacco addiction are similar to those that determine addiction to drugs such as heroin and cocaine.
This 1988 report provided convincing evidence that nicotine is addicting and summarized the state of knowledge regarding biological and psychological mechanisms relevant to addiction. Extensive information was presented about mechanisms of nicotine addiction, and an extraordinary amount of information has been revealed since that time. The report sparked research activities investigating mechanisms of nicotine addiction and the development of nicotine-replacement therapies to help smokers abstain from tobacco use.
Neurobiological investigations (10–14) have revealed that nicotine acts at cholinergic receptors (nAChRs) throughout the brain and nervous system and through several neurochemical mechanisms, including acetylcholine, dopamine, glutamate, GABA, endogenous opioid peptides, and serotonin. A remarkable amount of information is published regularly about the neurobiology of nicotine, but the emphasis has been on mechanisms underlying positive reinforcement (15–17). All of this information is relevant and important, but the key to addiction (vs. self-administration per se) is withdrawal and negative reinforcement; i.e., what motivates people and animals to crave drugs and to relapse to drug use after they have abstained? What makes it so difficult to maintain abstinence? These are the questions that George et al. (3) address. Tobacco withdrawal, of course, has been and continues to be studied by many investigators, some emphasizing the psychological aspects and some emphasizing the biological aspects of withdrawal. George et al. cleverly considered the stress–smoking relationship as the conceptual basis for their neurobiological studies.
Nicotine, Stress, and Negative Reinforcement
There is a strong correlation between stress and cigarette smoking, and it is clear that stress results in increased cigarette smoking (2, 18). Although cigarette smokers report that they smoke to help cope with stress, this perception does not necessarily mean that smoking actually reduces stress compared with nonsmokers not smoking. There is evidence that smoking helps to modulate mood (perhaps through serotonergic actions), relax skeletal muscles, and relieve pain, and that it has other effects that may be stress-reducing (2, 10). However, smokers may perceive and report that smoking reduces stress because abstinence from smoking causes stress and because cigarette smoking relieves withdrawal effects in smokers (i.e., negative reinforcement) (19). Therefore, smoking may be stress-reducing compared with the stress of withdrawal, but smoking might not reduce stress compared with controls (i.e., smokers not smoking). Benwell and Balfour (20) reported that nicotine withdrawal results in increased corticosterone, but the importance of that discovery to the understanding of nicotine abstinence (i.e., the connection between mechanisms of stress and mechanisms of nicotine withdrawal) was not fully appreciated at the time. Other investigators suggested that stress alters nicotine pharmacokinetics (i.e., nicotine self-administration increases under stress because stress decreases the availability of nicotine) and that stress alters nicotine pharmacodynamics (i.e., nicotine becomes more rewarding under stress) (2, 15). A few investigators (e.g., refs. 21 and 22) have focused on nicotine withdrawal, and there has been speculation about the biological commonalities of stress and drug abuse (2). However, most of the neurobiology of nicotine emphasizes the actions of nicotine rather than the actions of abstinence from nicotine. The brilliance of George et al. (3) was to pick up on the connection (as has been done with other drugs of addiction) between stress and withdrawal and to conduct careful and programmatic experiments.
Smokers may perceive and report that smoking reduces stress because abstinence from smoking causes stress.
George et al. (3) report that (i) precipitated nicotine withdrawal in rats increases CRF levels in the central nucleus of the amygdala; (ii) precipitated withdrawal increases anxiety-like behavior through activation of CRF1 receptors; (iii) cessation of nicotine exposure in rats previously exposed to nicotine increases nicotine self-administration; and (iv) antagonism of CRF1 receptors prevents “abstinence”-induced increases in nicotine intake. This series of experiments provides strong support for the idea that CRF1 is involved in the biology and behavior of nicotine withdrawal, including negative reinforcement (i.e., offsetting the unpleasantness of cessation) and relapse (i.e., a return to self-administration). In other words, nicotine withdrawal is indeed a stressor that acts via the CRF–CRF1 system, which in turn results in increased nicotine self-administration to offset stress. This finding also suggests that pharmaceutical interventions should be developed to intervene in the stress system, to attenuate withdrawal-induced smoking relapse. Several nicotine-replacement therapies (e.g., gum, patch, lozenge, inhaler) and other pharmaceutical treatments (buproprion, varenecline) to help people quit smoking are now available, but none of these treatments focuses on the CRF system.
What To Do Next
The report by George et al. (3) is just the beginning of what should be a vibrant area of research. For example, it would be valuable to expand this line of work to include other anxiety-like behaviors (e.g., elevated plus-maze center time) and behavioral controls (e.g., open-field locomotor activity) to more fully understand the types of and extent to which anxiety-like behaviors are involved in, and altered by, nicotine cessation. It also would be valuable to measure brain levels of nicotine and the central binding of nicotine (including receptor subtypes and loci) that are involved in the nicotine cessation–CRF effects. In addition, it is important to consider individual differences (including sex, age, and genotype) in the nicotine cessation–CRF effects, to help tailor pharmaceutical treatments to individual needs and to optimally integrate pharmacological and psychological tobacco-cessation treatments because it is clear that these variables are relevant to the actions of nicotine and to the responses of stress systems (23). With so many people in need of help to abstain from smoking and to deal with stress, it is wonderful when basic science makes a meaningful contribution.
Footnotes
- *E-mail: ngrunberg{at}usuhs.mil
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Author contributions: N.E.G. wrote the paper.
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The author declares no conflict of interest.
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See companion article on page 17198 in issue 43 of volume 104.
- © 2007 by The National Academy of Sciences of the USA
