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Home , Nicotine withdrawal

COMMENTARY

A neurobiological basis for withdrawal

Neil E. Grunberg* Department of Medical and Clinical Psychology and Neuroscience Program, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814

obacco products have been week, all year round. Nicotine is the use. Their collective findings used for Ͼ1,000 years, and the primary drug of addiction in tobacco, were summarized in the U.S. Surgeon key active psychopharmacologi- and it maintains a powerful hold on its General’s Report, The Health Conse- cal ingredient, nicotine, has user, despite knowledge about the quences of : Nicotine Addiction Tbeen studied for almost 200 years (1, 2). deadly effects of tobacco. Yet nicotine (2), which concluded that The health hazards of tobacco use have also offers promise as a treatment for Y been studied and documented exten- obesity, attention disorders, , and other forms of tobacco sively in dozens of reports from U.S. Parkinson’s disease, Alzheimer’s disease, are addicting. Surgeons General, the Centers for Dis- senile dementia, and pain. Y Nicotine is the drug in tobacco that ease Control and Prevention, the World Arguably, nicotine is also the most causes addiction. Health Organization, and other govern- interesting drug of addiction in history. Y The pharmacologic and behavioral ment offices, as well by not-for-profit Certainly, all of the drugs of addiction processes that determine tobacco ad- organizations, epidemiologists, physi- are fascinating, and each has biological diction are similar to those that de- cians, psychologists, nurses, and others. and psychological actions and mecha- termine addiction to drugs such as Nicotine also has received an extraordi- nisms that are well worth studying. heroin and . nary amount of research attention for its However, only nicotine can bring us up This 1988 report provided convincing role in tobacco use and as a possible when we are down and calm us down evidence that nicotine is addicting and treatment for physical and mental health when we are up. Nicotine can have a summarized the state of knowledge re- disorders. Therefore, it is noteworthy mild euphoric effect, control hunger, garding biological and psychological and impressive when a new investigation focus attention, attenuate pain, relieve mechanisms relevant to addiction. Ex- of nicotine makes a meaningful contri- and depression, and help us tensive information was presented about bution to the research literature. The cope with stress. Other addictive drugs article by George et al. (3) in a recent are either CNS (e.g., co- mechanisms of nicotine addiction, and issue of PNAS does just that. These in- caine, , ) or CNS an extraordinary amount of information vestigators address the critical, and depressants (e.g., , opiates, bar- has been revealed since that time. The poorly understood, biological mecha- biturates). Although nicotine is catego- report sparked research activities investi- nism for the nicotine abstinence syn- rized as a CNS , its effects gating mechanisms of nicotine addiction drome (or nicotine ‘‘withdrawal’’). seem to depend on the state or needs and the development of nicotine- They make a sound argument that of its user (animal or human) and have replacement therapies to help smokers corticotropin-releasing factor (CRF)– earned it the nickname of a ‘‘paradoxi- abstain from tobacco use. Neurobiological investigations (10–14) CRF1 system activation underlies nico- cal’’ drug (4). tine withdrawal. They also suggest that have revealed that nicotine acts at cho- this system is the biological basis of neg- Tobacco and Nicotine Research linergic receptors (nAChRs) throughout ative reinforcement that plays a key role Understanding the importance of the brain and nervous system and in difficulty abstaining from tobacco George et al.’s article (3) requires a per- through several neurochemical mecha- and in relapsing to tobacco use. If cor- spective on what has been studied about nisms, including acetylcholine, dopa- rect, then this article is a watershed pa- nicotine and what is missing. Histori- mine, glutamate, GABA, endogenous per in the science of nicotine addiction cally, the study of tobacco and the study peptides, and serotonin. A re- and suggests new pharmaceutical direc- of nicotine were on separate tracks. To- markable amount of information is pub- tions to help tobacco users abstain. bacco has played, and continues to play, lished regularly about the neurobiology Arguably, nicotine is the most im- a monumental role in the U.S. economy, of nicotine, but the emphasis has been portant drug of addiction in history. and centuries of study focused on issues on mechanisms underlying positive rein- Alcohol, opiates, caffeine, cocaine, am- related to agriculture, manufacturing, forcement (15–17). All of this informa- phetamines, and other drugs certainly production, marketing, and so on. tion is relevant and important, but the are important, but nicotine has the dis- Tobacco science has a long and sophisti- key to addiction (vs. self-administration tinction of wreaking more havoc cated history within and outside the to- per se) is withdrawal and negative rein- through tobacco use and offering more bacco industry. Separately, nicotine— forcement; i.e., what motivates people hope as a medicine than all of the other isolated, identified, and synthesized in and animals to crave drugs and to re- drugs. Tobacco-related illnesses cause the 19th century—became a valuable lapse to drug use after they have ab- more deaths each year (440,000 per year tool in pharmacology and played a key stained? What makes it so difficult to in the United States and 5 million per role in the discovery of neurotransmis- maintain abstinence? These are the year worldwide) than do all other drugs sion and receptor biology (2). In the questions that George et al. (3) address. plus homicides, suicides, motor vehicle 20th century, investigators began to con- Tobacco withdrawal, of course, has been accidents, HIV/AIDS, and fires. Ciga- sider and study whether nicotine was and continues to be studied by many rette smoking causes approximately one the key ingredient responsible for many in every five deaths in the United of the effects of tobacco (5). In the States, and 1,200 Americans die each 1960s, a few investigators outside the Author contributions: N.E.G. wrote the paper. day from tobacco use. Put even more focused on nicotine’s The author declares no conflict of interest. starkly, tobacco use has a death toll role in tobacco use (6–9). By the late See companion article on page 17198 in issue 43 of volume equivalent to that of the 9/11 tragedy 20th century, dozens of laboratories 104. but occurring two to three times per were studying nicotine as it related to *E-mail: [email protected].

www.pnas.org͞cgi͞doi͞10.1073͞pnas.0708964104 PNAS ͉ November 13, 2007 ͉ vol. 104 ͉ no. 46 ͉ 17901–17902 Downloaded by guest on September 27, 2021 investigators, some emphasizing the psy- of nicotine) and that stress alters nico- self-administration). In other words, nico- chological aspects and some emphasiz- tine pharmacodynamics (i.e., nicotine tine withdrawal is indeed a stressor that ing the biological aspects of withdrawal. becomes more rewarding under stress) acts via the CRF–CRF1 system, which in George et al. cleverly considered the (2, 15). A few investigators (e.g., refs. 21 turn results in increased nicotine self- stress–smoking relationship as the con- and 22) have focused on nicotine with- administration to offset stress. This find- ceptual basis for their neurobiological drawal, and there has been speculation ing also suggests that pharmaceutical studies. about the biological commonalities of interventions should be developed to in- stress and drug abuse (2). However, tervene in the stress system, to attenuate Nicotine, Stress, and Negative withdrawal-induced smoking relapse. Sev- Reinforcement eral nicotine-replacement therapies (e.g., There is a strong correlation between Smokers may perceive gum, patch, lozenge, inhaler) and other stress and smoking, and it is pharmaceutical treatments (buproprion, clear that stress results in increased ciga- and report that smoking varenecline) to help people quit smoking rette smoking (2, 18). Although ciga- are now available, but none of these treat- rette smokers report that they smoke to reduces stress because ments focuses on the CRF system. help cope with stress, this perception What To Do Next does not necessarily mean that smoking abstinence from smoking actually reduces stress compared with The report by George et al. (3) is just nonsmokers not smoking. There is evi- causes stress. the beginning of what should be a vi- dence that smoking helps to modulate brant area of research. For example, it mood (perhaps through serotonergic would be valuable to expand this line of actions), relax skeletal muscles, and re- most of the neurobiology of nicotine work to include other anxiety-like be- haviors (e.g., elevated plus-maze center lieve pain, and that it has other effects emphasizes the actions of nicotine time) and behavioral controls (e.g., that may be stress-reducing (2, 10). rather than the actions of abstinence open-field locomotor activity) to more However, smokers may perceive and from nicotine. The brilliance of George fully understand the types of and extent report that smoking reduces stress be- et al. (3) was to pick up on the connec- to which anxiety-like behaviors are in- cause abstinence from smoking causes tion (as has been done with other drugs volved in, and altered by, nicotine ces- stress and because cigarette smoking of addiction) between stress and with- sation. It also would be valuable to relieves withdrawal effects in smokers drawal and to conduct careful and pro- measure brain levels of nicotine and the (i.e., negative reinforcement) (19). grammatic experiments. central binding of nicotine (including Therefore, smoking may be stress- George et al. (3) report that (i) precipi- receptor subtypes and loci) that are in- reducing compared with the stress of tated nicotine withdrawal in rats increases volved in the nicotine cessation–CRF withdrawal, but smoking might not re- CRF levels in the central nucleus of the effects. In addition, it is important to duce stress compared with controls (i.e., amygdala; (ii) precipitated withdrawal in- consider individual differences (includ- smokers not smoking). Benwell and creases anxiety-like behavior through acti- ing sex, age, and genotype) in the nico- Balfour (20) reported that nicotine vation of CRF1 receptors; (iii) cessation of tine cessation–CRF effects, to help withdrawal results in increased cortico- nicotine exposure in rats previously ex- tailor pharmaceutical treatments to indi- sterone, but the importance of that dis- posed to nicotine increases nicotine self- vidual needs and to optimally integrate covery to the understanding of nicotine administration; and (iv) antagonism of pharmacological and psychological abstinence (i.e., the connection between CRF1 receptors prevents ‘‘abstinence’’- tobacco-cessation treatments because it mechanisms of stress and mechanisms of induced increases in nicotine intake. This is clear that these variables are relevant nicotine withdrawal) was not fully ap- series of experiments provides strong sup- to the actions of nicotine and to the re- preciated at the time. Other investiga- port for the idea that CRF1 is involved in sponses of stress systems (23). With so tors suggested that stress alters nicotine the biology and behavior of nicotine with- many people in need of help to abstain pharmacokinetics (i.e., nicotine self- drawal, including negative reinforcement from smoking and to deal with stress, it administration increases under stress (i.e., offsetting the unpleasantness of is wonderful when basic science makes because stress decreases the availability cessation) and relapse (i.e., a return to a meaningful contribution.

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