Review
Tobacco addiction and the dysregulation of brain stress systems

https://doi.org/10.1016/j.neubiorev.2012.02.015Get rights and content

Abstract

Tobacco is a highly addictive drug and is one of the most widely abused drugs in the world. The first part of this review explores the role of stressors and stress-associated psychiatric disorders in the initiation of smoking, the maintenance of smoking, and relapse after a period of abstinence. The reviewed studies indicate that stressors facilitate the initiation of smoking, decrease the motivation to quit, and increase the risk for relapse. Furthermore, people with depression or an anxiety disorder are more likely to smoke than people without these disorders. The second part of this review describes animal studies that investigated the role of brain stress systems in nicotine addiction. These studies indicate that corticotropin-releasing factor, Neuropeptide Y, the hypocretins, and norepinephrine play a pivotal role in nicotine addiction. In conclusion, the reviewed studies indicate that smoking briefly decreases subjective stress levels but also leads to a further dysregulation of brain stress systems. Drugs that decrease the activity of brain stress systems may diminish nicotine withdrawal and improve smoking cessation rates.

Highlights

► Stressors increase the number of cigarettes smoked and increase the risk for relapse. ► Depression increases the risk for smoking and vice versa. ► Smoking increases the risk for developing an anxiety disorder. ► A hyperactivity of brain stress systems plays a role in nicotine withdrawal in rats. ► Drugs that decrease the activity of brain stress systems may help people quit smoking.

Introduction

Tobacco is one of the most widely abused drugs in the world. It has been estimated that worldwide there are about 1 billion males who smoke and 250 million females (World Health Organization, 2011). Half of the smokers die as a direct consequence of their tobacco addiction. Worldwide about 5.4 million people die each year from smoking including 400,000 people in the United States and 640,000 in Europe (ASPECT Consortium, 2005, Mokdad et al., 2004, World Health Organization, 2011). It has been estimated that about 600,000 people die each year from exposure to second hand tobacco smoke (World Health Organization, 2009). The World Health Organization has indicated that the tobacco pandemic is moving from Western countries to developing nations and has estimated that about 80% of the people who die from smoking now live in low and middle income countries (World Health Organization, 2011). Considering the large number of smokers and the highly addictive properties of tobacco, a better understanding of the environmental, genetic, and neurobiological factors that contribute to the development and maintenance of a tobacco addiction is warranted.

Several lines of evidence suggest that the positive reinforcing effects of cigarettes play a pivotal role in the initiation of smoking (Finkenauer et al., 2009, Wise, 1996). The positive reinforcing effects of smoking include mild euphoria, relaxation, and improved attention and working memory (Ague, 1973, Benowitz, 1988, Wesnes and Warburton, 1983). Discontinuation of smoking leads to negative affective symptoms such as depressed mood, increased anxiety, and impaired memory and attention (Hughes et al., 1991, Hughes and Hatsukami, 1986). The negative affective symptoms associated with smoking cessation may increase the risk for relapse to smoking (Bruijnzeel and Gold, 2005, Koob, 2008). Preclinical studies suggest that nicotine is the main component of tobacco that leads to smoking and prevents people from quitting smoking (Bardo et al., 1999, Crooks and Dwoskin, 1997, Stolerman and Jarvis, 1995). There is, however, evidence that other components in tobacco smoke may also have positive reinforcing effects and/or potentiate the effects of nicotine (Fowler et al., 2003, Talhout et al., 2007). Acetaldehyde is one of the compounds in smoke that may contribute to the development of a tobacco addiction. The pyrolysis of carbohydrates in cigarettes leads to the formation of acetaldehyde and this compound is self-administered by rodents and induces conditioned place preference (Brown et al., 1979, Myers et al., 1982, Smith et al., 1984). Self-administration studies show that acetaldehyde also potentiates the positive reinforcing effects of nicotine in rats (Belluzzi et al., 2005). Furthermore, tobacco smoke contains high concentrations of the β-carbolines norharman and harman which inhibit monoamine oxidase (MAO)-A and MAO-B (Hauptmann and Shih, 2001, Herraiz and Chaparro, 2005, Totsuka et al., 1999). Positron emission tomography imaging studies show that smoking inhibits MAO-A and MAO-B in the human brain (Fowler et al., 1996, Fowler et al., 1998). In humans, MAO-A metabolizes norepinephrine, serotonin and dopamine and MAO-B metabolizes phenylethylamine and dopamine (Shih et al., 1999). Norharman and harman have antidepressant-like effects in rodents (Aricioglu and Altunbas, 2003, Farzin and Mansouri, 2006) and clinical studies indicate that drugs that inhibit MAO-A, but not MAO-B, have antidepressant effects in humans (Blier and de Montigny, 1994). Tobacco smoke-induced MAO-B inhibition may also explain the fact that smoking decreases the risk for Parkinson's disease in humans (Chen et al., 2010, Morens et al., 1995). Therefore, in addition to nicotine, many other compounds in tobacco smoke affect brain function.

During the last decades, several treatments have been developed to help people quit smoking. The U.S. Food and Drug Administration approved nicotine replacement therapy, varenicline (brand name Chantix) and bupropion (brand name Zyban) for smoking cessation. Varenicline is a partial agonist of α4β2 nicotinic acetylcholine receptors (nAChRs). This drug may improve smoking cessation rates by inhibiting the positive reinforcing effects of nicotine, attenuating nicotine withdrawal, and decreasing craving for cigarettes (Rollema et al., 2007). The precise pharmacological mechanisms by which bupropion improves smoking cessation rates are not known. However, it may improve smoking cessation rates by blocking nAChRs, inhibiting the reuptake of dopamine, norepinephrine, and serotonin, or inhibiting the firing of noradrenergic neurons (Cryan et al., 2003a). A recent literature review suggests that varenicline may be slightly more effective in preventing relapse to smoking than bupropion or nicotine replacement therapy (Cahill et al., 2010). Although the aforementioned drugs help people quit smoking, relapse rates are still very high (80–85% over 1-year period) among people receiving treatment for smoking cessation (Gonzales et al., 2006). Moreover, bupropion increases the risk for seizures and treatment with varenicline may lead to depressed mood, suicidal thoughts, drowsiness, and aggressive behavior in a subgroup of smokers (Davidson, 1989, Johnston et al., 1991, Moore and Furberg, 2009). Varenicline use in humans also leads to an increased risk for cardiovascular events such as stroke and congestive heart failure (Singh et al., 2011). Therefore, despite the fact that significant progress has been made in the development of treatments for tobacco addiction, there remains an urgent need for safer and more effective treatment options.

This review explores the role of brain stress systems in tobacco addiction. The first part of this review examines the role of stressors in the onset of smoking, maintenance of smoking, and relapse to smoking after a period of abstinence. The comorbidity between smoking and stress-associated psychiatric disorders is also discussed. Specifically, it will be investigated if depression, post-traumatic stress disorder (PTSD), and other anxiety disorders increase the risk for smoking and/or if people with these disorders are more likely to experiment with cigarettes and develop a tobacco addiction. The second part of this review provides an overview of studies that investigated the role of brain stress systems in animal models for tobacco addiction. This review focuses mainly on the role of neuropeptides in nicotine addiction. During the last decades, extensive progress has been made in the understanding of the role of neuropeptides in modulating behavioral, endocrine, and autonomic responses. One of the first milestones in this field was the observation by David de Wied that endocrine hormones produced in the pituitary also serve as precursors for peptides that have effects in the central nervous system (i.e., neuropeptide concept) (De Wied, 1969, De Wied, 1977). Another major milestone was the isolation of corticotropin-releasing factor (CRF) from the ovine hypothalamus (Vale et al., 1981). CRF plays an important role in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis and also affects behavioral responses independent of its affect on the HPA axis (Eaves et al., 1985). Pioneering studies by Nemeroff, Koob and others showed that CRF plays a critical role in depression and drug addiction (Baldwin et al., 1991, Koob, 1996, Nemeroff et al., 1984). More recent studies have provided evidence for a role of neuropeptide Y and the hypocretins in the regulation of mood states and drug addiction (Boutrel et al., 2005, Gilpin et al., 2003). In the second half of this review, the role of CRF, hypocretins, neuropeptide Y (NPY), norepinephrine, and the HPA axis in nicotine addiction will be discussed.

It should be noted that in addition to the aforementioned neuropeptides and neurotransmitters, other cholinergic and non-cholinergic brain systems have also been implicated in the rewarding effects of nicotine, nicotine withdrawal, and the reinstatement of extinguished nicotine-seeking behavior. It is, however, beyond the scope of this review to discuss all the brain systems that may play a role in nicotine addiction. For an overview of the role of acetylcholine, dynorphin, and other neurotransmitters in nicotine addiction, the readers are referred to previous reviews (Balfour, 2009, Bruijnzeel, 2009, Castane et al., 2005, Dani and Balfour, 2011, Maldonado and Berrendero, 2010, Markou, 2007).

Section snippets

Stressors and smoking

Extensive evidence indicates that brain stress systems play a critical role in the initiation of smoking, the maintenance of smoking, and relapse to smoking after a period of abstinence. Smokers indicate in surveys that stress relief and relaxation are their main reasons for smoking (Ikard et al., 1969). In one study with 16-year-old female smokers, about 50% of the girls indicated that they started smoking because they experienced a lot of stress in their lives and they believed that smoking

Brain corticotropin-releasing factor systems

CRF is a 41-amino acid neuropeptide that was first isolated from the ovine hypothalamus (Fig. 2) (Vale et al., 1981). CRF-immunoreactive cells have been detected in the paraventricular nucleus of the hypothalamus (PVN) and in other brain areas such as the central nucleus of the amygdala (CeA), bed nucleus of the stria terminalis (BNST), and locus coeruleus (LC) (Swanson et al., 1983). Scattered CRF-immunoreactive cells have also been found throughout the neocortex (Swanson et al., 1983). PVN

Concluding remarks

The first part of this review investigated the role of stressors and stress-associated psychiatric disorders in tobacco addiction. The epidemiological and clinical studies that were discussed indicate that brain stress systems play a critical role in tobacco addiction. Smokers indicate that they smoke for stress relief and to relax. Exposure to stressors in the real world or in the laboratory increases the number of cigarettes smoked. There is also a high comorbidity between smoking and

Acknowledgements

This research was supported by the National Institute on Drug Abuse (DA023575) and the Flight Attendant Medical Research Institute (Grant 52312).

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