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ScienceWeek
PUBLIC HEALTH: GENES AND NICOTINE ADDICTION
The following points are made by R.C. Hogg and D. Brtrand (Science 2004 306:983):
1) Much has been written about the sociopsychological factors involved in cigarette smoking. However, the rewarding effects of tobacco consumption, and the craving associated with withdrawal, reflect a chemical dependence. The alkaloid nicotine found in tobacco leaves is the addictive compound that drives smoking behavior, and its effects suggest a direct action on the central nervous system. In addition to its many other physiological effects, nicotine also increases mental alertness and improves memory. But how do nanomolar concentrations of nicotine exert such effects on the brain? Recent research (1) has demonstrated that a mutation in the alpha-4 subunit of nicotinic acetylcholine receptors (nAChRs) expressed by neurons lowers the threshold for the induction of nicotine dependence. These results not only identify one of the nAChR subunits involved in nicotine dependence, but also reveal the mechanism by which nicotine produces its addictive effects.
2) The neuronal nAChRs are a family of ligand-gated ion channels widely expressed in the central and peripheral nervous systems. They are activated by the endogenous neurotransmitter acetylcholine. The nAChRs are closely related to the receptors at the neuromuscular junction, which mediate the transmission of nerve impulses to the muscles. The nAChRs are cation-permeable channels formed from the coassembly of five subunits, and their activation causes excitation of the neuron. Eleven neuronal nAChR subunits have been identified in humans, and these combine to give different receptor subtypes with distinct functional properties and pharmacological characteristics (2). At the molecular level, the nAChR is possibly the best characterized of all the ligand-gated receptors. Nevertheless, given the existence of numerous receptor subtypes and the lack of accurate information about which subunits make up functional receptors in vivo, the mechanism whereby binding of nicotine to this receptor leads to dependence is still poorly understood.
3) The distribution of nAChRs in the nervous system has been revealed by radiolabeled nicotine or related ligands. These analyses show that brains from smokers exhibit an increased number (that is, "up-regulation" of high-affinity nicotine-binding sites, supposedly containing the alpha-4 and beta-2 nAChR subunits. Paradoxically, in vitro experiments demonstrate that chronic exposure to nicotine can "desensitize" these receptors, making them less sensitive to the natural neurotransmitter acetylcholine. It is thought that the up-regulation of binding sites might reflect an increased number of receptors that may compensate for nicotine-induced desensitization.
4) Previous attempts to assess the contribution of nAChRs to the physiology and behavior of nicotine addiction used knockout mice lacking specific nAChR subunits. These studies demonstrated that mice lacking the beta-2 subunit exhibit reduced sensitivity to the addictive effects of nicotine (3). Blockade of the high-affinity alpha-4- and beta-2-containing receptors by a competitive antagonist also attenuates the rewarding effect of nicotine (4). The experiments of Tapper et al (1) further support the crucial role of the alpha-4-beta-2 nAChRs in nicotine addiction (1). These authors postulated that if the gene encoding the alpha-4 subunit of the nAChR is engineered to confer a higher affinity to nicotine, animals expressing such a mutation should be more prone to its addictive effects. Accordingly, the authors found that mice genetically modified to express this mutant alpha-4 subunit display a higher sensitivity to the multiple effects of nicotine, with lower doses required to increase locomotor activity, sensitization, and reward.(5)
References (abridged):
1. A. R. Tapper et al., Science 306, 1029 (2004)
2. N. Le Novere, P. J. Corringer, J. P. Changeux, J. Neurobiol. 53, 447 (2002)
3. C. Lena, J. P. Changeux, Ann. N. Y. Acad. Sci. 868, 611 (1999)
4. S. R. Laviolette, D. van der Kooy, Nat. Rev. Neurosci. 5, 55 (2004)
5. O. K. Steinlein, Prog. Brain Res. 145, 275 (2004)
Science http://www.sciencemag.org
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SCIENCE POLICY: TOBACCO CONTROL UPDATE
The following points are made by Steven A. Schroeder (New Engl. J. Med. 2004 350:293):
1) Tobacco takes an enormous toll on the health of the public as the cause of 440,000 deaths annually in the US and 4.8 million deaths worldwide.(1,2) An estimated 8.6 million persons in the US have serious smoking-related illness.(3) The World Health Organization projects that by the year 2030 the use of tobacco will kill 10 million persons annually -- including 7 million in developing countries -- which will make tobacco use the world's leading cause of preventable death.(4)
2) In 2001, the prevalence of smoking in the US stood at 25.5 percent among men and 21.5 percent among women, down from the peaks of 57 percent among men in 1955 and 34 percent among women in 1965.(5) Rates of smoking have plateaued, however, since 1990.(5) The prevalence varies by state, ranging from 31 percent in Kentucky to 13 percent in Utah, and it is increasingly concentrated in populations that have relatively little education and low incomes. Smoking rates are declining in all age groups, except among persons 18 to 24 years of age, among whom the prevalence rose from 23 percent in 1991 to 27 percent in 2000.
3) Mental illness and smoking have been closely linked. For example, smoking rates have been reported to be over 80 percent among persons who have schizophrenia, 50 to 60 percent among persons with depression, 55 to 80 percent among those who have alcoholism, and 50 to 66 percent among those who have substance-abuse problems. One study estimated that smokers with coexisting psychiatric or substance-abuse disorders account for 44 percent of all cigarettes smoked in the US, a percentage that reflects both the high prevalence of smoking in connection with these conditions and the fact that patients with these disorders are very heavy smokers.
4) Worldwide, it is estimated that 47 percent of men but only 12 percent of women smoke. As compared with smoking rates among men in other countries, in the US the rate ranks in the lowest fifth, but it is higher than in Australia, Sweden, and many of the developing countries. By contrast, smoking rates among women in the US are in the highest third for women worldwide. Globally, smoking rates among men are highest in Asia (e.g., 67 percent in China, 65 percent in Korea, and 53 percent in Japan), but the rates are also high in Russia (63 percent), Yugoslavia (52 percent), and Mexico (51 percent). In almost all nations, women are much less likely to smoke than men; among women, the smoking rate is a mere 4 percent in China and in Korea (and the rate is even lower in most Arab countries) but is about 33 percent in Argentina and Norway.(4)
5) In the relatively few countries that have antitobacco policies, government has provided the essential leadership; the exception is the United States, where grassroots action and litigation by citizens have generated most of the changes, including changes that were mediated by laws and regulations. In the face of an aggressive tobacco industry that in 2001 spent $11.2 billion on advertising and promotion in the United States alone, effective control of the use of tobacco requires multiple policy strategies. Most of the promising approaches have not been fully implemented.
References (abridged):
1. Annual smoking-attributable mortality, years of potential life lost, and economic costs -- United States, 1995-1999. MMWR Morb Mortal Wkly Rep 2002;51:300-303
2. Ezzati M, Lopez AD. Estimates of global mortality attributable to smoking in 2000. Lancet 2003;362:847-852
3. Cigarette smoking-attributable morbidity -- United States, 2000. MMWR Morb Mortal Wkly Rep 2003;52:842-844
4. Quantifying selected major risks to health. World health report 2002. Geneva: World Health Organization, 2002
5. Prevalence of current cigarette smoking among adults and changes in prevalence of current and some day smoking -- United States, 1996-2001. MMWR Morb Mortal Wkly Rep 2003;52:303-4, 306
New Engl. J. Med. http://www.nejm.org
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ON THE TOBACCO INDUSTRY AND NICOTINE AS AN ADDICTIVE DRUG
Notes by ScienceWeek:
In 1994 the state of Minnesota filed suit against the tobacco industry, and although this trial is now history, there are many people who feel the legacy of the trial will carry on into the 21st century because of the revelations contained in the millions of pages of previously secret internal tobacco industry documents made public in the trial.
The following points are made by R.D. Hurt and C.R. Robertson (J. Am. Med. Assoc. 1998 280:1173):
1) The litigation tobacco industry documents reveal that for decades the tobacco industry knew and internally acknowledged that *nicotine is an addictive drug and that cigarettes are the ultimate nicotine delivery device. The following statements by executives, for example, are found in tobacco industry documents: "Very few consumers are aware of the effects of nicotine, i.e., its addictive nature and that nicotine is a poison." (H.D. Steele, Brown and Williamson Tobacco Company, 1978). And in another Brown and Williamson memo: "Nicotine is the addicting agent in cigarettes." (A.J. Mellman, Brown and Williamson Tobacco Company, 1983). Concerning cigarettes as a drug delivery device, the litigation documents reveal that C.E. Teague Jr., assistant director of research at R.J. Reynolds Tobacco Company, wrote in 1972 in an internal memorandum: "In a sense, the tobacco industry may be thought of as being a specialized, highly ritualized and stylized segment of the pharmaceutical industry. Tobacco products, uniquely, contain and deliver nicotine, a potent drug with a variety of physiological effects... Thus a tobacco product is, in essence, a vehicle for delivery of nicotine."
2) The authors report that perhaps their most surprising finding in the document review was the evidence of tobacco industry efforts spanning 3 decades to alter the chemical form of nicotine to increase the percentage of freebase nicotine delivered to smokers. Depending on pH, nicotine exists as a diprotonated salt, a monoprotonated salt, or an uncharged neutral species. The salt forms are called the "bound" forms, and the neutral species is called the "freebase" form. Nicotine favors the salt form at low values of pH (e.g., pH = 3) and the freebase form at high values of pH (e.g., pH = 8). Freebase nicotine apparently crosses biological membranes more easily than the charged counterparts, and this affects the physiological response to the drug.
3) The tobacco industry was apparently well aware of these properties of nicotine as far back as 1966, and for 3 decades the tobacco industry had a focus on developing high pH delivery of nicotine to increase its physiological effects. The authors conclude: "When the breadth and depth of tobacco industry actions are understood, it becomes evident that allowing a tobacco settlement that honors the industry demands for legal and financial immunity would be a public health disaster of epic proportions and would allow the industry to continue to promote its deadly product throughout the 21st century. Congress must use its power to stop the carnage of more than 400,000 Americans dying each year of cigarette-related diseases."
J. Am. Med. Assoc. http://www.jama.com
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Notes by ScienceWeek:
nicotine: The alkaloid nicotine [3-(1-methyl-pyrrolidyl)pyridine] is a tertiary amine composed of pyridine and pyrrolidine rings. The current consensus among neuropharmacologists is that nicotine is the psychoactive drug primarily responsible for the addictive nature of tobacco use. Nicotine is highly selective for so-called "nicotinic receptors" for *acetylcholine in the peripheral and central nervous systems, and activation of these receptors is the likely source of the psychoactive effects of the drug. The nicotinic-acetylcholine receptor is a molecularly well-characterized receptor, and its activation evidently leads to conformation changes in its 5 subunits that result in a transient increase of permeability of the neuron membrane to the sodium ion. The nicotinic-acetylcholine receptor is therefore characterized as a neurotransmitter-gated ion channel. Concentrations of nicotine in blood rise quickly during cigarette smoking and peak at its completion.
Nicotine is also deposited in the lungs, spleen, liver, and brain, where concentrations are typically twice those of measurable blood concentrations. Nicotine readily crosses the *blood-brain barrier, leading to the release of acetylcholine, *norepinephrine, *dopamine, *serotonin, *vasopressin, *growth hormone, *cortisol, *prolactin, *neurophysin 1, and *adrenocorticotropic hormone, and release of these substances causes various neuropharmacological effects. Apart from the neuropharmacological effects of nicotine, nicotine and other constituents in cigarette smoke elevate blood pressure, cause *tachycardia, *arrhythmia, and *vasoconstriction in *cutaneous tissue and skin; lower body temperature; inhibit *diuresis; increase *gastrointestinal tonus; antagonize ulcer healing; and decrease pain threshold.
acetylcholine: A prevalent *neurotransmitter substance, both in the brain and in the peripheral nervous system, where it controls the actions of skeletal and smooth muscle.
neurotransmitter substance: Neurotransmitters are chemical substances released at the terminals of nerve axons in response to the propagation of an impulse to the end of that axon. The neurotransmitter substance diffuses into the synapse, the junction between the presynaptic nerve ending and the postsynaptic neuron, and at the membrane of the postsynaptic neuron the transmitter substance interacts with a receptor. Depending on the type of receptor, the result may be an excitatory or an inhibitory effect on the postsynaptic nerve cell.
blood-brain barrier: A selective mechanism opposing the passage of most ions and large molecular-weight compounds from the blood to brain tissue, the mechanism operating in a continuous layer of endothelial cells connected by tight junctions between cells. (Endothelial cells are flat cells forming a layer lining blood vessels, lymphatic vessels, the heart, etc.)
norepinephrine: The principal neurotransmitter substance released from nerve endings of the sympathetic nervous system. (The sympathetic nervous system is a part of the autonomic nervous system involved in the mobilization of energy resources during stress and arousal.
dopamine: A neurotransmitter substance.
serotonin: A neurotransmitter substance involved in nearly everything occurring in the brain, including psychological states such as anxiety and depression, and dysfunctions producing migraine and epilepsy.
vasopressin: A peptide hormone important in the regulation of *diuresis.
growth hormone: A vertebrate polypeptide hormone that regulates growth. In general, hormones are signaling molecules secreted into the blood stream by endocrine cells and acting on target cells that possess receptors for the hormone.
cortisol: A corticosteroid hormone secreted by the adrenal gland.
prolactin: A polypeptide hormone synthesized and released by the pituitary gland.
neurophysin 1: Neurophysins are a family of proteins synthesized in the hypothalamus, and function as carriers in the transport and storage of a number of hypothalamic-pituitary hormones.
adrenocorticotropic hormone: (ACTH) A pituitary hormone.
tachycardia: Rapid beating of the heart, conventionally applied to rates over 100 per minute.
arrhythmia: Irregularity of the heartbeat.
vasoconstriction: Narrowing of the blood vessels.
cutaneous tissue: In general, tissue associated with skin.
diuresis: Excretion of large volumes of urine.
gastrointestinal tonus: In general, contraction of gastrointestinal muscle.
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