Cellular mechanisms of nicotine addiction
Introduction
It is now clear that tobacco use is a major worldwide health problem (Leshner, 2000). The World Health Organization estimates that one-third of the global adult population smokes. Because tobacco usage is on the rise in less developed countries, it is one of the very few causes of mortality that is increasing (Peto et al., 1996). It is common to begin smoking as an adolescent, and about half of those who continue throughout life will die from smoking-related diseases (WHO, 1997). In developed countries, smoking causes 20% of all premature deaths, and is the cause of more than one-third of all deaths in men aged 35–69. Therefore, it is not surprising that in developed countries tobacco use is estimated to be the largest single cause of premature death (Peto et al., 1992).
Tobacco is addictive, and it is difficult to quit smoking. More than 80% of the attempts to quit smoking fail within a year, and those who succeed usually have tried to quit repeatedly Balfour and Fagerstrom, 1996, Schelling, 1992. In the United States, 70% of smokers say that they would like to quit, but only 3% are successful each year (Benowitz, 1999). The accumulated evidence from a wide range of studies indicates that nicotine is the major addictive component of tobacco that drives continued use despite the harmful consequences Balfour et al., 2000, Dani and Heinemann, 1996, Dani et al., 2001, Di Chiara, 2000, Schelling, 1992, Stolerman and Shoaib, 1991.
When studied under laboratory conditions in the absence of smoke or other extraneous factors, nicotine elicits behaviors associated with addictive drugs. Under restricted doses, nicotine functions as a reinforcer for both animals and humans. At higher doses, however, there are aversive effects caused by nicotine that complicate its reinforcing effectiveness when compared with other drugs, which serve as reinforcers over a wider range of doses and test situations. Despite these complications, nicotine elicits drug-seeking behavior in animal studies, where it supports self-administration and reinforces place preference Corrigall, 1999, Corrigall and Coen, 1989, Di Chiara, 2000, Stolerman and Shoaib, 1991. In drug discrimination tasks, there is some cross-generalization between nicotine and other addictive drugs, i.e., nicotine is mistakenly discriminated in place of a different addictive drug Di Chiara, 2000, Stolerman and Jarvis, 1995. Nicotine cessation also produces a withdrawal syndrome, and those symptoms can be relieved by nicotine replacement (Stolerman and Jarvis, 1995). In summary, nicotine produces effects that are commonly seen with other addictive drugs such as amphetamines and cocaine: nicotine reinforces self-administration, increases locomotor activity, enhances reward from brain stimulation and reinforces place preference Clarke, 1990, Clarke, 1991, Corrigall, 1999, Dani and Heinemann, 1996, Di Chiara, 2000, Goldberg and Henningfield, 1988, Stolerman and Jarvis, 1995, Stolerman and Shoaib, 1991.
Section snippets
Neuronal nicotinic acetylcholine receptors (nAChRs)
Nicotine initiates its action by binding to nAChRs. Nicotinic receptors belong to a superfamily of ligand-gated ion channels that include glycine, GABAA and 5-HT3 serotonin receptors Albuquerque et al., 1997, Broide and Leslie, 1999, Buisson and Bertrand, 1998, Dani, 2001, Dani et al., 2001, Jones et al., 1999, Lena and Changeux, 1998, Lindstrom, 1997, Lindstrom et al., 1996, Luetje et al., 1990, McGehee and Role, 1995, Paterson and Nordberg, 2000, Role and Berg, 1996, Sargent, 1993, Wonnacott,
Nicotinic cholinergic mechanisms in the brain
Cholinergic neurons project throughout the CNS, providing diffuse, sparse innervation to practically all of the brain, but a relatively small number of cholinergic neurons innervate each neural area Kasa, 1986, Oh et al., 1992, Woolf, 1991. Thus, the activity of a rather small number of cholinergic neurons can influence diverse and relatively large neuronal structures. Although cholinergic cell bodies are distributed in a loosely contiguous axis running from the spinal cord and brain stem to
Nicotinic influences on dopaminergic neurons
Many recent addiction studies have focused on reward circuitry and modifications of those pathways during drug use Berke and Hyman, 2000, Dani et al., 2001, Di Chiara, 1999, Wise, 2000. Although many psychopharmacological factors contribute to addiction, dopaminergic systems have received much attention because of their roles in reward. Reward, motivation and the roles of the dopaminergic systems are far from completely understood, and are active areas of experimental and theoretical research
Nicotine activates and desensitizes nAChRs on mesolimbic neurons
Smoking a cigarette delivers about 50–300 nM nicotine to the brain Gourlay and Benowitz, 1997, Henningfield et al., 1993, Rose et al., 1999. Fig. 1A shows that nicotine, in exactly the range experienced by smokers, both activates and desensitizes nAChRs on dopaminergic neurons from the VTA (see Pidoplichko et al., 1997). A dopamine neuron from a rat brain slice was whole-cell voltage clamped near its resting potential at −60 mV. A pipette filled with 1 mM ACh was positioned next to the neuron,
Hypotheses to extrapolate the cellular results to smokers
Based on these results (Pidoplichko et al., 1997), we can infer some of the effects of smoking a cigarette, which will deliver about 0.1 μM nicotine to the brain Gourlay and Benowitz, 1997, Rose et al., 1999. Initially, the brain is free of nicotine, and the nAChRs should be responding normally to cholinergic synaptic activity. When the nicotine first arrives, nAChRs are activated, causing the neurons to depolarize and fire action potentials. This process occurs throughout the brain, with
Acknowledgements
Work from our laboratories is supported by US NIH grants from the National Institute of Neurological Disorders and Stroke (NS21229) and the National Institute on Drug Abuse (DA09411 and DA12661).
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