Neurophysiology of Nicotine Addiction

Department of Neuroscience, Center on Addiction, Learning, Memory, Baylor College of Medicine, Houston, Texas 77030-3498, USA

*Corresponding Author:

Dr. Dr. John A. Dani
Department of Neuroscience
Center on Addiction, Learning, Memory
Baylor College of Medicine
Houston, Texas 77030-3498, USA
Tel: (713)-798-3710
Fax: (713)-798-3946
E-mail: jdani@bcm.edu

Received January 19, 2011; Accepted April 14, 2011; Published April 20, 2011

Citation: Dani JA, Jenson D, Broussard JI, Biasi MD (2011) Neurophysiology of Nicotine Addiction. J Addict Res Ther S1:001. doi:10.4172/2155-6105.S1-001

Copyright: © 2011 Dani JA, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

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Abstract

Tobacco use is a major health problem, and nicotine is the main addictive component. Nicotine binds to nicotinic acetylcholine receptors (nAChR) to produce its initial effects. The nAChRs subtypes are composed of five subunits that can form in numerous combinations with varied functional and pharmacological characteristics. Diverse psychopharmacological effects contribute to the overall process of nicotine addiction, but two general neural systems are emerging as critical for the initiation and maintenance of tobacco use. Mesocorticolimbic circuitry that includes the dopaminergic pathway originating in the ventral tegmental area and projecting to the nucleus accumbens is recognized as vital for reinforcing behaviors during the initiation of nicotine addiction. In this neural system β2, a4, and a6 are the most important nAChR subunits underlying the rewarding aspects of nicotine and nicotine self-administration. On the other hand, the epithalamic habenular complex and the interpeduncular nucleus, which are connected via the fasciculus retroflexus, are critical contributors regulating nicotine dosing and withdrawal symptoms. In this case, the a5 and β4 nAChR subunits have critical roles in combination with other subunits. In both of these neural systems, particular nAChR subtypes have roles that contribute to the overall nicotine addiction process

Introduction

It is estimated that 1/3 of the world’s adult population smokes tobacco [1-3]. In developed countries, tobacco use is estimated to be the largest single cause of premature death, and about 1/2 of those who smoke from adolescence throughout life will die from smokingrelated diseases [4]. In less developed countries, tobacco use is on the rise; thus, it is one of the few causes of mortality that is increasing worldwide [2]. Tobacco is projected to be responsible for 10% of all deaths globally by 2015 [2,3].

When studied under laboratory conditions in the absence of other factors, nicotine elicits classically defined addictive behaviors. In animal studies at a narrowly defined dose, nicotine reinforces selfadministration, elicits drug-seeking behavior, induces conditioned place preference, increases locomotor activity, and enhances reward from intracranial stimulation [5-9]. In drug discrimination tasks there is some cross-generalization between nicotine and other addictive drugs. That is, nicotine is in some cases mistakenly chosen in place of a different addictive drug [7,10]. Similar to other addictive drugs, nicotine cessation after chronic use also produces a withdrawal syndrome, and those symptoms can be relieved by nicotine replacement [9,10]. Although other substances and factors are important during the tobacco addiction process, nicotine is the major addictive component [11]. This issue was directly examined recently, supporting the conclusion that nicotine is the main substance reinforcing the use of tobacco [12].

Nicotine from smoke to the brain

Nicotine is an alkaloid and a tertiary amine that consists of a pyridine and a pyrrolidine ring. The unprotonated (uncharged) form of nicotine is absorbed from cigarette smoke through the mucous membranes, and the protonated form deposited in the lungs during smoking is buffered to the physiological pH and then absorbed [13- 15]. The uncharged form of nicotine passes through lipid barriers, such as cellular membranes and enters the intracellular space, where the charged form may be held longer. Nicotine begins to reach the brain quickly, in tens of seconds after inhalation, but the concentration continues to increase gradually. PET imaging indicates that the distribution of nicotine onto nAChRs is slower than the rise in the blood stream [16]. Thus, nicotine blood concentrations undergo peaks and troughs following each cigarette, but those variations are significantly smoothed out within the brain.

Because multiple nicotine doses are obtained by repeated smoking throughout the day and the half-life of nicotine is two hours or more in humans, the background level of nicotine rises during the day for a regular smoker, which leads to considerable accumulation of nicotine in the brain and body tissues [17]. In the early afternoon, the plasma nicotine level usually nears a plateau typically ranging between 10 and 50 ng/mL [15]. Smoking a single cigarette increases the blood nicotine concentration from roughly 5 to 30 ng/mL, depending on how the cigarette is smoked [18]. The widespread use of cigarettes likely arises because it is an easily controlled dosing device that smokers use to achieve their desired, and narrowly defined, nicotine dose. Although smoking habits vary, it is not uncommon for smokers to manipulate their nicotine intake to maintain a consistent level from day to day [19].

Nicotine interaction with nicotinic acetylcholine receptors

Neuronal nicotinic acetylcholine receptors (nAChRs) provide the main binding sites and primary site of action of nicotine [9,20], but other sites of action influencing intracellular events are likely [21]. Neuronal nAChRs are assembled from α and β subunits that are arranged around a central water-filled pore [20,22,23]. The α2–α6 and the β2–β4 subunits form nAChRs in combinations. The α7–α9 subunits are capable of forming homomeric nAChRs, but of these only the α7 subunit is widely distributed in the mammalian brain. The α4β2-containing (α4β2*) nAChRs often in combination with α5 or a6 provide the higher affinity binding sites for nicotine [24,25].

Nicotinic AChRs have complex kinetic behavior that is dependent on their subunit composition. The activation, closure, and desensitization of nAChR subtypes are influenced by the exact amino acid sequence of the subunits, and the dose and kinetics of agonist application or arrival. Both the endogenous acetylcholine arriving from neuronal sources and the exogenous nicotine arising from tobacco use have to be considered. The kinetic response of nAChRs depends on the agonist dose-response profile. As nicotine arrives in the brain, occupancy of nAChRs increases over a period of many minutes, and the high affinity nAChRs are significantly occupied out to the time scale of hours. Desensitization of nAChRs becomes a more important issue as low levels of nicotine linger in the brain for many minutes or hours.

Desensitization is mainly an agonist-dependent conformational transition of the receptor to an inactive state that cannot be activated by agonist [20,26-28]. At a cholinergic synapse, vesicular neurotransmitter release usually produces a high ACh concentration in the synaptic cleft that lasts for only a few milliseconds before diffusion and acetylcholinesterase removes the neurotransmitter. Under these conditions, desensitization is not strong. However, the slowly rising and falling, low concentrations of nicotine obtained from tobacco will cause some desensitization over time. Because of desensitization, acute tolerance occurs to multiple cigarettes in an episode of smoking. Because the background level of nicotine rises throughout the day, the effects of individual cigarettes tend to lessen as the day (and smoking) progresses. Overnight abstinence from tobacco/nicotine allows considerable, but not necessarily complete, recovery from desensitization [15,17].

Reinforcement of rewarding behaviors by nicotine

Mesocorticolimbic circuitry that is normally critical for reinforcing successful behaviors also participates in the addiction process [9,29-31]. The dopaminergic centers of the midbrain and their targets have received much attention because of their roles in arousal, motivation, cognition, motor function, and processes associated with reinforcing behaviors that lead to reward. One of the important dopaminergic pathways originates in the ventral tegmental area (VTA) of the midbrain and projects to forebrain structures, including the prefrontal cortex, and areas such as the olfactory tubercle, the amygdala, the septal region, and the striatum, which includes a particularly important target, the nucleus accumbens.

The accumulation of evidence implicates these mesocorticolimbic circuits in addiction [7,9,32-34]. Many addictive drugs, including nicotine, elevate dopamine (DA) in the nucleus accumbens, and that elevation correlates with the reinforcement of drug use, particularly during the acquisition phase [7,9,35-38]. Blocking dopamine release in the nucleus accumbens with antagonists or lesions reduces nicotine self-administration in rats, which is interpreted to mean that inhibited dopamine release attenuates the rewarding effects of nicotine [8,36]. Nicotine administration activates dopamine neuron firing as has been shown using rodent brain slices [39] and using in vivo recordings from freely-moving rodents [40,41]. Thus, the concentration of nicotine obtained from tobacco can activate nAChRs on midbrain dopamine neurons and influence associated excitatory and inhibitor circuitry and, thereby, increase dopamine neuron firing.

The midbrain DA area receives afferent cholinergic innervation from the nearby pedunculopontine tegmentum (PPT) and the laterodorsal tegmentum (LDT), which are a loose collection of cholinergic neurons interspersed with GABAergic and glutamatergic neurons [42]. The midbrain DA area expresses diverse nAChR subtypes [25,39,43], and particularly nAChRs containing the b2 subunit, usually in combination with α4 and/or α6 subunits, mediate nicotine-induced dopamine signals [44-48]. Activation of nAChRs directly depolarizes DA neurons [39] and, consequently, increases their firing [40]. In addition, nicotine influences excitatory and inhibitory circuitry and local synaptic plasticity, which have longer lasting influences over midbrain activity [40,46,49-51]. In this manner, nicotine supercedes the actions of normal environmental events that act upon the midbrain circuitry. The drug acts directly upon this circuitry, as if a reward-related sensory input has been received.

DA neurons fire in different modes [52-54], commonly firing at low tonic frequencies interspersed with higher frequency phasic bursts that can be induced by unpredicted reward or unanticipated cues that have been conditioned to a known reward [55,56]. Disrupting phasic bursts diminishes the ability to learn cues about reward and impairs the processing of reward [56]. Nicotine administration increases the firing of DA neurons and increases the number and length of phasic bursts [40,46,57], which particularly boosts DA concentrations in the nucleus accumbens [40]. This action by nicotine requires β2- containing nAChRs. In mice lacking the β2 nAChR subunit (β2 -/-), nicotine does not produce burst firing from DA neurons [46] and does not support self-administration [44]. In β2 null mice, when β2 is reexpressed in the ventral tegmental area, nicotine self-administration is reinstated [48,58]. In addition, nicotine self-administration also is influenced by the α4 and the α6 nAChR subunits, and those two subunits cannot completely substitute for each other even though they are abundantly expressed in VTA neurons [59,60]. The results are consistent with the expression of α4β2 and α4α6β2 nAChRs in the VTA [48] and consistent with the importance of these receptors in the VTA for the reinforcing properties of nicotine.

Chronic nicotine induces neuroadaptations

Prolonged exposure to the exogenous drug, nicotine, produces neuroadaptations that influence diverse signaling pathways and circuits [61]. The most well studied neuroadaptation is the subtypespecific upregulation of nAChRs [21,24,62-71]. The populations of nAChR subtypes begins to change as molecular mechanisms involving neuroadaptations come into play after days and weeks of tobacco use [32,72,73]. Various molecular mechanisms have been proposed to underlie nAChR upregulation [73-79], which may be viewed as a homeostatic adaptation [68]. Unlike ACh, nicotine is not hydrolyzed by acetylcholinesterase, and nicotine’s long-lasting presence favors nAChR desensitization (i.e., turning down nAChR tone). The homeostatic response to desensitized receptors is upregulation [68,80,81]. Nicotinic receptor upregulation differs among the diverse nAChR subtypes, varies among brain regions for the same nAChR subtype, and depends on the contingency of nicotine administration [62,63,82-86].

Chronic nicotine also causes a number of other heterologous neuroadaptations: changes in glutamate receptors often associated with synaptic plasticity [51,87], changes in DA receptor subtype densities [88], changes in scaffolding proteins [21,89], changes in protein turnover [21], and others. Because nAChRs affect the release of virtually every major neurotransmitter [20,90-95], these overall neuroadaptations can have far-reaching effects and contribute to the mechanisms that maintain nicotine consumption, as well as underlying the nicotine-withdrawal syndrome [95,96].

Withdrawal from chronic nicotine

The withdrawal syndrome arises when the abrupt absence of nicotine disrupts homeostasis maintained in the presence of chronic nicotine. Specifically, withdrawal from nicotine produces somatic effects such as twitches, tremors, and bradycardia, as well as affective symptoms such as elevated anxiety levels. The withdrawal of nicotine begins a new process of neuroadaptations to counteract the negative state. Just as specific nAChR subtypes support the induction of nicotine addiction, other specific nAChR subtypes underlie the withdrawal syndrome. For instance, α5, α3, and β4 subunits are all found in the same gene cluster, and all of these subunits seem to help regulate consequences of nicotine withdrawal [97,98]. α5-null and β4- null mice lack the somatic signs of withdrawal [99,100]. Consistent with the role of anxiety and stress in relapse [96], both α5-null and β4-null mice have reduced anxiety-related behaviors [101,102], but β2- null mice show normal anxiety-like responses [103]. The α2 subunit also contributes to the somatic signs of withdrawal [100], and this role likely arises from its expression in the interpeduncular nucleus (IPN) of rodents [104,105].

In the mouse, the α5, α2, and β4 nAChR subunits are expressed at high levels in the medial habenula (MHb) and in its main target the IPN [96,106]. The MHb projects to the IPN via the fasciculus retroflexus, forming an axis involved in the somatic signs of withdrawal. Withdrawal symptoms are reduced when nAChRs in the Hb/IPN are inhibited [100], and α5-null mice self-administer nicotine at high doses that elicit aversion in wild-type mice, indicating that α5-containing nAChRs in the MHb regulate the upper limit of the self-administered nicotine dose [107]. It is intriguing and likely not a coincidence that a single nucleotide polymorphism (SNP) within the α5 gene (CHRNA5) reduces α5-nAChR function and correlates with greater nicotine dependence risk, heavier smoking, and increased pleasurable sensation from cigarettes [108-111]. The MHb/IPN axis helps to mediate the CNS component of the aversive effects of nicotine, and the nAChRs within this axis are important contributors to the nicotine withdrawal symptoms.

Taken together the results suggest reward and withdrawal circuits have partially overlapping functions. The VTA/NAc and the dopaminergic system are established in reinforcement of rewarding behaviors, and the MHb/IPN axis is emerging as the critical anatomical structures processing the aversive effects and withdrawal from nicotine.

Therapies to assist smoking cessation

More than 70% of smokers in the United States have attempted to quit, and approximately 46% try to quit each year [112,113]. After a year’s time, only about 3% to 7% of those who attempt to quit are still tobacco free [113,114]. There are many behavioral and environmental issues that contribute to the low success rate [9,15,32]. An important physiological factor is that during withdrawal from chronic nicotine a hypofunctional DA state is created that alters brain reward function [115]. Studies support the hypothesis that a low DA state may induce drug seeking to reverse the nicotine-induced DA deficiencies because the majority of people who attempt unaided to quit smoking relapse within the first 2 weeks [116,117]. Those results suggest that the early withdrawal period is a critical time for relapse and, potentially, for intervention.

The most commonly used aid to quitting is nicotine replacement therapy, which partially relieves withdrawal symptoms and tobacco (mainly nicotine) craving [112,118]. Nicotine replacement therapy is most successful with smokers willing to attempt an abrupt cessation with this aid: the success rate is around 16% with replacement versus 10% with placebo [119].

Bupropion, an atypical antidepressant, acts upon multiple targets as an aid to smoking cessation [120]. One action of bupropion is inhibition of catecholamine reuptake, which increases extracellular concentrations of norepinephrine and DA, thereby, helping to relieve the hypo-dopaminergic state of withdrawal [121]. Another action of bupropion that may contribute to its efficacy is that it functions as a non-competitive antagonist of various nAChR subtypes [122]. In addition, animal studies suggest that bupropion may exert some systems-level effects similar to nicotine. Both drugs are psychomotor stimulants [123] and both increase catecholamine concentrations in mesolimbic regions [120]. Bupropion on its own improves abstinence rates, and it is most effective combined with nicotine replacement therapy, which augments cessation to about 29% [124,125].

Another approved smoking cessation therapy is varenicline, which is a derivative of the nAChR agonist cytisine. Originally it was thought to act as a selective agonist for α4β2 nAChRs, but further preclinical studies indicated it has agonist action at many nAChR subtypes [126,127]. Varenicline’s partial agonist action at α4β2 nAChRs is thought to decrease withdrawal and cravings [128]. In addition, varenicline inhibits nicotine-induced decreases in brain stimulation thresholds, suggesting that it makes smoking less rewarding [129]. Just over 20% of patients taking varenicline for 12 weeks maintained abstinence when examined at 52 weeks, which was an improvement over bupropion alone or placebo, but the rates of cessation were not consistently better than nicotine replacement therapy [130].

Although a causal relationship has not been established between bupropion and varenicline therapies and serious adverse effects, safety concerns have arisen and warnings have been added to the prescribing information of the two drugs. Adverse events in patients treated with bupropion or varenicline include changes in behavior, depression, and suicidal behavior [131]. The occurrence of serious side effects and the relatively small long-term improvements in cessation rates serves as a spur to develop improved therapeutic approaches [128].

Disclosure Statement

The authors are not aware of any affiliations, memberships, funding, financial holdings, or any other conflicts of interests that might be perceived as affecting the objectivity of this review.

Acknowledgements

We are supported by grants from the Cancer Prevention and Research Institute of Texas and the National Institutes of Health (NINDS NS21229 and NIDA DA09411, DA017173, DA029157).

References

1. Peto R, Lopez AD, Boreham J, Thun M, Heath C Jr., et al. (1996) Mortality from smoking worldwide. Br Med Bull 52: 12-21.
2. Mathers CD, Loncar D (2006) Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med 3: e442.
3. Benowitz NL (2008) Clinical pharmacology of nicotine: implications for understanding, preventing, and treating tobacco addiction. Clin Pharmacol Ther 83: 531-541.
4. WHO (1997) Tobacco or health, a global status report. World Health Organization: 495.
5. Corrigall WA (1999) Nicotine self-administration in animals as a dependence model. Nicotine Tob Res 1: 11-20.
6. Corrigall WA, Coen KM (1989) Nicotine maintains robust self-administration in rats on a limited-access schedule. Psychopharmacology (Berl) 99: 473- 478.
7. Di Chiara G (2000) Role of dopamine in the behavioural actions of nicotine related to addiction. Eur J Pharmacol 393: 295-314.
8. Stolerman IP, Shoaib M (1991) The neurobiology of tobacco addiction. Trends Pharmacol Sci 12: 467-473.
9. De Biasi M, Dani JA (2011) Reward, addiction, withdrawal to nicotine. Annu Rev Neurosci 34: 105-130.
10. Stolerman IP, Jarvis MJ (1995) The scientific case that nicotine is addictive. Psychopharmacology (Berl) 117: 2-10; discussion 4-20.
11. DHHS (1988) The Health Consequences of Smoking - Nicotine Addiction: A Report of the Surgeon General: 639.
12. Marti F, Arib O, Morel C, Dufresne V, Maskos U, Corringer PJ, et al. (2011) Smoke Extracts and Nicotine, but not Tobacco Extracts, Potentiate Firing and Burst Activity of Ventral Tegmental Area Dopaminergic Neurons in Mice. Neuropsychopharmacology.
13. Benowitz NL (1988) Pharmacologic aspects of cigarette smoking and nicotine addiction. N Engl J Med 319: 1318-1330.
14. Henningfield JE, Radzius A, Cooper TM, Clayton RR (1990) Drinking coffee and carbonated beverages blocks absorption of nicotine from nicotine polacrilex gum. JAMA 264: 1560-1564.
15. Dani JA, Kosten TR, Benowitz NL (2009) The pharmacology of nicotine and tobacco. In: Ries RK, Fiellin DA, Miller SC, Saitz R, editors. Principles of Addiction Medicine. Philadelphia, PA: Lippincott Williams & Wilkins, Wolters Kluwer 179-191.
16. Brody AL, Mandelkern MA, London ED, Olmstead RE, Farahi J, et al. (2006) Cigarette smoking saturates brain alpha 4 beta 2 nicotinic acetylcholine receptors. Arch Gen Psychiatry 63: 907-915.
17. Benowitz NL (2009) Pharmacology of nicotine: addiction, smoking-induced disease, and therapeutics. Annu Rev Pharmacol Toxicol 49: 57-71.
18. Hukkanen J, Jacob P, 3rd, Benowitz NL (2005) Metabolism and disposition kinetics of nicotine. Pharmacol Rev 57: 79-115.
19. Benowitz NL (2001) Compensatory smoking of low yield cigarettes. In: Risks Associated with Smoking Cigarettes with Low Machine-Measured Yields of Tar and Nicotine In: Shopland DR, editor. NIH Publication No 02-5074. Bethesda, MD: NIH p. 39-64.
20. Dani JA, Bertrand D (2007) Nicotinic acetylcholine receptors and nicotinic cholinergic mechanisms of the central nervous system. Annu Rev Pharmacol Toxicol 47: 699-729.
21. Rezvani K, Teng Y, Shim D, De Biasi M (2007) Nicotine regulates multiple synaptic proteins by inhibiting proteasomal activity. J Neurosci 27: 10508- 10519.
22. McGehee DS, Role LW (1995) Physiological diversity of nicotinic acetylcholine receptors expressed by vertebrate neurons. Annu Rev Physiol 57: 521-546.
23. Jones S, Sudweeks S, Yakel JL (1999) Nicotinic receptors in the brain: correlating physiology with function. Trends Neurosci 22: 555-61.
24. Buisson B, Bertrand D (2001) Chronic exposure to nicotine upregulates the human (alpha)4((beta)2 nicotinic acetylcholine receptor function. J Neurosci 21: 1819-1829.
25. Klink R, de Kerchove d’Exaerde A, Zoli M, Changeux JP (2001) Molecular and physiological diversity of nicotinic acetylcholine receptors in the midbrain dopaminergic nuclei. J Neurosci 21: 1452-1463.
26. Dani JA, Radcliffe KA, Pidoplichko VI (2000) Variations in desensitization of nicotinic acetylcholine receptors from hippocampus and midbrain dopamine areas. Eur J Pharmacol 393: 31-38.
27. Quick MW, Lester RA (2002) Desensitization of neuronal nicotinic receptors. J Neurobiol 53: 457-478.
28. Giniatullin R, Nistri A, Yakel JL (2005) Desensitization of nicotinic ACh receptors: shaping cholinergic signaling. Trends Neurosci 28: 371-378.
29. Berke JD, Hyman SE (2000) Addiction, dopamine, and the molecular mechanisms of memory. Neuron 25: 515-32.
30. Di Chiara G (1999) Drug addiction as dopamine-dependent associative learning disorder. Eur J Pharmacol 375: 13-30.
31. Wise RA (2000) Interactions between medial prefrontal cortex and mesolimbic components of brain reward circuitry. Prog Brain Res 126: 255-262.
32. Dani JA, Harris RA (2005) Nicotine addiction and comorbidity with alcohol abuse and mental illness. Nat Neurosci 8: 1465-70.
33. Di Chiara G, Bassareo V, Fenu S, De Luca MA, Spina L, et al. (2004) Dopamine and drug addiction: the nucleus accumbens shell connection. Neuropharmacology 47: 227-241.
34. Hyman SE, Malenka RC, Nestler EJ (2006) Neural mechanisms of addiction: the role of reward-related learning and memory. Annu Rev Neurosci 29: 565- 598.
35. Balfour DJ, Wright AE, Benwell ME, Birrell CE (2000) The putative role of extra-synaptic mesolimbic dopamine in the neurobiology of nicotine dependence. Behav Brain Res 113: 73-83.
36. Corrigall WA, Franklin KB, Coen KM, Clarke PB (1992) The mesolimbic dopaminergic system is implicated in the reinforcing effects of nicotine. Psychopharmacology (Berl) 107: 285-289.
37. Nestler EJ (2005) Is there a common molecular pathway for addiction? Nat Neurosci 8: 1445-1449.
38. Spanagel R, Weiss F (1999) The dopamine hypothesis of reward: past and current status. Trends Neurosci 122: 521-527.
39. Pidoplichko VI, DeBiasi M, Williams JT, Dani JA (1997) Nicotine activates and desensitizes midbrain dopamine neurons. Nature 390: 401-404.
40. Zhang T, Zhang L, Liang Y, Siapas AG, Zhou FM, Dani JA (2009) Dopamine signaling differences in the nucleus accumbens and dorsal striatum exploited by nicotine. J Neurosci 29: 4035-4043.
41. Dong Y, Zhang T, Li W, Doyon WM, Dani JA (2010) Route of nicotine administration influences in vivo dopamine neuron activity: habituation, needle injection, and cannula infusion. J Mol Neurosci 40: 164-171.
42. Omelchenko N, Sesack SR (2005) Laterodorsal tegmental projections to identified cell populations in the rat ventral tegmental area. J Comp Neurol 483: 217-235.
43. Wooltorton JR, Pidoplichko VI, Broide RS, Dani JA (2003) Differential desensitization and distribution of nicotinic acetylcholine receptor subtypes in midbrain dopamine areas. J Neurosci 23: 3176-3185.
44. Picciotto MR, Zoli M, Rimondini R, Lena C, Marubio LM, et al. (1998) Acetylcholine receptors containing the beta2 subunit are involved in the reinforcing properties of nicotine. Nature 391: 173-177.
45. Tapper AR, McKinney SL, Nashmi R, Schwarz J, Deshpande P, et al. (2004) Nicotine activation of alpha4* receptors: sufficient for reward, tolerance, and sensitization. Science 306:1029-1032.
46. Mameli-Engvall M, Evrard A, Pons S, Maskos U, Svensson TH, et al. (2006) Hierarchical control of dopamine neuron-firing patterns by nicotinic receptors. Neuron 50: 911-921.
47. Drenan RM, Grady SR, Steele AD, McKinney S, Patzlaff NE, et al. (2010) Cholinergic modulation of locomotion and striatal dopamine release is mediated by alpha6alpha4* nicotinic acetylcholine receptors. J Neurosci 30: 9877-9889.
48. Pons S, Fattore L, Cossu G, Tolu S, Porcu E, et al. (2008) Crucial role of alpha4 and alpha6 nicotinic acetylcholine receptor subunits from ventral tegmental area in systemic nicotine self-administration. J Neurosci 28: 12318-12327.
49. Schilstrom B, Fagerquist MV, Zhang X, Hertel P, Panagis G, et al. (2000) Putative role of presynaptic alpha7* nicotinic receptors in nicotine stimulated increases of extracellular levels of glutamate and aspartate in the ventral tegmental area. Synapse 38: 375-383.
50. Schilstrom B, Rawal N, Mameli-Engvall M, Nomikos GG, Svensson TH (2003) Dual effects of nicotine on dopamine neurons mediated by different nicotinic receptor subtypes. Int J Neuropsychopharmacol 6:1-11.
51. Mansvelder HD, McGehee DS (2002) Cellular and synaptic mechanisms of nicotine addiction. J Neurobiol 53: 606-617.
52. Grace AA, Floresco SB, Goto Y, Lodge DJ (2007) Regulation of firing of dopaminergic neurons and control of goal-directed behaviors. Trends Neurosci 30: 220-227.
53. Hyland BI, Reynolds JN, Hay J, Perk CG, Miller R (2002) Firing modes of midbrain dopamine cells in the freely moving rat. Neuroscience 114: 475-492.
54. Robinson S, Smith DM, Mizumori SJ, Palmiter RD (2004) Firing properties of dopamine neurons in freely moving dopamine-deficient mice: effects of dopamine receptor activation and anesthesia. Proc Natl Acad Sci USA 101: 13329-13334.
55. Schultz W, Dayan P, Montague PR (1997) A neural substrate of prediction and reward. Science 275: 1593-1599.
56. Schultz W (2007) Multiple dopamine functions at different time courses. Annu Rev Neurosci 30: 259-288.
57. Grenhoff J, Aston-Jones G, Svensson TH (1986) Nicotinic effects on the firing pattern of midbrain dopamine neurons. Acta Physiol Scand 128: 351-358.
58. Avale ME, Faure P, Pons S, Robledo P, Deltheil T, et al. (2008) Interplay of beta2* nicotinic receptors and dopamine pathways in the control of spontaneous locomotion. Proc Natl Acad Sci USA 105: 15991-15996.
59. Champtiaux N, Gotti C, Cordero-Erausquin M, David DJ, Przybylski C, et al. (2003) Subunit composition of functional nicotinic receptors in dopaminergic neurons investigated with knock-out mice. J Neurosci 23: 7820-7829.
60. Salminen O, Drapeau JA, McIntosh JM, Collins AC, Marks MJ, et al. (2007) Pharmacology of alpha-conotoxin MII-sensitive subtypes of nicotinic acetylcholine receptors isolated by breeding of null mutant mice. Mol Pharmacol 71: 1563-1571.
61. Koob GF, Le Moal M (2001) Drug addiction, dysregulation of reward, and allostasis. Neuropsycho pharmacology 24: 97-129.
62. Marks MJ, Burch JB, Collins AC (1983) Effects of chronic nicotine infusion on tolerance development and nicotinic receptors. J Pharmacol Exp Ther 226: 817-825.
63. Schwartz RD, Kellar KJ (1983) Nicotinic cholinergic receptor binding sites in the brain: regulation in vivo. Science 220: 214-216.
64. Changeux JP, Devillers-Thiery A, Chemouilli P (1984) Acetylcholine receptor: an allosteric protein. Science 225: 1335-1345.
65. Flores CM, Davila-Garcia MI, Ulrich YM, Kellar KJ (1997) Differential regulation of neuronal nicotinic receptor binding sites following chronic nicotine administration. J Neurochem 69: 2216-2219.
66. Perry E, Walker M, Grace J, Perry R (1999) Acetylcholine in mind: a neurotransmitter correlate of consciousness? Trends Neurosci 22: 273-280.
67. Mansvelder HD, Keath JR, McGehee DS (2002) Synaptic mechanisms underlie nicotine-induced excitability of brain reward areas. Neuron 33: 905- 919.
68. Dani JA, Heinemann S (1996) Molecular and cellular aspects of nicotine abuse. Neuron 16: 905-908.
69. Marks MJ, Pauly JR, Gross SD, Deneris ES, Hermans-Borgmeyer I, et al. (1992) Nicotine binding and nicotinic receptor subunit RNA after chronic nicotine treatment. J Neurosci 12: 2765-2784.
70. Rezvani K, Teng Y, De Biasi M (2009) The ubiquitin-proteasome system regulates the stability of neuronal nicotinic acetylcholine receptors. J Mol Neurosci 40: 177-184.
71. Rowell PP, Wonnacott S (1990) Evidence for functional activity of upregulated nicotine binding sites in rat striatal synaptosomes. J Neurochem 55: 2105-110.
72. Mathieu-Kia AM, Kellogg SH, Butelman ER, Kreek MJ (2002) Nicotine addiction: insights from recent animal studies. Psychopharmacology (Berl) 162: 102-118.
73. Corringer PJ, Sallette J, Changeux JP (2006) Nicotine enhances intracellular nicotinic receptor maturation: a novel mechanism of neural plasticity? J Physiol Paris 99: 162-171.
74. Peng X, Gerzanich V, Anand R, Wang F, Lindstrom J (1997) Chronic nicotine treatment up-regulates alpha3 and alpha7 acetylcholine receptor subtypes expressed by the human neuroblastoma cell line SH-SY5Y. Mol Pharmacol 51: 776-784.
75. Rezvani AH, Slade S, Wells C, Petro A, Lumeng L, et al. (2010) Effects of sazetidine-A, a selective alpha4beta2 nicotinic acetylcholine receptor desensitizing agent on alcohol and nicotine self-administration in selectively bred alcohol-preferring (P) rats. Psychopharmacology (Berl) 211: 161-74.
76. Sallette J, Pons S, Devillers-Thiery A, Soudant M, Prado de Carvalho L, et al (2005) Nicotine upregulates its own receptors through enhanced intracellular maturation. Neuron 46: 595-607.
77. Darsow T, Booker TK, Pina-Crespo JC, Heinemann SF (2005) Exocytic trafficking is required for nicotine-induced up-regulation of alpha 4 beta 2 nicotinic acetylcholine receptors. J Biol Chem 280: 18311-20.
78. Buisson B, Bertrand D (2002) Nicotine addiction: the possible role of functional upregulation. Trends Pharmacol Sci 23: 130-6.
79. Vallejo YF, Buisson B, Bertrand D, Green WN (2005) Chronic nicotine exposure upregulates nicotinic receptors by a novel mechanism. J Neurosci 25: 5563-72.
80. Fenster CP, Whitworth TL, Sheffield EB, Quick MW, Lester RA (1999) Upregulation of surface alpha4beta2 nicotinic receptors is initiated by receptor desensitization after chronic exposure to nicotine. J Neurosci 19: 4804-4814.
81. Picciotto MR, Addy NA, Mineur YS, Brunzell DH (2008) It is not “either/ or”: activation and desensitization of nicotinic acetylcholine receptors both contribute to behaviors related to nicotine addiction and mood. Prog Neurobiol 84: 329-342.
82. Pauly JR, Marks MJ, Robinson SF, van de Kamp JL, Collins AC (1996) Chronic nicotine and mecamylamine treatment increase brain nicotinic receptor binding without changing alpha 4 or beta 2 mRNA levels. J Pharmacol Exp Ther 278: 361-369.
83. Nguyen HN, Rasmussen BA, Perry DC (2004) Binding and functional activity of nicotinic cholinergic receptors in selected rat brain regions are increased following long-term but not short-term nicotine treatment. J Neurochem 90: 40-49.
84. McCallum SE, Parameswaran N, Bordia T, Fan H, McIntosh JM, et al. (2006) Differential regulation of mesolimbic alpha 3/alpha 6 beta 2 and alpha 4 beta 2 nicotinic acetylcholine receptor sites and function after long-term oral nicotine to monkeys. J Pharmacol Exp Ther 318: 381-388.
85. Gaimarri A, Moretti M, Riganti L, Zanardi A, Clementi F, et al. (2007) Regulation of neuronal nicotinic receptor traffic and expression. Brain Res Rev 55: 134-143.
86. Metaxas A, Bailey A, Barbano MF, Galeote L, Maldonado R, (2010) Differential region-specific regulation of alpha4beta2* nAChRs by self-administered and non-contingent nicotine in C57BL/6J mice. Addict Biol 15: 464-479.
87. Dani JA, Ji D, Zhou FM (2001) Synaptic plasticity and nicotine addiction. Neuron 31: 349-352.
88. Novak G, Seeman P, Le Foll B (2010) Exposure to nicotine produces an increase in dopamine D2(High) receptors: a possible mechanism for dopamine hypersensitivity. Int J Neurosci 120: 691-697.
89. Hwang YY, Li MD (2006) Proteins differentially expressed in response to nicotine in five rat brain regions: identification using a 2-DE/MS-based proteomics approach. Proteomics 6: 3138-3153.
90. McGehee DS, Heath MJ, Gelber S, Devay P, Role LW (1995) Nicotine enhancement of fast excitatory synaptic transmission in CNS by presynaptic receptors. Science 269: 1692-1696.
91. Pidoplichko VI (1996) Dependence of solution exchange time on cell or patch linear dimensions in concentration jump experiments using patch-clamped sensory neurones. Pflugers Arch 432: 1074-1079.
92. Role LW, Berg DK (1996) Nicotinic receptors in the development and modulation of CNS synapses. Neuron 16: 1077-1085.
93. Alkondon M, Pereira EF, Barbosa CT, Albuquerque EX (1997) Neuronal nicotinic acetylcholine receptor activation modulates gamma-aminobutyric acid release from CA1 neurons of rat hippocampal slices. J Pharmacol Exp Ther 283: 1396-1411.
94. Kenny PJ (2010) Tobacco dependence, the insular cortex and the hypocretin connection. Pharmacol Biochem Behav.
95. Hadjiconstantinou M, Neff NH (2010) Nicotine and endogenous opioids: Neurochemical and pharmacological evidence. Neuropharmacology.
96. De Biasi M, Salas R (2008) Influence of neuronal nicotinic receptors over nicotine addiction and withdrawal. Exp Biol Med (Maywood) 233: 917-929.
97. Salas R, Cook KD, Bassetto L, De Biasi M (2004) The alpha3 and beta4 nicotinic acetylcholine receptor subunits are necessary for nicotine-induced seizures and hypolocomotion in mice. Neuropharmacology 47: 401-407.
98. Salas R, Orr-Urtreger A, Broide RS, Beaudet A, Paylor R, et al. (2003) The nicotinic acetylcholine receptor subunit alpha 5 mediates short-term effects of nicotine in vivo. Mol Pharmacol 63: 1059-1066.
99. Salas R, Pieri F, De Biasi M (2004) Decreased signs of nicotine withdrawal in mice null for the beta4 nicotinic acetylcholine receptor subunit. J Neurosci 24: 10035-10039.
100. Salas R, Sturm R, Boulter J, De Biasi M. Nicotinic receptors in the habenulointerpeduncular system are necessary for nicotine withdrawal in mice. J Neurosci 2009;29: 3014-3018.
101. Salas R, Pieri F, Fung B, Dani JA, De Biasi M (2003) Altered anxiety-related responses in mutant mice lacking the beta4 subunit of the nicotinic receptor. J Neurosci 23: 6255-6263.
102. Gangitano D, Salas R, Teng Y, Perez E, De Biasi M (2009) Progesterone modulation of alpha5 nAChR subunits influences anxiety-related behavior during estrus cycle. Genes Brain Behav 8: 398-406.
103. Maskos U, Molles BE, Pons S, Besson M, Guiard BP, et al. (2005) Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors. Nature 436: 103-107.
104. Whiteaker P, Davies AR, Marks MJ, Blagbrough IS, Potter BV, et al. (1999) An autoradiographic study of the distribution of binding sites for the novel alpha7-selective nicotinic radioligand [3H]-methyllycaconitine in the mouse brain. Eur J Neurosci 11: 2689-2696.
105. Ishii K, Wong JK, Sumikawa K (2005) Comparison of alpha2 nicotinic acetylcholine receptor subunit mRNA expression in the central nervous system of rats and mice. J Comp Neurol 493: 241-260.
106. Grady SR, Moretti M, Zoli M, Marks MJ, Zanardi A, et al. (2009) Rodent habenulo-interpeduncular pathway expresses a large variety of uncommon nAChR subtypes, but only the alpha3beta4* and alpha3beta3beta4* subtypes mediate acetylcholine release. J Neurosci 29: 2272-2282.
107. Fowler CD, Arends MA, Kenny PJ (2008) Subtypes of nicotinic acetylcholine receptors in nicotine reward, dependence, and withdrawal: evidence from genetically modified mice. Behav Pharmacol 19: 461-484.
108. Saccone SF, Hinrichs AL, Saccone NL, Chase GA, Konvicka K, et al. (2007) Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs. Hum Mol Genet 16: 36-49.
109. Berrettini W, Yuan X, Tozzi F, Song K, Francks C, et al. (2008) Alpha-5/ alpha-3 nicotinic receptor subunit alleles increase risk for heavy smoking. Mol Psychiatry 13: 368-373.
110. Bierut LJ, Stitzel JA, Wang JC, Hinrichs AL, Grucza RA, et al. (2008) Variants in nicotinic receptors and risk for nicotine dependence. Am J Psychiatry 165: 1163-1171.
111. Thorgeirsson TE, Geller F, Sulem P, Rafnar T, Wiste A, et al. (2008) A variant associated with nicotine dependence, lung cancer and peripheral arterial disease. Nature 452: 638-642.
112. Benowitz NL (2010) Nicotine addiction. N Engl J Med 62: 2295-2303.
113. Kenford SL, Fiore MC (2004) Promoting tobacco cessation and relapse prevention. Med Clin North Am 88: 1553-1574, xi-xii.
114. MMWR (2005) State-specific prevalence of cigarette smoking and quitting among adults--United States. 54: 1124-1127.
115. Epping-Jordan MP, Watkins SS, Koob GF, Markou A (1998) Dramatic decreases in brain reward function during nicotine withdrawal. Nature 393: 76-79.
116. Ward KD, Klesges RC, Zbikowski SM, Bliss RE, Garvey AJ (1997) Gender differences in the outcome of an unaided smoking cessation attempt. Addict Behav 22: 521-533.
117. Shiffman S (2006) Reflections on smoking relapse research. Drug Alcohol Rev 25: 15-20.
118. Benowitz NL (1993) Nicotine replacement therapy. What has been accomplished can we do better? Drugs 45: 157-170.
119. Wang D, Connock M, Barton P, Fry-Smith A, Aveyard P (2008) ‘Cut down to quit’ with nicotine replacement therapies in smoking cessation: a systematic review of effectiveness and economic analysis. Health Technol Assess 12: iii-iv, ix-xi, 1-135.
120. Dwoskin LP, Rauhut AS, King-Pospisil KA, Bardo MT (2006) Review of the pharmacology and clinical profile of bupropion, an antidepressant and tobacco use cessation agent. CNS Drug Rev 12: 178-207.
121. Li SX, Perry KW, Wong DT (2002) Influence of fluoxetine on the ability of bupropion to modulate extracellular dopamine and norepinephrine concentrations in three mesocorticolimbic areas of rats. Neuropharmacology 42: 181-190.
122. Fryer JD, Lukas RJ (1999) Noncompetitive functional inhibition at diverse, human nicotinic acetylcholine receptor subtypes by bupropion, phencyclidine, and ibogaine. J Pharmacol Exp Ther 288: 88-92.
123. Wilkinson JL, Bevins RA (2007) Bupropion hydrochloride produces conditioned hyperactivity in rats. Physiol Behav 90: 790-796.
124. Jorenby DE, Leischow SJ, Nides MA, Rennard SI, Johnston JA, et al. (1999) A controlled trial of sustained-release bupropion, a nicotine patch, or both for smoking cessation. N Engl J Med 340: 685-691.
125. Smith SS, McCarthy DE, Japuntich SJ, Christiansen B, Piper ME, et al. (2009) Comparative effectiveness of 5 smoking cessation pharmacotherapies in primary care clinics. Arch Intern Med 169: 2148-2155.
126. Coe JW, Brooks PR, Vetelino MG, Wirtz MC, Arnold EP, et al. (2005) Varenicline: an alpha4beta2 nicotinic receptor partial agonist for smoking cessation. J Med Chem 48: 3474-3477.
127. Mihalak KB, Carroll FI, Luetje CW (2006) Varenicline is a partial agonist at alpha4beta2 and a full agonist at alpha7 neuronal nicotinic receptors. Mol Pharmacol 70: 801-805.
128. Polosa R, Benowitz NL (2011) Treatment of nicotine addiction: present therapeutic options and pipeline developments. Trends Pharmacol Sci 32: 281-289.
129. Spiller K, Xi ZX, Li X, Ashby CR, Jr., Callahan PM, et al. (2009) Varenicline attenuates nicotine-enhanced brain-stimulation reward by activation of alpha4beta2 nicotinic receptors in rats. Neuropharmacology 57: 60-6.
130. Aubin HJ, Bobak A, Britton JR, Oncken C, Billing CB, Jr., et al. (2008) Varenicline versus transdermal nicotine patch for smoking cessation: results from a randomised open-label trial. Thorax 63: 717-724.
131. Hays JT, Ebbert JO ( 2010) Adverse effects and tolerability of medications for the treatment of tobacco use and dependence. Drugs 70: 2357-2372.