Abstract
Human behavior can be controlled by physical or psychological dependencies associated with addiction. One of the most insidious addictions in our society is the use of tobacco products which contain nicotine. This addiction can be associated with specific receptors in the brain that respond to the natural neurotransmitter acetylcholine. These nicotinic acetylcholine receptors (nAChR) are ligand-gated ion channels formed by the assembly of one or multiple types of nAChR receptor subunits. In this paper, we review the structure and diversity of nAChR subunits and our understanding for how different nAChR subtypes play specific roles in the phenomenon of nicotine addiction. We focus on receptors containing β2 and/or α6 subunits and the special significance of α5-containing receptors. These subtypes all have roles in regulating dopamine-mediated neurotransmission in the mesolimbic reward pathways of the brain. We also discuss the unique roles of homomeric α7 nAChR in behavioral responses to nicotine and how our knowledge of nAChR functional diversity may help guide pharmacotherapeutic approaches for treating nicotine addiction. While nicotine addiction is a truly global problem, the use of areca nut (betel) products is also a serious addiction associated with public health issues across most of South Asia, impacting as many as 600 million people. We discuss how cholinergic receptors of the brain are also involved with areca addiction and the unique challenges for dealing with addiction to this substance.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
Adler LE, Hoffer LJ, Griffith J, Waldo MC, Freedman R (1992) Normalization by nicotine of deficient auditory sensory gating in the relatives of schizophrenics. Biol Psychiatry 32(7):607–616
Amos CI, Wu X, Broderick P, Gorlov IP, Gu J, Eisen T, Dong Q, Zhang Q, Gu X, Vijayakrishnan J, Sullivan K, Matakidou A, Wang Y, Mills G, Doheny K, Tsai YY, Chen WV, Shete S, Spitz MR, Houlston RS (2008) Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nat Genet 40(5):616–622
Atzori G, Lemmonds CA, Kotler ML, Durcan MJ, Boyle J (2008) Efficacy of a nicotine (4 mg)-containing lozenge on the cognitive impairment of nicotine withdrawal. J Clin Psychopharmacol 28(6):667–674
Auluck A, Hislop G, Poh C, Zhang L, Rosin MP (2009) Areca nut and betel quid chewing among South Asian immigrants to Western countries and its implications for oral cancer screening. Rural Remote Health 9(2):1118
Bachman SA (2013) Betel nut product characteristics and availability in King County, Washington: a secret shopper study. In: Global health. University of Washington, Seattle
Bailey CD, De Biasi M, Fletcher PJ, Lambe EK (2011) The nicotinic acetylcholine receptor alpha5 subunit plays a key role in attention circuitry and accuracy. J Neurosci 30(27):9241–9252
Banks ML, Smith DA, Blough BE (2016) Methamphetamine-like discriminative stimulus effects of bupropion and its two hydroxy metabolites in male rhesus monkeys. Behav Pharmacol 27(2–3 Spec Issue):196–203
Benowitz NL (2009) Pharmacology of nicotine: addiction, smoking-induced disease, and therapeutics. Annu Rev Pharmacol Toxicol 49:57–71
Benwell ME, Balfour DJ, Anderson JM (1988) Evidence that tobacco smoking increases the density of (-)-[3H]nicotine binding sites in human brain. J Neurochem 50(4):1243–1247
Bergen AW, Javitz HS, Krasnow R, Nishita D, Michel M, Conti DV, Liu J, Lee W, Edlund CK, Hall S, Kwok PY, Benowitz NL, Baker TB, Tyndale RF, Lerman C, Swan GE (2013) Nicotinic acetylcholine receptor variation and response to smoking cessation therapies. Pharmacogenet Genomics 23(2):94–103
Berrettini W, Yuan X, Tozzi F, Song K, Francks C, Chilcoat H, Waterworth D, Muglia P, Mooser V (2008) Alpha-5/alpha-3 nicotinic receptor subunit alleles increase risk for heavy smoking. Mol Psychiatry 13(4):368–373
Bierut LJ, Stitzel JA, Wang JC, Hinrichs AL, Grucza RA, Xuei X, Saccone NL, Saccone SF, Bertelsen S, Fox L, Horton WJ, Breslau N, Budde J, Cloninger CR, Dick DM, Foroud T, Hatsukami D, Hesselbrock V, Johnson EO, Kramer J, Kuperman S, Madden PA, Mayo K, Nurnberger J Jr, Pomerleau O, Porjesz B, Reyes O, Schuckit M, Swan G, Tischfield JA, Edenberg HJ, Rice JP, Goate AM (2008) Variants in nicotinic receptors and risk for nicotine dependence. Am J Psychiatry 165(9):1163–1171
Boulter J, Connolly J, Deneris E, Goldman D, Heinemann S, Patrick J (1987) Functional expression of two neural nicotinic acetylcholine receptors from cDNA clones identifies a gene family. Proc Natl Acad Sci U S A 84:7763–7767
Boulter J, O’Shea-Greenfield A, Duvoisin RM, Connolly JG, Wada E, Jensen A, Gardner PD, Ballivet M, Deneris ES, McKinnon D et al (1990) Alpha 3, alpha 5, and beta 4: three members of the rat neuronal nicotinic acetylcholine receptor-related gene family form a gene cluster. J Biol Chem 265(8):4472–4482
Brunzell DH, McIntosh JM (2012) Alpha7 nicotinic acetylcholine receptors modulate motivation to self-administer nicotine: implications for smoking and schizophrenia. Neuropsychopharmacology 37(5):1134–1143
Brunzell DH, Boschen KE, Hendrick ES, Beardsley PM, McIntosh JM (2010) Alpha-conotoxin MII-sensitive nicotinic acetylcholine receptors in the nucleus accumbens shell regulate progressive ratio responding maintained by nicotine. Neuropsychopharmacology 35(3):665–673
Brunzell DH, McIntosh JM, Papke RL (2014) Diverse strategies targeting alpha7 homomeric and alpha6beta2∗ heteromeric nicotinic acetylcholine receptors for smoking cessation. Ann N Y Acad Sci 1327:27–45
Changrani J, Gany FM, Cruz G, Kerr R, Katz R (2006) Paan and gutka use in the United States: a pilot study in Bangladeshi and Indian-Gujarati immigrants in New York City. J Immigr Refug Stud 4(1):99–110
Charpantier E, Barneoud P, Moser P, Besnard F, Sgard F (1998) Nicotinic acetylcholine subunit mRNA expression in dopaminergic neurons of the rat substantia nigra and ventral tegmental area. Neuroreport 9(13):3097–3101
Chini B, Clementi F, Hukovic N, Sher E (1992) Neuronal-type alpha-bungarotoxin receptors and the alpha 5-nicotinic receptor subunit gene are expressed in neuronal and nonneuronal human cell lines. Proc Natl Acad Sci U S A 89(5):1572–1576
Clarke PBS, Pert CB, Pert A (1984) Autoradiographic distribution of nicotinic receptors in rat brain. Brain Res 323:390–395
Clarke PBS, Schwartz RD, Paul SM, Pert CB, Pert A (1985) Nicotinic binding in rat brain: autoradiographic comparison of [3H] acetylcholine [3H] nicotine and [125I]-alpha-bungarotoxin. J Neurosci 5:1307–1315
Coe JW, Brooks PR, Vetelino MG, Wirtz MC, Arnold EP, Huang J, Sands SB, Davis TI, Lebel LA, Fox CB, Shrikhande A, Heym JH, Schaeffer E, Rollema H, Lu Y, Mansbach RS, Chambers LK, Rovetti CC, Schulz DW, Tingley FD 3rd, O’Neill BT (2005) Varenicline: an alpha4beta2 nicotinic receptor partial agonist for smoking cessation. J Med Chem 48(10):3474–3477
Cordero-Erausquin M, Marubio LM, Klink R, Changeux JP (2000) Nicotinic receptor function: new perspectives from knockout mice. Trends Pharmacol Sci 21(6):211–217
Corrigall WA, Franklin KB, Coen KM, Clarke PB (1992) The mesolimbic dopaminergic system is implicated in the reinforcing effects of nicotine. Psychopharmacology (Berl) 107(2-3):285–289
Corrigall WA, Coen KM, Adamson KL (1994) Self-administered nicotine activates the mesolimbic dopamine system through the ventral tegmental area. Brain Res 653(1–2):278–284
Corringer PJ, Le Novere N, Changeux JP (2000) Nicotinic receptors at the amino acid level. Annu Rev Pharmacol Toxicol 40:431–458
Corriveau RA, Berg DK (1993) Coexpression of multiple acetylcholine receptor genes in neurons: quantification of transcripts during development. J Neurosci 13(6):2662–2671
Cryan JF, Gasparini F, van Heeke G, Markou A (2003) Non-nicotinic neuropharmacological strategies for nicotine dependence: beyond bupropion. Drug Discov Today 8(22):1025–1034
Cui C, Booker TK, Allen RS, Grady SR, Whiteaker P, Marks MJ, Salminen O, Tritto T, Butt CM, Allen WR, Stitzel JA, McIntosh JM, Boulter J, Collins AC, Heinemann SF (2003) The beta3 nicotinic receptor subunit: a component of alpha-conotoxin MII-binding nicotinic acetylcholine receptors that modulate dopamine release and related behaviors. J Neurosci 23(35):11045–11053
De Biasi M (2002) Nicotinic mechanisms in the autonomic control of organ systems. J Neurobiol 53(4):568–579
De Biasi M, Dani JA (2011) Reward, addiction, withdrawal to nicotine. Annu Rev Neurosci 34:105–130
De Luca V, Wong AH, Muller DJ, Wong GW, Tyndale RF, Kennedy JL (2004) Evidence of association between smoking and alpha7 nicotinic receptor subunit gene in schizophrenia patients. Neuropsychopharmacology 29(8):1522–1526
Dent JA (2010) The evolution of pentameric ligand-gated ion channels. Adv Exp Med Biol 683:11–23
Drenan RM, Grady SR, Steele AD, McKinney S, Patzlaff NE, McIntosh JM, Marks MJ, Miwa JM, Lester HA (2010) Cholinergic modulation of locomotion and striatal dopamine release is mediated by alpha6alpha4∗ nicotinic acetylcholine receptors. J Neurosci 30(29):9877–9889
Duvoisin RM, Deneris E, Patrick J, Heinemann S (1989) The functional diversity of the neuronal acetylcholine receptors is increased by a novel subunit: b4. Neuron 3:487–496
Elgoyhen AB, Johnson DS, Boulter J, Vetter DE, Heinemann S (1994) a9: an acetylcholine receptor with novel pharmacological properties expressed in rat cochlear hair cells. Cell 79:705–715
Elgoyhen AB, Vetter DE, Katz E, Rothlin CV, Heinemann SF, Boulter J (2001) alpha10: a determinant of nicotinic cholinergic receptor function in mammalian vestibular and cochlear mechanosensory hair cells. Proc Natl Acad Sci U S A 98(6):3501–3506
Eng CM, Kozak CA, Beaudet AL, Zoghbi HY (1991) Map** of multiple subunits of the neuronal nicotinic acetylcholine receptor to chromosome 15 in man and chromosome 9 in mouse. Genomics 9(2):278–282
Epstein D (1932) The responses of the batrachian alimentary canal to autonomic drugs. Rana and Bufo arecoline. J Physiol 75(1):99–111
Etter JF, Lukas RJ, Benowitz NL, West R, Dresler CM (2008) Cytisine for smoking cessation: a research agenda. Drug Alcohol Depend 92(1-3):3–8
Exley R, Clements MA, Hartung H, McIntosh JM, Cragg SJ (2008) Alpha6-containing nicotinic acetylcholine receptors dominate the nicotine control of dopamine neurotransmission in nucleus accumbens. Neuropsychopharmacology 33(9):2158–2166
Exley R, Maubourguet N, David V, Eddine R, Evrard A, Pons S, Marti F, Threlfell S, Cazala P, McIntosh JM, Changeux JP, Maskos U, Cragg SJ, Faure P (2011) Distinct contributions of nicotinic acetylcholine receptor subunit alpha4 and subunit alpha6 to the reinforcing effects of nicotine. Proc Natl Acad Sci U S A 108(18):7577–7582
Farsalinos K, Niaura R (2019) E-cigarettes and smoking cessation in the United States according to frequency of e-cigarette use and quitting duration: analysis of the 2016 and 2017 National Health Interview Surveys. Nicotine Tob Res 22(5):655–662
Fasoli F, Moretti M, Zoli M, Pistillo F, Crespi A, Clementi F, Mc Clure-Begley T, Marks MJ, Gotti C (2016) In vivo chronic nicotine exposure differentially and reversibly affects upregulation and stoichiometry of alpha4beta2 nicotinic receptors in cortex and thalamus. Neuropharmacology 108:324–331
Fowler CD, Lu Q, Johnson PM, Marks MJ, Kenny PJ (2011) Habenular alpha5 nicotinic receptor subunit signalling controls nicotine intake. Nature 471(7340):597–601
Freedman R (2007) Exacerbation of schizophrenia by varenicline. Am J Psychiatry 164(8):1269
Freedman R, Adams CE, Leonard S (2000) The alpha7-nicotinic acetylcholine receptor and the pathology of hippocampal interneurons in schizophrenia. J Chem Neuroanat 20(3-4):299–306
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(4):398–406
Garg A, Chaturvedi P, Gupta PC (2014) A review of the systemic adverse effects of areca nut or betel nut. Indian J Med Paediatr Oncol 35(1):3–9
Gee KW, Olincy A, Kanner R, Johnson L, Hogenkamp D, Harris J, Tran M, Edmonds SA, Sauer W, Yoshimura R, Johnstone T, Freedman R (2017) First in human trial of a type I positive allosteric modulator of alpha7-nicotinic acetylcholine receptors: pharmacokinetics, safety, and evidence for neurocognitive effect of AVL-3288. J Psychopharmacol 31(4):434–441
Gerzanich V, Wang F, Kuryatov A, Lindstrom J (1998) Alpha5 Subunit alters desensitization, pharmacology, Ca++ permeability and Ca++ modulation of human neuronal alpha 3 nicotinic receptors. J Pharmacol Exp Ther 286(1):311–320
Gotti C, Zoli M, Clementi F (2006) Brain nicotinic acetylcholine receptors: native subtypes and their relevance. Trends Pharmacol Sci 27(9):482–491
Gotti C, Guiducci S, Tedesco V, Corbioli S, Zanetti L, Moretti M, Zanardi A, Rimondini R, Mugnaini M, Clementi F, Chiamulera C, Zoli M (2010) Nicotinic acetylcholine receptors in the mesolimbic pathway: primary role of ventral tegmental area alpha6beta2∗ receptors in mediating systemic nicotine effects on dopamine release, locomotion, and reinforcement. J Neurosci 30(15):5311–5325
Grady SR, Salminen O, Laverty DC, Whiteaker P, McIntosh JM, Collins AC, Marks MJ (2007) The subtypes of nicotinic acetylcholine receptors on dopaminergic terminals of mouse striatum. Biochem Pharmacol 74(8):1235–1246
Grady SR, Salminen O, McIntosh JM, Marks MJ, Collins AC (2010) Mouse striatal dopamine nerve terminals express alpha4alpha5beta2 and two stoichiometric forms of alpha4beta2∗-nicotinic acetylcholine receptors. J Mol Neurosci 40(1–2):91–95
Grady SR, Wageman CR, Patzlaff NE, Marks MJ (2012) Low concentrations of nicotine differentially desensitize nicotinic acetylcholine receptors that include alpha5 or alpha6 subunits and that mediate synaptosomal neurotransmitter release. Neuropharmacology 62(5–6):1935–1943
Graff H (1969) Marihuana and scopolamine “High”. Am J Psychiatry 125(9):1258–1259
Grucza RA, Wang JC, Stitzel JA, Hinrichs AL, Saccone SF, Saccone NL, Bucholz KK, Cloninger CR, Neuman RJ, Budde JP, Fox L, Bertelsen S, Kramer J, Hesselbrock V, Tischfield J, Nurnberger JI Jr, Almasy L, Porjesz B, Kuperman S, Schuckit MA, Edenberg HJ, Rice JP, Goate AM, Bierut LJ (2008) A risk allele for nicotine dependence in CHRNA5 is a protective allele for cocaine dependence. Biol Psychiatry 64(11):922–929
Guan ZZ, Zhang X, Blennow K, Nordberg A (1999) Decreased protein level of nicotinic receptor alpha7 subunit in the frontal cortex from schizophrenic brain. Neuroreport 10(8):1779–1782
Gulsevin A, Papke RL, Stokes C, Garai S, Thakur GA, Quadri M, Horenstein N (2019) Allosteric agonism of alpha7 nicotinic acetylcholine receptors. Mol Pharmacol 95(6):604–614
Gupta PC, Warnakulasuriya S (2002) Global epidemiology of areca nut usage. Addict Biol 7(1):77–83
Hall FS, Sora I, Drgonova J, Li XF, Goeb M, Uhl GR (2004) Molecular mechanisms underlying the rewarding effects of cocaine. Ann N Y Acad Sci 1025:47–56
Han ZY, Le Novere N, Zoli M, Hill JA Jr, Champtiaux N, Changeux JP (2000) Localization of nAChR subunit mRNAs in the brain of Macaca mulatta. Eur J Neurosci 12(10):3664–3674
Harenza JL, Muldoon PP, De Biasi M, Damaj MI, Miles MF (2014) Genetic variation within the Chrna7 gene modulates nicotine reward-like phenotypes in mice. Genes Brain Behav 13(2):213–225
Hasin DS, O’Brien CP, Auriacombe M, Borges G, Bucholz K, Budney A, Compton WM, Crowley T, Ling W, Petry NM, Schuckit M, Grant BF (2013) DSM-5 criteria for substance use disorders: recommendations and rationale. Am J Psychiatry 170(8):834–851
Heinemann S, Boulter J, Deneris E, Conolly J, Duvoisin R, Papke R, Patrick J (1990) The brain nicotinic acetylcholine receptor gene family. Prog Brain Res 86:195–203
Helekar SA, Char D, Neff S, Patrick J (1994) Prolyl isomerase requirement for the expression of functional homo-oligomeric ligand-gated ion channels. Neuron 12(1):179–189
Herzog TA, Murphy KL, Little MA, Suguitan GS, Pokhrel P, Kawamoto CT (2014) The Betel Quid Dependence Scale: replication and extension in a Guamanian sample. Drug Alcohol Depend 138:154–160
Hogg RC, Bertrand D (2007) Partial agonists as therapeutic agents at neuronal nicotinic acetylcholine receptors. Biochem Pharmacol 73(4):459–468
Hughes JR, Hatsukami DK, Mitchell JE, Dahlgren LA (1986) Prevalence of smoking among psychiatric outpatients. Am J Psychiatry 143(8):993–997
IARC (2004) Betel-quid and areca-nut chewing and some areca-nut derived nitrosamines. IARC Monogr Eval Carcinog Risks Hum 85:1–334. PMID: 15635762
Jackson KJ, McIntosh JM, Brunzell DH, Sanjakdar SS, Damaj MI (2009) The role of alpha6-containing nicotinic acetylcholine receptors in nicotine reward and withdrawal. J Pharmacol Exp Ther 331(2):547–554
Jackson A, Bagdas D, Muldoon PP, Lichtman AH, Carroll FI, Greenwald M, Miles MF, Damaj MI (2017) In vivo interactions between alpha7 nicotinic acetylcholine receptor and nuclear peroxisome proliferator-activated receptor-alpha: Implication for nicotine dependence. Neuropharmacology 118:38–45
Jain V, Garg A, Parascandola M, Chaturvedi P, Khariwala SS, Stepanov I (2017) Analysis of alkaloids in areca nut-containing products by liquid chromatography-Tandem mass spectrometry. J Agric Food Chem 65(9):1977–1983
Jaiteh M, Taly A, Henin J (2016) Evolution of pentameric ligand-gated ion channels: pro-loop receptors. PLoS One 11(3):e0151934
Jones SR, Joseph JD, Barak LS, Caron MG, Wightman RM (1999) Dopamine neuronal transport kinetics and effects of amphetamine. J Neurochem 73(6):2406–2414
Jones JD, Comer SD, Metz VE, Manubay JM, Mogali S, Ciccocioppo R, Martinez S, Mumtaz M, Bisaga A (2017) Pioglitazone, a PPARgamma agonist, reduces nicotine craving in humans, with marginal effects on abuse potential. Pharmacol Biochem Behav 163:90–100
Kem WR, Olincy A, Johnson L, Harris J, Wagner BD, Buchanan RW, Christians U, Freedman R (2017) Pharmacokinetic limitations on effects of an alpha7 nicotinic receptor agonist in schizophrenia: randomized trial with an extended release formulation. Neuropsychopharmacology 43(3):583–589
Khan MS, Bawany FI, Shah SR, Hussain M, Arshad MH, Nisar N (2013) Comparison of knowledge, attitude and practices of betelnut users in two socio-economic areas of Karachi. J Pak Med Assoc 63(10):1319–1325
Koukouli F, Rooy M, Tziotis D, Sailor KA, O’Neill HC, Levenga J, Witte M, Nilges M, Changeux JP, Hoeffer CA, Stitzel JA, Gutkin BS, DiGregorio DA, Maskos U (2017) Nicotine reverses hypofrontality in animal models of addiction and schizophrenia. Nat Med 23(3):347–354
Kumari V, Postma P (2005) Nicotine use in schizophrenia: the self medication hypotheses. Neurosci Biobehav Rev 29(6):1021–1034
Kuryatov A, Lindstrom J (2011) Expression of functional human alpha6beta2beta3∗ acetylcholine receptors in Xenopus laevis oocytes achieved through subunit chimeras and concatamers. Mol Pharmacol 79(1):126–140
Kuryatov A, Luo J, Cooper J, Lindstrom J (2005) Nicotine acts as a pharmacological chaperone to up-regulate human alpha4beta2 acetylcholine receptors. Mol Pharmacol 68(6):1839–1851
Kuryatov A, Berrettini W, Lindstrom J (2011) Acetylcholine receptor (AChR) alpha5 subunit variant associated with risk for nicotine dependence and lung cancer reduces (alpha4beta2)alpha5 AChR function. Mol Pharmacol 79(1):119–125
Lee CH, Ko AM, Yang FM, Hung CC, Warnakulasuriya S, Ibrahim SO, Zain RB, Ko YC (2018) Association of DSM-5 Betel-quid use disorder with oral potentially malignant disorder in 6 Betel-quid endemic Asian populations. JAMA Psychiat 75(3):261–269
Leonard S, Mexal S, Freedman R (2007) Smoking, genetics and schizophrenia: evidence for self medication. J Dual Diagn 3(3-4):43–59
Li MD, Yoon D, Lee JY, Han BG, Niu T, Payne TJ, Ma JZ, Park T (2010) Associations of variants in CHRNA5/A3/B4 gene cluster with smoking behaviors in a Korean population. PLoS One 5(8):e12183
Lin CC, Tami-Maury I, Ma WF, Lam C, Tsai MH, Lin MT, Li CI, Liu CS, Li TC, Chiu CF, Lu IY, Gritz ER (2017) Social and cultural context of Betel quid consumption in Taiwan and implications for prevention and cessation interventions. Subst Use Misuse 52(5):646–655
Little MA, Papke RL (2015) Betel, the orphan addiction. J Addiction Res Ther 6:130–132
Little MA, Pokhrel P, Murphy KL, Kawamoto CT, Suguitan GS, Herzog TA (2014) Intention to quit betel quid: a comparison of betel quid chewers and cigarette smokers. Oral Health Dental Manag 13(2):512–518
Liu ME, Tsai SJ, Jeang SY, Peng SL, Wu SL, Chen MC, Tsai YL, Yang ST (2011) Varenicline prevents affective and cognitive exacerbation during smoking abstinence in male patients with schizophrenia. Psychiatry Res 190(1):79–84
Liu L, Zhao-Shea R, McIntosh JM, Gardner PD, Tapper AR (2012) Nicotine persistently activates ventral tegmental area dopaminergic neurons via nicotinic acetylcholine receptors containing alpha4 and alpha6 subunits. Mol Pharmacol 81(4):541–548
Lucero LM, Weltzin MM, Eaton JB, Cooper JF, Lindstrom JM, Lukas RJ, Whiteaker P (2016) Differential alpha4(+)/(-)beta2 agonist-binding site contributions to alpha4beta2 nicotinic acetylcholine receptor function within and between isoforms. J Biol Chem 291(5):2444–2459
Luetje CW, Patrick J (1991) Both a- and b-subunits contribute to the agonist sensitivity of neuronal nicotinic acetylcholine receptors. J Neurosci 11(3):837–845
Mallet J, Le Strat Y, Schurhoff F, Mazer N, Portalier C, Andrianarisoa M, Aouizerate B, Berna F, Brunel L, Capdevielle D, Chereau I, D’Amato T, Denizot H, Dubreucq J, Faget C, Gabayet F, Lancon C, Llorca PM, Misdrahi D, Rey R, Roux P, Schandrin A, Urbach M, Vidailhet P, Fond G, Dubertret C, FACE-SZ (FondaMental Academic Centers of Expertise for Schizophrenia) Group (2017) Cigarette smoking and schizophrenia: a specific clinical and therapeutic profile? Results from the FACE-Schizophrenia cohort. Prog Neuropsychopharmacol Biol Psychiatry 79(Pt B):332–339
Mansvelder HD, Keath JR, McGehee DS (2002) Synaptic mechanisms underlie nicotine-induced excitability of brain reward areas. Neuron 33(6):905–919
Markou A, Paterson NE (2001) The nicotinic antagonist methyllycaconitine has differential effects on nicotine self-administration and nicotine withdrawal in the rat. Nicotine Tob Res 3(4):361–373
Marubio LM, Changeux J (2000) Nicotinic acetylcholine receptor knockout mice as animal models for studying receptor function. Eur J Pharmacol 393(1–3):113–121
Maskos U, Molles BE, Pons S, Besson M, Guiard BP, Guilloux JP, Evrard A, Cazala P, Cormier A, Mameli-Engvall M, Dufour N, Cloez-Tayarani I, Bemelmans AP, Mallet J, Gardier AM, David V, Faure P, Granon S, Changeux JP (2005) Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors. Nature 436(7047):103–107
Mehrtash H, Duncan K, Parascandola M, David A, Gritz ER, Gupta PC, Mehrotra R, Amer Nordin AS, Pearlman PC, Warnakulasuriya S, Wen CP, Zain RB, Trimble EL (2017) Defining a global research and policy agenda for betel quid and areca nut. Lancet Oncol 18(12):e767–e775
Melis M, Scheggi S, Carta G, Madeddu C, Lecca S, Luchicchi A, Cadeddu F, Frau R, Fattore L, Fadda P, Ennas MG, Castelli MP, Fratta W, Schilstrom B, Banni S, De Montis MG, Pistis M (2013) PPARalpha regulates cholinergic-driven activity of midbrain dopamine neurons via a novel mechanism involving alpha7 nicotinic acetylcholine receptors. J Neurosci 33(14):6203–6211
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(3):801–805
Millar NS, Gotti C (2009) Diversity of vertebrate nicotinic acetylcholine receptors. Neuropharmacology 56(1):237–246
Miller DK, Sumithran SP, Dwoskin LP (2002) Bupropion inhibits nicotine-evoked [(3)H]overflow from rat striatal slices preloaded with [(3)H]dopamine and from rat hippocampal slices preloaded with [(3)H]norepinephrine. J Pharmacol Exp Ther 302(3):1113–1122
Mogg AJ, Whiteaker P, McIntosh JM, Marks M, Collins AC, Wonnacott S (2002) Methyllycaconitine is a potent antagonist of alpha-conotoxin-MII-sensitive presynaptic nicotinic acetylcholine receptors in rat striatum. J Pharmacol Exp Ther 302(1):197–204
Mokdad AH, Marks JS, Stroup DF, Gerberding JL (2004) Actual causes of death in the United States, 2000. JAMA 291(10):1238–1245
Morel C, Fattore L, Pons S, Hay YA, Marti F, Lambolez B, De Biasi M, Lathrop M, Fratta W, Maskos U, Faure P (2014) Nicotine consumption is regulated by a human polymorphism in dopamine neurons. Mol Psychiatry 19(8):930–936
Moroni M, Zwart R, Sher E, Cassels BK, Bermudez I (2006) alpha4beta2 nicotinic receptors with high and low acetylcholine sensitivity: pharmacology, stoichiometry, and sensitivity to long-term exposure to nicotine. Mol Pharmacol 70(2):755–768
Murphy KL, Herzog TA (2015) Sociocultural factors that affect chewing behaviors among betel nut chewers and ex-chewers on Guam. Hawai’i J Med Publ Health 74(12):406–411
Murray TA, Bertrand D, Papke RL, George AA, Pantoja R, Srinivasan R, Liu Q, Wu J, Whiteaker P, Lester HA, Lukas RJ (2012) alpha7beta2 nicotinic acetylcholine receptors assemble, function, and are activated primarily via their alpha7-alpha7 interfaces. Mol Pharmacol 81(2):175–188
Nadalin S, Buretic-Tomljanovic A, Rebic J, Plesa I, Sendula Jengic V (2016) An association between the PPARalpha-L162V polymorphism and nicotine dependency among patients with schizophrenia. Compr Psychiatry 70:118–124
Nelson BS, Heischober B (1999) Betel nut: a common drug used by naturalized citizens from India, Far East Asia, and the South Pacific Islands. Ann Emerg Med 34(2):238–243
Nelson ME, Kuryatov A, Choi CH, Zhou Y, Lindstrom J (2003) Alternate stoichiometries of alpha4beta2 nicotinic acetylcholine receptors. Mol Pharmacol 63(2):332–341
Notley C, Ward E, Dawkins L, Holland R (2018) The unique contribution of e-cigarettes for tobacco harm reduction in supporting smoking relapse prevention. Harm Reduct J 15(1):31
O’Neill HC, Wageman CR, Sherman SE, Grady SR, Marks MJ, Stitzel JA (2018) The interaction of the Chrna5 D398N variant with developmental nicotine exposure. Genes Brain Behav 17(7):e12474
Ortells MO, Lunt GG (1995) Evolutionary history of the ligand-gated ion-channel superfamily of receptors. Trends Neurosci 18(3):121–127
Oxenham MF, Locher C, Nguyen LC, Nguyen KT (2002) Identification of Areca catechu (betel nut) residues on the dentitions of bronze age inhabitants of Nui Nap, Northern Vietnam. J Archeol Sci 29:909–915
Pachas GN, Cather C, Pratt SA, Hoeppner B, Nino J, Carlini SV, Achtyes ED, Lando H, Mueser KT, Rigotti NA, Goff DC, Evins AE (2012) Varenicline for smoking cessation in Schizophrenia: safety and effectiveness in a 12-week, open-label trial. J Dual Diagn 8(2):117–125
Palma E, Bertrand S, Binzoni T, Bertrand D (1996) Neuronal nicotinic alpha 7 receptor expressed in Xenopus oocytes presents five putative binding sites for methyllycaconitine. J Physiol 491:151–161
Papke RL (2014) Merging old and new perspectives on nicotinic acetylcholine receptors. Biochem Pharmacol 89(1):1–11
Papke RL, Heinemann SF (1994) The partial agonist properties of cytisine on neuronal nicotinic receptors containing the beta2 subunit. Mol Pharm 45:142–149
Papke RL, Papke JKP (2002) Comparative pharmacology of rat and human alpha7 nAChR conducted with net charge analysis. Br J Pharmacol 137(1):49–61
Papke RL, Stokes C (2010) Working with OpusXpress: methods for high volume oocyte experiments. Methods 51(1):121–133
Papke RL, Boulter J, Patrick J, Heinemann S (1989) Single-channel currents of rat neuronal nicotinic acetylcholine receptors expressed in Xenopus laevis oocytes. Neuron 3:589–596
Papke RL, Dwoskin LP, Crooks PA, Zheng G, Zhang Z, McIntosh JM, Stokes C (2008) Extending the analysis of nicotinic receptor antagonists with the study of alpha6 nicotinic receptor subunit chimeras. Neuropharmacology 54(8):1189–1200
Papke RL, Trocme-Thibierge C, Guendisch D, Abbas Al Rubaiy SA, Bloom SA (2011) Electrophysiological perspectives on the therapeutic use of nicotinic acetylcholine receptor partial agonists. J Pharmacol Exp Ther 337(2):367–379
Papke RL, Stokes C, Muldoon P, Imad Damaj M (2013) Similar activity of mecamylamine stereoisomers in vitro and in vivo. Eur J Pharmacol 720(1-3):264–275
Papke RL, Horenstein NA, Stokes C (2015) Nicotinic activity of arecoline, the psychoactive element of “Betel Nuts”, suggests a basis for habitual use and anti-inflammatory activity. PLoS One 10(10):e0140907
Papke RL, Bhattacharyya I, Hatsukami DK, Moe I, Glatman S (2019) Betel nut (areca) and smokeless tobacco use in Myanmar. Subst Use Misuse 54(10):1–10
Patidar KA, Parwani R, Wanjari SP, Patidar AP (2015) Various terminologies associated with areca nut and tobacco chewing: a review. J Oral Maxillofac Pathol 19(1):69–76
Peng C, Engle SE, Yan Y, Weera MM, Berry JN, Arvin MC, Zhao G, McIntosh JM, Chester JA, Drenan RM (2017) Altered nicotine reward-associated behavior following alpha4 nAChR subunit deletion in ventral midbrain. PLoS One 12(7):e0182142
Perkins KA, Karelitz JL, Boldry MC (2017) Nicotine acutely enhances reinforcement from non-drug rewards in humans. Front Psych 8:65
Perry DC, Davila-Garcia MI, Stockmeier CA, Kellar KJ (1999) Increased nicotinic receptors in brains from smokers: membrane binding and autoradiography studies. J Pharmacol Exp Ther 289(3):1545–1552
Picciotto MR, Mineur YS (2014) Molecules and circuits involved in nicotine addiction: the many faces of smoking. Neuropharmacology 76(Pt B):545–553
Picciotto M, Zoli M, Rimondini R, Lena C, Marubio L, Pich E, Fuxe K, Changeux J (1998) Acetylcholine receptors containing the beta2 subunit are involved in the reinforcing properties of nicotine. Nature 391:173–177
Pillai SG, Ge D, Zhu G, Kong X, Shianna KV, Need AC, Feng S, Hersh CP, Bakke P, Gulsvik A, Ruppert A, Lodrup Carlsen KC, Roses A, Anderson W, Rennard SI, Lomas DA, Silverman EK, Goldstein DB, Investigators I (2009) A genome-wide association study in chronic obstructive pulmonary disease (COPD): identification of two major susceptibility loci. PLoS Genet 5(3):e1000421
Pobutsky AM, Neri EI (2012) Betel nut chewing in Hawai’i: is it becoming a public health problem? Historical and socio-cultural considerations. Hawai’i J Med Publ Health 71(1):23–26
Pons S, Fattore L, Cossu G, Tolu S, Porcu E, McIntosh JM, Changeux JP, Maskos U, Fratta W (2008) Crucial role of alpha4 and alpha6 nicotinic acetylcholine receptor subunits from ventral tegmental area in systemic nicotine self-administration. J Neurosci 28(47):12318–12327
Raghavan V, Baruah HK (1958) Arecanut: India’s popular masticatory history, chemistry and utilization. Econ Bot 12(4):315–345
Rahman S, Zhang Z, Papke RL, Crooks PA, Dwoskin LP, Bardo MT (2007) Region-specific effects of N,N'-dodecane-1,12-diyl-bis-3-picolinium dibromide on nicotine-induced increase in extracellular dopamine in vivo. Br J Pharmacol 153(4):792–804
Rakhilin S, Drisdel RC, Sagher D, McGehee DS, Vallejo Y, Green WN (1999) alpha-bungarotoxin receptors contain alpha7 subunits in two different disulfide-bonded conformations. J Cell Biol 146(1):203–218
Ramirez-Latorre J, Yu CR, Qu X, Perin F, Karlin A, Role L (1996) Functional contributions of alpha5 subunit to neuronal acetylcholine receptor channels. Nature 380(6572):347–351
Robinson TE, Berridge KC (2003) Addiction. Annu Rev Psychol 54:25–53
Robinson JH, Pritchard WS (1992) The role of nicotine in tobacco use. Psychopharmacology (Berl) 108(4):397–407
Rooney DF (1993) Betel chewing traditions in South-East Asia. Oxford University Press, Kuala Lumpur
Rose JE, Levin ED, Behm FM, Adivi C, Schur C (1990) Transdermal nicotine facilitates smoking cessation. Clin Pharmacol Ther 47(3):323–330
Saccone NL, Wang JC, Breslau N, Johnson EO, Hatsukami D, Saccone SF, Grucza RA, Sun L, Duan W, Budde J, Culverhouse RC, Fox L, Hinrichs AL, Steinbach JH, Wu M, Rice JP, Goate AM, Bierut LJ (2009) The CHRNA5-CHRNA3-CHRNB4 nicotinic receptor subunit gene cluster affects risk for nicotine dependence in African-Americans and in European-Americans. Cancer Res 69(17):6848–6856
Salas R, Orr-Urtreger A, Broide RS, Beaudet A, Paylor R, De Biasi M (2003) The nicotinic acetylcholine receptor subunit alpha 5 mediates short-term effects of nicotine in vivo. Mol Pharmacol 63(5):1059–1066
Salas R, Sturm R, Boulter J, De Biasi M (2009) Nicotinic receptors in the habenulo-interpeduncular system are necessary for nicotine withdrawal in mice. J Neurosci 29(10):3014–3018
Sanjakdar SS, Maldoon PP, Marks MJ, Brunzell DH, Maskos U, McIntosh JM, Bowers MS, Damaj MI (2015) Differential roles of alpha6beta2∗ and alpha4beta2∗ neuronal nicotinic receptors in nicotine- and cocaine-conditioned reward in mice. Neuropsychopharmacology 40(2):350–360
Schlaepfer IR, Hoft NR, Collins AC, Corley RP, Hewitt JK, Hopfer CJ, Lessem JM, McQueen MB, Rhee SH, Ehringer MA (2008) The CHRNA5/A3/B4 gene cluster variability as an important determinant of early alcohol and tobacco initiation in young adults. Biol Psychiatry 63(11):1039–1046
Schuster RM, Pachas GN, Stoeckel L, Cather C, Nadal M, Mischoulon D, Schoenfeld DA, Zhang H, Ulysse C, Dodds EB, Sobolewski S, Hudziak V, Hanly A, Fava M, Evins AE (2018) Phase IIb trial of an alpha7 nicotinic receptor partial agonist with and without nicotine patch for withdrawal-associated cognitive deficits and tobacco abstinence. J Clin Psychopharmacol 38(4):307–316
Sciaccaluga M, Moriconi C, Martinello K, Catalano M, Bermudez I, Stitzel JA, Maskos U, Fucile S (2015) Crucial role of nicotinic alpha5 subunit variants for Ca2+ fluxes in ventral midbrain neurons. FASEB J 29(8):3389–3398
Seguela P, Wadiche J, Dinely-Miller K, Dani JA, Patrick JW (1993) Molecular cloning, functional properties and distribution of rat brain alpha 7: a nicotinic cation channel highly permeable to calcium. J Neurosci 13(2):596–604
Sivilotti LG, McNeil DK, Lewis TM, Nassar MA, Schoepfer R, Colquhoun D (1997) Recombinant nicotinic receptors, expressed in Xenopus oocytes, do not resemble native rat sympathetic ganglion receptors in single-channel behaviour. J Physiol 500(Pt 1):123–138
Skok VI (2002) Nicotinic acetylcholine receptors in autonomic ganglia. Auton Neurosci 97(1):1–11
Slemmer JE, Martin BR, Damaj MI (2000) Bupropion is a nicotinic antagonist. J Pharmacol Exp Ther 295(1):321–327
Smit AB, Syed NI, Schaap D, van Minnen J, Klumperman J, Kits KS, Lodder H, van der Schors RC, van Elk R, Sorgedrager B, Brejc K, Sixma TK, Geraerts WP (2001) A glia-derived acetylcholine-binding protein that modulates synaptic transmission. Nature 411(6835):261–268
Smith TT, Hatsukami DK, Benowitz NL, Colby SM, McClernon FJ, Strasser AA, Tidey JW, White CM, Donny EC (2018) Whether to push or pull? Nicotine reduction and non-combusted alternatives – two strategies for reducing smoking and improving public health. Prev Med 117:8–14
Stevens VL, Bierut LJ, Talbot JT, Wang JC, Sun J, Hinrichs AL, Thun MJ, Goate A, Calle EE (2008) Nicotinic receptor gene variants influence susceptibility to heavy smoking. Cancer Epidemiol Biomarkers Prev 17(12):3517–3525
Stolerman IP, Shoaib M (1991) The neurobiology of tobacco addiction. Trends Pharmacol Sci 12:467–473
Tammimaki A, Herder P, Li P, Esch C, Laughlin JR, Akk G, Stitzel JA (2012) Impact of human D398N single nucleotide polymorphism on intracellular calcium response mediated by alpha3beta4alpha5 nicotinic acetylcholine receptors. Neuropharmacology 63(6):1002–1011
Tapper AR, McKinney SL, Nashmi R, Schwarz J, Deshpande P, Labarca C, Whiteaker P, Marks MJ, Collins AC, Lester HA (2004) Nicotine activation of alpha4∗ receptors: sufficient for reward, tolerance, and sensitization. Science 306(5698):1029–1032
Threlfell S, Lalic T, Platt NJ, Jennings KA, Deisseroth K, Cragg SJ (2012) Striatal dopamine release is triggered by synchronized activity in cholinergic interneurons. Neuron 75(1):58–64
Tregellas JR, Olincy A, Johnson L, Tanabe J, Shatti S, Martin LF, Singel D, Du YP, Soti F, Kem WR, Freedman R (2010) Functional magnetic resonance imaging of effects of a nicotinic agonist in Schizophrenia. Neuropsychopharmacology 35(4):938–942
Uhl GR, Hall FS, Sora I (2002) Cocaine, reward, movement and monoamine transporters. Mol Psychiatry 7(1):21–26
Uteshev VV, Meyer EM, Papke RL (2002) Activation and inhibition of native neuronal alpha-bungarotoxin-sensitive nicotinic ACh receptors. Brain Res 948(1-2):33–46
Vailati S, Moretti M, Longhi R, Rovati GE, Clementi F, Gotti C (2003) Developmental expression of heteromeric nicotinic receptor subtypes in chick retina. Mol Pharmacol 63(6):1329–1337
Wada E, Wada K, Boulter J, Deneris E, Heinemann S, Patrick J, Swanson LW (1989) Distribution of alpha2, alpha3, alpha4, and beta2 neuronal nicotinic receptor subunit mRNAs in the central nervous system: a hybridization histochemical study in the rat. J Comp Neurol 284:314–335
Walling D, Marder SR, Kane J, Fleischhacker WW, Keefe RS, Hosford DA, Dvergsten C, Segreti AC, Beaver JS, Toler SM, Jett JE, Dunbar GC (2016) Phase 2 trial of an alpha-7 nicotinic receptor agonist (TC-5619) in negative and cognitive symptoms of Schizophrenia. Schizophr Bull 42(2):335–343
Walters CL, Brown S, Changeux JP, Martin B, Damaj MI (2006) The beta2 but not alpha7 subunit of the nicotinic acetylcholine receptor is required for nicotine-conditioned place preference in mice. Psychopharmacology (Berl) 184(3–4):339–344
Wang J, Lindstrom J (2017) Orthosteric and allosteric potentiation of heteromeric neuronal nicotinic acetylcholine receptors. Br J Pharmacol 175(11):1805–1821
Wang F, Gerzanich V, Wells GB, Anand R, Peng X, Keyser K, Lindstrom J (1996) Assembly of human neuronal nicotinic receptor alpha5 subunits with alpha3, beta2, and beta4 subunits. J Biol Chem 271(30):17656–17665
Wang Y, Lee JW, Oh G, Grady SR, McIntosh JM, Brunzell DH, Cannon JR, Drenan RM (2014) Enhanced synthesis and release of dopamine in transgenic mice with gain-of-function alpha6∗ nAChRs. J Neurochem 129(2):315–327
Williams DK, Stokes C, Horenstein NA, Papke RL (2011) The effective opening of nicotinic acetylcholine receptors with single agonist binding sites. J Gen Physiol 137(4):369–384
Williams DK, Peng C, Kimbrell MR, Papke RL (2012a) The intrinsically low open probability of alpha7 nAChR can be overcome by positive allosteric modulation and serum factors leading to the generation of excitotoxic currents at physiological temperatures. Mol Pharmacol 82(4):746–759
Williams JM, Anthenelli RM, Morris CD, Treadow J, Thompson JR, Yunis C, George TP (2012b) A randomized, double-blind, placebo-controlled study evaluating the safety and efficacy of varenicline for smoking cessation in patients with schizophrenia or schizoaffective disorder. J Clin Psychiatry 73(5):654–660
Zoli M, Pucci S, Vilella A, Gotti C (2018) Neuronal and extraneuronal nicotinic acetylcholine receptors. Curr Neuropharmacol 16(4):338–349
Acknowledgments
RLP is supported by NIH RO1 GM57481, DHB is supported by NIH RO1 DA042749, and MDB is supported by NIH RO1 DA044205 and UO1 AA025931.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2020 Springer Nature Switzerland AG
About this chapter
Cite this chapter
Papke, R.L., Brunzell, D.H., De Biasi, M. (2020). Cholinergic Receptors and Addiction. In: Shoaib, M., Wallace, T. (eds) Behavioral Pharmacology of the Cholinergic System. Current Topics in Behavioral Neurosciences, vol 45. Springer, Cham. https://doi.org/10.1007/7854_2020_139
Download citation
DOI: https://doi.org/10.1007/7854_2020_139
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-56012-6
Online ISBN: 978-3-030-56013-3
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)