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Nicotinic Acetylcholine Receptors Along the Habenulo-Interpeduncular Pathway: Roles in Nicotine Withdrawal and Other Aversive Aspects

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Nicotinic Receptors

Part of the book series: The Receptors ((REC,volume 26))

Abstract

Addiction to tobacco smoking is a deadly disease that consumes millions of lives each year. However, the neurobiology underlying the disease remains an enigma. One reason for this is the relative complexity of nicotine’s effects on the brain, with a multitude of targets throughout many different brain regions, each subserving individual components of the disease. Still, a handful of brain circuits mediate particularly significant roles in the disease. The epithalamic habenulo-interpeduncular (Hb-IPN) pathway participates in the aversive aspects of nicotine dependence, including the aversive experience of nicotine withdrawal. Many hypotheses regarding the exact mechanisms for these behavioral roles exist, but the convergent feature of those hypotheses is that nicotine acts at populations of nicotinic acetylcholine receptors (nAChRs) across the brain, including the Hb-IPN pathway. Of note, the Hb-IPN pathway is one of the brain regions with the highest density of nAChRs, including both heteromeric (e.g., α3β4 and α4β2) and homomeric (i.e., α7) receptors. As nAChR subtypes that subserve multiple aspects of affective and reinforcement behaviors are expressed along this pathway, it is of no surprise that the Hb-IPN pathway participates in similar affective behaviors. This chapter will discuss the roles of nAChRs along the Hb-IPN in aversive nicotine-associated behaviors, as well as touch upon the innate roles of those populations of nAChRs over biology and behavior in healthy animals.

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References

  1. Vineis P, Alavanja M, Buffler P, et al. Tobacco and cancer: recent epidemiological evidence. J Natl Cancer Inst. 2004;96(2):99–106.

    CAS  PubMed  Google Scholar 

  2. Kenfield SA, Stampfer MJ, Rosner BA, Colditz GA. Smoking and smoking cessation in relation to mortality in women. JAMA. 2008;299(17):2037–47.

    CAS  PubMed Central  PubMed  Google Scholar 

  3. Benowitz NL. Pharmacology of nicotine: addiction, smoking-induced disease, and therapeutics. Annu Rev Pharmacol Toxicol. 2009;49:57–71.

    CAS  PubMed Central  PubMed  Google Scholar 

  4. Tonini G, D’Onofrio L, Dell’Aquila E, Pezzuto A. New molecular insights in tobacco-induced lung cancer. Future Oncol. 2013;9(5):649–55.

    CAS  PubMed  Google Scholar 

  5. Giovino GA, Mirza SA, Samet JM, et al. Tobacco use in 3 billion individuals from 16 countries: an analysis of nationally representative cross-sectional household surveys. Lancet. 2012;380(9842):668–79.

    PubMed  Google Scholar 

  6. Kabir MA, Goh KL, Khan MH. A cross-country comparison of tobacco consumption among youths from selected South-Asian countries. BMC Public Health. 2013;13(1):379.

    PubMed Central  PubMed  Google Scholar 

  7. Dani JA, Bertrand D. Nicotinic acetylcholine receptors and nicotinic cholinergic mechanisms of the central nervous system. Annu Rev Pharmacol Toxicol. 2007;47:699–729.

    CAS  PubMed  Google Scholar 

  8. Mansvelder HD, McGehee DS. Cellular and synaptic mechanisms of nicotine addiction. J Neurobiol. 2002;53(4):606–17.

    CAS  PubMed  Google Scholar 

  9. De Biasi M, Dani JA. Reward, addiction, withdrawal to nicotine. Annu Rev Neurosci. 2011;34:105–30.

    PubMed Central  PubMed  Google Scholar 

  10. Piasecki TM, Jorenby DE, Smith SS, Fiore MC, Baker TB. Smoking withdrawal dynamics: I. Abstinence distress in lapsers and abstainers. J Abnorm Psychol. 2003;112(1):3–13.

    PubMed  Google Scholar 

  11. Hughes JR. Effects of abstinence from tobacco: valid symptoms and time course. Nicotine Tob Res. 2007;9(3):315–27.

    PubMed  Google Scholar 

  12. al’Absi M, Amunrud T, Wittmers LE. Psychophysiological effects of nicotine abstinence and behavioral challenges in habitual smokers. Pharmacol Biochem Behav. 2002;72(3):707–16.

    PubMed  Google Scholar 

  13. Swan GE, Ward MM, Jack LM. Abstinence effects as predictors of 28-day relapse in smokers. Addict Behav. 1996;21(4):481–90.

    CAS  PubMed  Google Scholar 

  14. De Biasi M, Salas R. Influence of neuronal nicotinic receptors over nicotine addiction and withdrawal. Exp Biol Med (Maywood). 2008;233(8):917–29.

    Google Scholar 

  15. Drenan RM, Lester HA. Insights into the neurobiology of the nicotinic cholinergic system and nicotine addiction from mice expressing nicotinic receptors harboring gain-of-function mutations. Pharmacol Rev. 2012;64(4):869–79.

    CAS  PubMed Central  PubMed  Google Scholar 

  16. Jasinska AJ, Zorick T, Brody AL, Stein EA. Dual role of nicotine in addiction and cognition: a review of neuroimaging studies in humans. Neuropharmacology. 2014;84C:111–22.

    Google Scholar 

  17. Role LW, Berg DK. Nicotinic receptors in the development and modulation of CNS synapses. Neuron. 1996;16(6):1077–85.

    CAS  PubMed  Google Scholar 

  18. Picciotto MR, Mineur YS. Molecules and circuits involved in nicotine addiction: the many faces of smoking. Neuropharmacology. 2014;76:543–53.

    Google Scholar 

  19. McGehee DS, Role LW. Physiological diversity of nicotinic acetylcholine receptors expressed by vertebrate neurons. Annu Rev Physiol. 1995;57:521–46.

    CAS  PubMed  Google Scholar 

  20. Alkondon M, Pereira EF, Barbosa CT, Albuquerque EX. Neuronal nicotinic acetylcholine receptor activation modulates gamma-aminobutyric acid release from CA1 neurons of rat hippocampal slices. J Pharmacol Exp Ther. 1997;283(3):1396–411.

    CAS  PubMed  Google Scholar 

  21. Tomizawa M, Casida JE. Structure and diversity of insect nicotinic acetylcholine receptors. Pest Manag Sci. 2001;57(10):914–22.

    CAS  PubMed  Google Scholar 

  22. Kent WJ, Sugnet CW, Furey TS, et al. The human genome browser at UCSC. Genome Res. 2002;12(6):996–1006.

    CAS  PubMed Central  PubMed  Google Scholar 

  23. Meyer LR, Zweig AS, Hinrichs AS, et al. The UCSC Genome Browser database: extensions and updates 2013. Nucleic Acids Res. 2013;41(Database issue):D64–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  24. Nelson ME, Lindstrom J. Single channel properties of human alpha3 AChRs: impact of beta2, beta4 and alpha5 subunits. J Physiol. 1999;516(Pt 3):657–78.

    CAS  PubMed Central  PubMed  Google Scholar 

  25. Peng X, Gerzanich V, Anand R, Wang F, Lindstrom J. Chronic nicotine treatment up-regulates alpha3 and alpha7 acetylcholine receptor subtypes expressed by the human neuroblastoma cell line SH-SY5Y. Mol Pharmacol. 1997;51(5):776–84.

    CAS  PubMed  Google Scholar 

  26. Tapia L, Kuryatov A, Lindstrom J. Ca2+ permeability of the (alpha4)3(beta2)2 stoichiometry greatly exceeds that of (alpha4)2(beta2)3 human acetylcholine receptors. Mol Pharmacol. 2007;71(3):769–76.

    CAS  PubMed  Google Scholar 

  27. Wang F, Gerzanich V, Wells GB, et al. Assembly of human neuronal nicotinic receptor alpha5 subunits with alpha3, beta2, and beta4 subunits. J Biol Chem. 1996;271(30):17656–65.

    CAS  PubMed  Google Scholar 

  28. Gerzanich V, Wang F, Kuryatov A, Lindstrom J. alpha 5 Subunit alters desensitization, pharmacology, Ca++ permeability and Ca++ modulation of human neuronal alpha 3 nicotinic receptors. J Pharmacol Exp Ther. 1998;286(1):311–20.

    CAS  PubMed  Google Scholar 

  29. Kuryatov A, Berrettini W, Lindstrom J. Acetylcholine receptor (AChR) alpha5 subunit variant associated with risk for nicotine dependence and lung cancer reduces (alpha4beta2)(2)alpha5 AChR function. Mol Pharmacol. 2011;79(1):119–25.

    CAS  PubMed Central  PubMed  Google Scholar 

  30. Albuquerque EX, Pereira EF, Alkondon M, Rogers SW. Mammalian nicotinic acetylcholine receptors: from structure to function. Physiol Rev. 2009;89(1):73–120.

    CAS  PubMed Central  PubMed  Google Scholar 

  31. Woolf NJ. Cholinergic systems in mammalian brain and spinal cord. Prog Neurobiol. 1991;37(6):475–524.

    CAS  PubMed  Google Scholar 

  32. Miwa JM, Freedman R, Lester HA. Neural systems governed by nicotinic acetylcholine receptors: emerging hypotheses. Neuron. 2011;70(1):20–33.

    CAS  PubMed  Google Scholar 

  33. Sutherland RJ. The dorsal diencephalic conduction system: a review of the anatomy and functions of the habenular complex. Neurosci Biobehav Rev. 1982;6(1):1–13.

    CAS  PubMed  Google Scholar 

  34. Fowler CD, Lu Q, Johnson PM, Marks MJ, Kenny PJ. Habenular alpha5 nicotinic receptor subunit signalling controls nicotine intake. Nature. 2011;471(7340):597–601.

    CAS  PubMed Central  PubMed  Google Scholar 

  35. Salas R, Baldwin P, de Biasi M, Montague PR. BOLD responses to negative reward prediction errors in human habenula. Front Hum Neurosci. 2010;4:36.

    PubMed Central  PubMed  Google Scholar 

  36. Karlin A. Emerging structure of the nicotinic acetylcholine receptors. Nat Rev Neurosci. 2002;3(2):102–14.

    CAS  PubMed  Google Scholar 

  37. Sine SM. The nicotinic receptor ligand binding domain. J Neurobiol. 2002;53(4):431–46.

    CAS  PubMed  Google Scholar 

  38. Galzi JL, Devillers-Thiery A, Hussy N, Bertrand S, Changeux JP, Bertrand D. Mutations in the channel domain of a neuronal nicotinic receptor convert ion selectivity from cationic to anionic. Nature. 1992;359(6395):500–5.

    CAS  PubMed  Google Scholar 

  39. Berridge MJ, Lipp P, Bootman MD. The versatility and universality of calcium signalling. Nat Rev Mol Cell Biol. 2000;1(1):11–21.

    CAS  PubMed  Google Scholar 

  40. Bootman MD, Berridge MJ, Roderick HL. Calcium signalling: more messengers, more channels, more complexity. Curr Biol. 2002;12(16):R563–5.

    CAS  PubMed  Google Scholar 

  41. Sudhof TC. Calcium control of neurotransmitter release. Cold Spring Harb Perspect Biol. 2012;4(1):a011353.

    PubMed Central  PubMed  Google Scholar 

  42. Ross WN. Understanding calcium waves and sparks in central neurons. Nat Rev Neurosci. 2012;13(3):157–68.

    CAS  PubMed  Google Scholar 

  43. Seguela P, Wadiche J, Dineley-Miller K, Dani JA, Patrick JW. Molecular cloning, functional properties, and distribution of rat brain alpha 7: a nicotinic cation channel highly permeable to calcium. J Neurosci. 1993;13(2):596–604.

    CAS  PubMed  Google Scholar 

  44. Bertrand D, Galzi JL, Devillers-Thiery A, Bertrand S, Changeux JP. Mutations at two distinct sites within the channel domain M2 alter calcium permeability of neuronal alpha 7 nicotinic receptor. Proc Natl Acad Sci U S A. 1993;90(15):6971–5.

    CAS  PubMed Central  PubMed  Google Scholar 

  45. Kuryatov A, Gerzanich V, Nelson M, Olale F, Lindstrom J. Mutation causing autosomal dominant nocturnal frontal lobe epilepsy alters Ca2+ permeability, conductance, and gating of human alpha4beta2 nicotinic acetylcholine receptors. J Neurosci. 1997;17(23):9035–47.

    CAS  PubMed  Google Scholar 

  46. Shen JX, Yakel JL. Nicotinic acetylcholine receptor-mediated calcium signaling in the nervous system. Acta Pharmacol Sin. 2009;30(6):673–80.

    CAS  PubMed Central  PubMed  Google Scholar 

  47. McGehee DS, Heath MJ, Gelber S, Devay P, Role LW. Nicotine enhancement of fast excitatory synaptic transmission in CNS by presynaptic receptors. Science. 1995;269(5231):1692–6.

    CAS  PubMed  Google Scholar 

  48. Garduno J, Galindo-Charles L, Jimenez-Rodriguez J, et al. Presynaptic alpha4beta2 nicotinic acetylcholine receptors increase glutamate release and serotonin neuron excitability in the dorsal raphe nucleus. J Neurosci. 2012;32(43):15148–57.

    CAS  PubMed  Google Scholar 

  49. Griguoli M, Scuri R, Ragozzino D, Cherubini E. Activation of nicotinic acetylcholine receptors enhances a slow calcium-dependent potassium conductance and reduces the firing of stratum oriens interneurons. Eur J Neurosci. 2009;30(6):1011–22.

    PubMed  Google Scholar 

  50. Ji D, Dani JA. Inhibition and disinhibition of pyramidal neurons by activation of nicotinic receptors on hippocampal interneurons. J Neurophysiol. 2000;83(5):2682–90.

    CAS  PubMed  Google Scholar 

  51. Hu M, Liu QS, Chang KT, Berg DK. Nicotinic regulation of CREB activation in hippocampal neurons by glutamatergic and nonglutamatergic pathways. Mol Cell Neurosci. 2002;21(4):616–25.

    CAS  PubMed  Google Scholar 

  52. McKay BE, Placzek AN, Dani JA. Regulation of synaptic transmission and plasticity by neuronal nicotinic acetylcholine receptors. Biochem Pharmacol. 2007;74(8):1120–33.

    CAS  PubMed Central  PubMed  Google Scholar 

  53. Dani JA, Radcliffe KA, Pidoplichko VI. Variations in desensitization of nicotinic acetylcholine receptors from hippocampus and midbrain dopamine areas. Eur J Pharmacol. 2000;393(1–3):31–8.

    CAS  PubMed  Google Scholar 

  54. Quick MW, Lester RA. Desensitization of neuronal nicotinic receptors. J Neurobiol. 2002;53(4):457–78.

    CAS  PubMed  Google Scholar 

  55. Wooltorton JR, Pidoplichko VI, Broide RS, Dani JA. Differential desensitization and distribution of nicotinic acetylcholine receptor subtypes in midbrain dopamine areas. J Neurosci. 2003;23(8):3176–85.

    CAS  PubMed  Google Scholar 

  56. Giniatullin R, Nistri A, Yakel JL. Desensitization of nicotinic ACh receptors: sha** cholinergic signaling. Trends Neurosci. 2005;28(7):371–8.

    CAS  PubMed  Google Scholar 

  57. Briggs CA, McKenna DG. Activation and inhibition of the human alpha7 nicotinic acetylcholine receptor by agonists. Neuropharmacology. 1998;37(9):1095–102.

    CAS  PubMed  Google Scholar 

  58. Papke RL, Porter Papke JK. Comparative pharmacology of rat and human alpha7 nAChR conducted with net charge analysis. Br J Pharmacol. 2002;137(1):49–61.

    CAS  PubMed Central  PubMed  Google Scholar 

  59. Fenster CP, Rains MF, Noerager B, Quick MW, Lester RA. Influence of subunit composition on desensitization of neuronal acetylcholine receptors at low concentrations of nicotine. J Neurosci. 1997;17(15):5747–59.

    CAS  PubMed  Google Scholar 

  60. Paradiso KG, Steinbach JH. Nicotine is highly effective at producing desensitization of rat alpha4beta2 neuronal nicotinic receptors. J Physiol. 2003;553(Pt 3):857–71.

    CAS  PubMed Central  PubMed  Google Scholar 

  61. Brody AL, Mandelkern MA, London ED, et al. Cigarette smoking saturates brain alpha 4 beta 2 nicotinic acetylcholine receptors. Arch Gen Psychiatry. 2006;63(8):907–15.

    CAS  PubMed Central  PubMed  Google Scholar 

  62. Khiroug L, Giniatullin R, Sokolova E, Talantova M, Nistri A. Imaging of intracellular calcium during desensitization of nicotinic acetylcholine receptors of rat chromaffin cells. Br J Pharmacol. 1997;122(7):1323–32.

    CAS  PubMed Central  PubMed  Google Scholar 

  63. Khiroug L, Sokolova E, Giniatullin R, Afzalov R, Nistri A. Recovery from desensitization of neuronal nicotinic acetylcholine receptors of rat chromaffin cells is modulated by intracellular calcium through distinct second messengers. J Neurosci. 1998;18(7):2458–66.

    CAS  PubMed  Google Scholar 

  64. Guo X, Lester RA. Regulation of nicotinic acetylcholine receptor desensitization by Ca2+. J Neurophysiol. 2007;97(1):93–101.

    CAS  PubMed  Google Scholar 

  65. Rezvani K, Teng Y, Shim D, De Biasi M. Nicotine regulates multiple synaptic proteins by inhibiting proteasomal activity. J Neurosci. 2007;27(39):10508–19.

    CAS  PubMed  Google Scholar 

  66. Lester HA, **ao C, Srinivasan R, et al. Nicotine is a selective pharmacological chaperone of acetylcholine receptor number and stoichiometry. Implications for drug discovery. AAPS J. 2009;11(1):167–77.

    CAS  PubMed Central  PubMed  Google Scholar 

  67. Christianson JC, Green WN. Regulation of nicotinic receptor expression by the ubiquitin-proteasome system. EMBO J. 2004;23(21):4156–65.

    CAS  PubMed Central  PubMed  Google Scholar 

  68. Rezvani K, Teng Y, Pan Y, et al. UBXD4, a UBX-containing protein, regulates the cell surface number and stability of alpha3-containing nicotinic acetylcholine receptors. J Neurosci. 2009;29(21):6883–96.

    CAS  PubMed Central  PubMed  Google Scholar 

  69. Rezvani K, Teng Y, De Biasi M. The ubiquitin-proteasome system regulates the stability of neuronal nicotinic acetylcholine receptors. J Mol Neurosci. 2010;40(1–2):177–84.

    CAS  PubMed Central  PubMed  Google Scholar 

  70. Marks MJ, Pauly JR, Gross SD, et al. Nicotine binding and nicotinic receptor subunit RNA after chronic nicotine treatment. J Neurosci. 1992;12(7):2765–84.

    CAS  PubMed  Google Scholar 

  71. Pauly JR, Marks MJ, Robinson SF, van de Kamp JL, Collins AC. Chronic nicotine and mecamylamine treatment increase brain nicotinic receptor binding without changing alpha 4 or beta 2 mRNA levels. J Pharmacol Exp Ther. 1996;278(1):361–9.

    CAS  PubMed  Google Scholar 

  72. Vallejo YF, Buisson B, Bertrand D, Green WN. Chronic nicotine exposure upregulates nicotinic receptors by a novel mechanism. J Neurosci. 2005;25(23):5563–72.

    CAS  PubMed Central  PubMed  Google Scholar 

  73. Huang YY, Kandel ER, Levine A. Chronic nicotine exposure induces a long-lasting and pathway-specific facilitation of LTP in the amygdala. Learn Mem. 2008;15(8):603–10.

    PubMed Central  PubMed  Google Scholar 

  74. Aydin C, Oztan O, Isgor C. Nicotine-induced anxiety-like behavior in a rat model of the novelty-seeking phenotype is associated with long-lasting neuropeptidergic and neuroplastic adaptations in the amygdala: effects of the cannabinoid receptor 1 antagonist AM251. Neuropharmacology. 2012;63(8):1335–45.

    CAS  PubMed Central  PubMed  Google Scholar 

  75. Vezina P, McGehee DS, Green WN. Exposure to nicotine and sensitization of nicotine-induced behaviors. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31(8):1625–38.

    CAS  PubMed Central  PubMed  Google Scholar 

  76. Buisson B, Vallejo YF, Green WN, Bertrand D. The unusual nature of epibatidine responses at the alpha4beta2 nicotinic acetylcholine receptor. Neuropharmacology. 2000;39(13):2561–9.

    CAS  PubMed  Google Scholar 

  77. Buisson B, Bertrand D. Chronic exposure to nicotine upregulates the human (alpha)4(beta)2 nicotinic acetylcholine receptor function. J Neurosci. 2001;21(6):1819–29.

    CAS  PubMed  Google Scholar 

  78. Nashmi R, Dickinson ME, McKinney S, et al. Assembly of alpha4beta2 nicotinic acetylcholine receptors assessed with functional fluorescently labeled subunits: effects of localization, trafficking, and nicotine-induced upregulation in clonal mammalian cells and in cultured midbrain neurons. J Neurosci. 2003;23(37):11554–67.

    CAS  PubMed  Google Scholar 

  79. Alkondon M, Albuquerque EX. Nicotinic receptor subtypes in rat hippocampal slices are differentially sensitive to desensitization and early in vivo functional up-regulation by nicotine and to block by bupropion. J Pharmacol Exp Ther. 2005;313(2):740–50.

    CAS  PubMed  Google Scholar 

  80. Govind AP, Walsh H, Green WN. Nicotine-induced upregulation of native neuronal nicotinic receptors is caused by multiple mechanisms. J Neurosci. 2012;32(6):2227–38.

    CAS  PubMed Central  PubMed  Google Scholar 

  81. Benowitz NL. Nicotine addiction. N Engl J Med. 2010;362(24):2295–303.

    CAS  PubMed Central  PubMed  Google Scholar 

  82. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC: American Psychiatric Association; 2000. Text Revision.

    Google Scholar 

  83. Volkow ND, Fowler JS, Wang GJ, Goldstein RZ. Role of dopamine, the frontal cortex and memory circuits in drug addiction: insight from imaging studies. Neurobiol Learn Mem. 2002;78(3):610–24.

    CAS  PubMed  Google Scholar 

  84. Hogle JM, Kaye JT, Curtin JJ. Nicotine withdrawal increases threat-induced anxiety but not fear: neuroadaptation in human addiction. Biol Psychiatry. 2010;68(8):719–25.

    CAS  PubMed Central  PubMed  Google Scholar 

  85. Buchhalter AR, Fant RV, Henningfield JE. Novel pharmacological approaches for treating tobacco dependence and withdrawal: current status. Drugs. 2008;68(8):1067–88.

    CAS  PubMed  Google Scholar 

  86. Yamamoto KI, Domino EF. Cholinergic agonist-antagonist interactions on neocortical and limbic EEG activation. Int J Neuropharmacol. 1967;6(5):357–73.

    CAS  PubMed  Google Scholar 

  87. Kadoya C, Domino EF, Matsuoka S. Relationship of electroencephalographic and cardiovascular changes to plasma nicotine levels in tobacco smokers. Clin Pharmacol Ther. 1994;55(4):370–7.

    CAS  PubMed  Google Scholar 

  88. Hughes JR, Gust SW, Skoog K, Keenan RM, Fenwick JW. Symptoms of tobacco withdrawal. A replication and extension. Arch Gen Psychiatry. 1991;48(1):52–9.

    CAS  PubMed  Google Scholar 

  89. Kenny PJ, Markou A. Neurobiology of the nicotine withdrawal syndrome. Pharmacol Biochem Behav. 2001;70(4):531–49.

    CAS  PubMed  Google Scholar 

  90. Malin DH, Lake JR, Newlin-Maultsby P, et al. Rodent model of nicotine abstinence syndrome. Pharmacol Biochem Behav. 1992;43(3):779–84.

    CAS  PubMed  Google Scholar 

  91. Malin DH, Lake JR, Carter VA, et al. The nicotinic antagonist mecamylamine precipitates nicotine abstinence syndrome in the rat. Psychopharmacology (Berl). 1994;115(1–2):180–4.

    CAS  Google Scholar 

  92. Salas R, Pieri F, De Biasi M. Decreased signs of nicotine withdrawal in mice null for the beta4 nicotinic acetylcholine receptor subunit. J Neurosci. 2004;24(45):10035–9.

    CAS  PubMed  Google Scholar 

  93. Salas R, Sturm R, Boulter J, De Biasi M. Nicotinic receptors in the habenulo-interpeduncular system are necessary for nicotine withdrawal in mice. J Neurosci. 2009;29(10):3014–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  94. Salas R, Orr-Urtreger A, Broide RS, Beaudet A, Paylor R, De Biasi M. The nicotinic acetylcholine receptor subunit alpha 5 mediates short-term effects of nicotine in vivo. Mol Pharmacol. 2003;63(5):1059–66.

    CAS  PubMed  Google Scholar 

  95. Flores CM, DeCamp RM, Kilo S, Rogers SW, Hargreaves KM. Neuronal nicotinic receptor expression in sensory neurons of the rat trigeminal ganglion: demonstration of alpha3beta4, a novel subtype in the mammalian nervous system. J Neurosci. 1996;16(24):7892–901.

    CAS  PubMed  Google Scholar 

  96. Salas R, Main A, Gangitano D, De Biasi M. Decreased withdrawal symptoms but normal tolerance to nicotine in mice null for the alpha7 nicotinic acetylcholine receptor subunit. Neuropharmacology. 2007;53(7):863–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  97. Lotfipour S, Byun JS, Leach P, et al. Targeted deletion of the mouse alpha2 nicotinic acetylcholine receptor subunit gene (Chrna2) potentiates nicotine-modulated behaviors. J Neurosci. 2013;33(18):7728–41.

    CAS  PubMed  Google Scholar 

  98. Boulter J, O’Shea-Greenfield A, Duvoisin RM, et al. 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. 1990;265(8):4472–82.

    CAS  PubMed  Google Scholar 

  99. Saccone SF, Hinrichs AL, Saccone NL, et al. Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs. Hum Mol Genet. 2007;16(1):36–49.

    CAS  PubMed Central  PubMed  Google Scholar 

  100. Thorgeirsson TE, Geller F, Sulem P, et al. A variant associated with nicotine dependence, lung cancer and peripheral arterial disease. Nature. 2008;452(7187):638–42.

    CAS  PubMed  Google Scholar 

  101. Amos CI, Wu X, Broderick P, et al. Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nat Genet. 2008;40(5):616–22.

    CAS  PubMed Central  PubMed  Google Scholar 

  102. Bierut LJ, Stitzel JA, Wang JC, et al. Variants in nicotinic receptors and risk for nicotine dependence. Am J Psychiatry. 2008;165(9):1163–71.

    PubMed Central  PubMed  Google Scholar 

  103. Stevens VL, Bierut LJ, Talbot JT, et al. Nicotinic receptor gene variants influence susceptibility to heavy smoking. Cancer Epidemiol Biomarkers Prev. 2008;17(12):3517–25.

    CAS  PubMed Central  PubMed  Google Scholar 

  104. Berrettini W, Yuan X, Tozzi F, et al. Alpha-5/alpha-3 nicotinic receptor subunit alleles increase risk for heavy smoking. Mol Psychiatry. 2008;13(4):368–73.

    CAS  PubMed Central  PubMed  Google Scholar 

  105. Berrettini WH, Doyle GA. The CHRNA5-A3-B4 gene cluster in nicotine addiction. Mol Psychiatry. 2012;17(9):856–66.

    CAS  PubMed  Google Scholar 

  106. Weiss RB, Baker TB, Cannon DS, et al. A candidate gene approach identifies the CHRNA5-A3-B4 region as a risk factor for age-dependent nicotine addiction. PLoS Genet. 2008;4(7):e1000125.

    PubMed Central  PubMed  Google Scholar 

  107. Boulter J, Evans K, Goldman D, et al. Isolation of a cDNA clone coding for a possible neural nicotinic acetylcholine receptor alpha-subunit. Nature. 1986;319(6052):368–74.

    CAS  PubMed  Google Scholar 

  108. Duvoisin RM, Deneris ES, Patrick J, Heinemann S. The functional diversity of the neuronal nicotinic acetylcholine receptors is increased by a novel subunit: beta 4. Neuron. 1989;3(4):487–96.

    CAS  PubMed  Google Scholar 

  109. Wada E, McKinnon D, Heinemann S, Patrick J, Swanson LW. The distribution of mRNA encoded by a new member of the neuronal nicotinic acetylcholine receptor gene family (alpha 5) in the rat central nervous system. Brain Res. 1990;526(1):45–53.

    CAS  PubMed  Google Scholar 

  110. Sheffield EB, Quick MW, Lester RA. Nicotinic acetylcholine receptor subunit mRNA expression and channel function in medial habenula neurons. Neuropharmacology. 2000;39(13):2591–603.

    CAS  PubMed  Google Scholar 

  111. Gahring LC, Persiyanov K, Rogers SW. Neuronal and astrocyte expression of nicotinic receptor subunit beta4 in the adult mouse brain. J Comp Neurol. 2004;468(3):322–33.

    CAS  PubMed  Google Scholar 

  112. Matsumoto M, Hikosaka O. Lateral habenula as a source of negative reward signals in dopamine neurons. Nature. 2007;447(7148):1111–5.

    CAS  PubMed  Google Scholar 

  113. Matsumoto M, Hikosaka O. Negative motivational control of saccadic eye movement by the lateral habenula. Prog Brain Res. 2008;171:399–402.

    PubMed Central  PubMed  Google Scholar 

  114. Matsumoto M, Hikosaka O. Representation of negative motivational value in the primate lateral habenula. Nat Neurosci. 2009;12(1):77–84.

    CAS  PubMed Central  PubMed  Google Scholar 

  115. Bromberg-Martin ES, Hikosaka O. Lateral habenula neurons signal errors in the prediction of reward information. Nat Neurosci. 2011;14(9):1209–16.

    CAS  PubMed Central  PubMed  Google Scholar 

  116. Frahm S, Slimak MA, Ferrarese L, et al. Aversion to nicotine is regulated by the balanced activity of beta4 and alpha5 nicotinic receptor subunits in the medial habenula. Neuron. 2011;70(3):522–35.

    CAS  PubMed  Google Scholar 

  117. Yamaguchi T, Danjo T, Pastan I, Hikida T, Nakanishi S. Distinct roles of segregated transmission of the septo-habenular pathway in anxiety and fear. Neuron. 2013;78(3):537–44.

    CAS  PubMed Central  PubMed  Google Scholar 

  118. Paterson NE, Markou A. Animal models and treatments for addiction and depression co-morbidity. Neurotox Res. 2007;11(1):1–32.

    CAS  PubMed  Google Scholar 

  119. Ep**-Jordan MP, Watkins SS, Koob GF, Markou A. Dramatic decreases in brain reward function during nicotine withdrawal. Nature. 1998;393(6680):76–9.

    CAS  PubMed  Google Scholar 

  120. Harrison AA, Liem YT, Markou A. Fluoxetine combined with a serotonin-1A receptor antagonist reversed reward deficits observed during nicotine and amphetamine withdrawal in rats. Neuropsychopharmacology. 2001;25(1):55–71.

    CAS  PubMed  Google Scholar 

  121. Watkins SS, Stinus L, Koob GF, Markou A. Reward and somatic changes during precipitated nicotine withdrawal in rats: centrally and peripherally mediated effects. J Pharmacol Exp Ther. 2000;292(3):1053–64.

    CAS  PubMed  Google Scholar 

  122. Suzuki T, Ise Y, Tsuda M, Maeda J, Misawa M. Mecamylamine-precipitated nicotine-withdrawal aversion in rats. Eur J Pharmacol. 1996;314(3):281–4.

    CAS  PubMed  Google Scholar 

  123. Dani JA, Harris RA. Nicotine addiction and comorbidity with alcohol abuse and mental illness. Nat Neurosci. 2005;8(11):1465–70.

    CAS  PubMed  Google Scholar 

  124. Pomerleau OF, Pomerleau CS, Mehringer AM, Snedecor SM, Ninowski R, Sen A. Nicotine dependence, depression, and gender: characterizing phenotypes based on withdrawal discomfort, response to smoking, and ability to abstain. Nicotine Tob Res. 2005;7(1):91–102.

    PubMed  Google Scholar 

  125. Pellow S, Chopin P, File SE, Briley M. Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods. 1985;14(3):149–67.

    CAS  PubMed  Google Scholar 

  126. Damaj MI, Kao W, Martin BR. Characterization of spontaneous and precipitated nicotine withdrawal in the mouse. J Pharmacol Exp Ther. 2003;307(2):526–34.

    CAS  PubMed  Google Scholar 

  127. Irvine EE, Cheeta S, File SE. Tolerance to nicotine’s effects in the elevated plus-maze and increased anxiety during withdrawal. Pharmacol Biochem Behav. 2001;68(2):319–25.

    CAS  PubMed  Google Scholar 

  128. Maren S, Phan KL, Liberzon I. The contextual brain: implications for fear conditioning, extinction and psychopathology. Nat Rev Neurosci. 2013;14(6):417–28.

    CAS  PubMed  Google Scholar 

  129. Coe JW, Brooks PR, Vetelino MG, et al. Varenicline: an alpha4beta2 nicotinic receptor partial agonist for smoking cessation. J Med Chem. 2005;48(10):3474–7.

    CAS  PubMed  Google Scholar 

  130. Portugal GS, Gould TJ. Genetic variability in nicotinic acetylcholine receptors and nicotine addiction: converging evidence from human and animal research. Behav Brain Res. 2008;193(1):1–16.

    CAS  PubMed Central  PubMed  Google Scholar 

  131. Andre JM, Gulick D, Portugal GS, Gould TJ. Nicotine withdrawal disrupts both foreground and background contextual fear conditioning but not pre-pulse inhibition of the acoustic startle response in C57BL/6 mice. Behav Brain Res. 2008;190(2):174–81.

    CAS  PubMed Central  PubMed  Google Scholar 

  132. Raybuck JD, Gould TJ. Nicotine withdrawal-induced deficits in trace fear conditioning in C57BL/6 mice – a role for high-affinity beta2 subunit-containing nicotinic acetylcholine receptors. Eur J Neurosci. 2009;29(2):377–87.

    CAS  PubMed Central  PubMed  Google Scholar 

  133. Kobayashi Y, Sano Y, Vannoni E, et al. Genetic dissection of medial habenula-interpeduncular nucleus pathway function in mice. Front Behav Neurosci. 2013;7:17.

    CAS  PubMed Central  PubMed  Google Scholar 

  134. Kobayakawa K, Kobayakawa R, Matsumoto H, et al. Innate versus learned odour processing in the mouse olfactory bulb. Nature. 2007;450(7169):503–8.

    CAS  PubMed  Google Scholar 

  135. Robbins TW. The 5-choice serial reaction time task: behavioural pharmacology and functional neurochemistry. Psychopharmacology (Berl). 2002;163(3–4):362–80.

    CAS  Google Scholar 

  136. Patel S, Stolerman IP, Asherson P, Sluyter F. Attentional performance of C57BL/6 and DBA/2 mice in the 5-choice serial reaction time task. Behav Brain Res. 2006;170(2):197–203.

    CAS  PubMed  Google Scholar 

  137. Qin C, Luo M. Neurochemical phenotypes of the afferent and efferent projections of the mouse medial habenula. Neuroscience. 2009;161(3):827–37.

    CAS  PubMed  Google Scholar 

  138. Gangitano D, Salas R, Teng Y, Perez E, De Biasi M. Progesterone modulation of alpha5 nAChR subunits influences anxiety-related behavior during estrus cycle. Genes Brain Behav. 2009;8(4):398–406.

    CAS  PubMed Central  PubMed  Google Scholar 

  139. Hikosaka O, Sesack SR, Lecourtier L, Shepard PD. Habenula: crossroad between the basal ganglia and the limbic system. J Neurosci. 2008;28(46):11825–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  140. Hikosaka O. The habenula: from stress evasion to value-based decision-making. Nat Rev Neurosci. 2010;11(7):503–13.

    CAS  PubMed Central  PubMed  Google Scholar 

  141. Brady JV, Nauta WJ. Subcortical mechanisms in emotional behavior: the duration of affective changes following septal and habenular lesions in the albino rat. J Comp Physiol Psychol. 1955;48(5):412–20.

    CAS  PubMed  Google Scholar 

  142. Nielson HC, McIver AH. Cold stress and habenular lesion effects on rat behaviors. J Appl Physiol. 1966;21(2):655–60.

    CAS  PubMed  Google Scholar 

  143. Dafny N, Qiao JT. Habenular neuron responses to noxious input are modified by dorsal raphe stimulation. Neurol Res. 1990;12(2):117–21.

    CAS  PubMed  Google Scholar 

  144. Cohen SR, Melzack R. The habenula and pain: repeated electrical stimulation produces prolonged analgesia but lesions have no effect on formalin pain or morphine analgesia. Behav Brain Res. 1993;54(2):171–8.

    CAS  PubMed  Google Scholar 

  145. Matsumoto N, Yahata F, Kawarada K, Kamata K, Suzuki TA. Tooth pulp stimulation induces c-fos expression in the lateral habenular nucleus of the cat. Neuroreport. 1994;5(17):2397–400.

    CAS  PubMed  Google Scholar 

  146. Mahieux G, Benabid AL. Naloxone-reversible analgesia induced by electrical stimulation of the habenula in the rat. Brain Res. 1987;406(1–2):118–29.

    CAS  PubMed  Google Scholar 

  147. Lee EH, Huang SL. Role of lateral habenula in the regulation of exploratory behavior and its relationship to stress in rats. Behav Brain Res. 1988;30(3):265–71.

    CAS  PubMed  Google Scholar 

  148. Thornton EW, Bradbury GE, Davies C. Increased immobility in an automated forced swimming test following lesion of the habenula in rats: absence of evidence for a contribution from motor impairment. Behav Neurosci. 1990;104(1):37–43.

    CAS  PubMed  Google Scholar 

  149. Wang RY, Aghajanian GK. Physiological evidence for habenula as major link between forebrain and midbrain raphe. Science. 1977;197(4298):89–91.

    CAS  PubMed  Google Scholar 

  150. Herkenham M, Nauta WJ. Efferent connections of the habenular nuclei in the rat. J Comp Neurol. 1979;187(1):19–47.

    CAS  PubMed  Google Scholar 

  151. Christoph GR, Leonzio RJ, Wilcox KS. Stimulation of the lateral habenula inhibits dopamine-containing neurons in the substantia nigra and ventral tegmental area of the rat. J Neurosci. 1986;6(3):613–9.

    CAS  PubMed  Google Scholar 

  152. Bromberg-Martin ES, Matsumoto M, Hikosaka O. Dopamine in motivational control: rewarding, aversive, and alerting. Neuron. 2010;68(5):815–34.

    CAS  PubMed Central  PubMed  Google Scholar 

  153. Matsumoto M, Hikosaka O. Electrical stimulation of the primate lateral habenula suppresses saccadic eye movement through a learning mechanism. PLoS One. 2011;6(10):e26701.

    CAS  PubMed Central  PubMed  Google Scholar 

  154. Wise RA. Roles for nigrostriatal – not just mesocorticolimbic – dopamine in reward and addiction. Trends Neurosci. 2009;32(10):517–24.

    CAS  PubMed Central  PubMed  Google Scholar 

  155. Dani JA, De Biasi M. Mesolimbic dopamine and habenulo-interpeduncular pathways in nicotine withdrawal. Cold Spring Harb Perspect Med. 2013;3(6):a012138.

    PubMed  Google Scholar 

  156. Hildebrand BE, Nomikos GG, Hertel P, Schilstrom B, Svensson TH. Reduced dopamine output in the nucleus accumbens but not in the medial prefrontal cortex in rats displaying a mecamylamine-precipitated nicotine withdrawal syndrome. Brain Res. 1998;779(1–2):214–25.

    CAS  PubMed  Google Scholar 

  157. Rada P, Jensen K, Hoebel BG. Effects of nicotine and mecamylamine-induced withdrawal on extracellular dopamine and acetylcholine in the rat nucleus accumbens. Psychopharmacology (Berl). 2001;157(1):105–10.

    CAS  Google Scholar 

  158. Rahman S, Zhang J, Engleman EA, Corrigall WA. Neuroadaptive changes in the mesoaccumbens dopamine system after chronic nicotine self-administration: a microdialysis study. Neuroscience. 2004;129(2):415–24.

    CAS  PubMed  Google Scholar 

  159. Carboni E, Bortone L, Giua C, Di Chiara G. Dissociation of physical abstinence signs from changes in extracellular dopamine in the nucleus accumbens and in the prefrontal cortex of nicotine dependent rats. Drug Alcohol Depend. 2000;58(1–2):93–102.

    CAS  PubMed  Google Scholar 

  160. Gaddnas H, Piepponen TP, Ahtee L. Mecamylamine decreases accumbal dopamine output in mice treated chronically with nicotine. Neurosci Lett. 2002;330(3):219–22.

    CAS  PubMed  Google Scholar 

  161. Weiss F, Markou A, Lorang MT, Koob GF. Basal extracellular dopamine levels in the nucleus accumbens are decreased during cocaine withdrawal after unlimited-access self-administration. Brain Res. 1992;593(2):314–8.

    CAS  PubMed  Google Scholar 

  162. Rossetti ZL, Hmaidan Y, Gessa GL. Marked inhibition of mesolimbic dopamine release: a common feature of ethanol, morphine, cocaine and amphetamine abstinence in rats. Eur J Pharmacol. 1992;221(2–3):227–34.

    CAS  PubMed  Google Scholar 

  163. Jhou TC, Geisler S, Marinelli M, Degarmo BA, Zahm DS. The mesopontine rostromedial tegmental nucleus: a structure targeted by the lateral habenula that projects to the ventral tegmental area of Tsai and substantia nigra compacta. J Comp Neurol. 2009;513(6):566–96.

    PubMed Central  PubMed  Google Scholar 

  164. Jhou TC, Fields HL, Baxter MG, Saper CB, Holland PC. The rostromedial tegmental nucleus (RMTg), a GABAergic afferent to midbrain dopamine neurons, encodes aversive stimuli and inhibits motor responses. Neuron. 2009;61(5):786–800.

    CAS  PubMed Central  PubMed  Google Scholar 

  165. McCallum SE, Cowe MA, Lewis SW, Glick SD. alpha3beta4 nicotinic acetylcholine receptors in the medial habenula modulate the mesolimbic dopaminergic response to acute nicotine in vivo. Neuropharmacology. 2012;63(3):434–40.

    CAS  PubMed Central  PubMed  Google Scholar 

  166. Kim U, Chang SY. Dendritic morphology, local circuitry, and intrinsic electrophysiology of neurons in the rat medial and lateral habenular nuclei of the epithalamus. J Comp Neurol. 2005;483(2):236–50.

    PubMed  Google Scholar 

  167. Nishikawa T, Fage D, Scatton B. Evidence for, and nature of, the tonic inhibitory influence of habenulo-interpeduncular pathways upon cerebral dopaminergic transmission in the rat. Brain Res. 1986;373(1–2):324–36.

    CAS  PubMed  Google Scholar 

  168. Groenewegen HJ, Ahlenius S, Haber SN, Kowall NW, Nauta WJ. Cytoarchitecture, fiber connections, and some histochemical aspects of the interpeduncular nucleus in the rat. J Comp Neurol. 1986;249(1):65–102.

    CAS  PubMed  Google Scholar 

  169. Lodge DJ, Grace AA. The laterodorsal tegmentum is essential for burst firing of ventral tegmental area dopamine neurons. Proc Natl Acad Sci U S A. 2006;103(13):5167–72.

    CAS  PubMed Central  PubMed  Google Scholar 

  170. Grace AA, Floresco SB, Goto Y, Lodge DJ. Regulation of firing of dopaminergic neurons and control of goal-directed behaviors. Trends Neurosci. 2007;30(5):220–7.

    CAS  PubMed  Google Scholar 

  171. Duchemin AM, Zhang H, Neff NH, Hadjiconstantinou M. Increased expression of VMAT2 in dopaminergic neurons during nicotine withdrawal. Neurosci Lett. 2009;467(2):182–6.

    CAS  PubMed  Google Scholar 

  172. Hadjiconstantinou M, Neff NH. Nicotine and endogenous opioids: neurochemical and pharmacological evidence. Neuropharmacology. 2011;60(7–8):1209–20.

    CAS  PubMed  Google Scholar 

  173. Thierry AM, Tassin JP, Blanc G, Glowinski J. Selective activation of mesocortical DA system by stress. Nature. 1976;263(5574):242–4.

    CAS  PubMed  Google Scholar 

  174. Inglis FM, Moghaddam B. Dopaminergic innervation of the amygdala is highly responsive to stress. J Neurochem. 1999;72(3):1088–94.

    CAS  PubMed  Google Scholar 

  175. Bradberry CW, Lory JD, Roth RH. The anxiogenic beta-carboline FG 7142 selectively increases dopamine release in rat prefrontal cortex as measured by microdialysis. J Neurochem. 1991;56(3):748–52.

    CAS  PubMed  Google Scholar 

  176. Broersen LM, Abbate F, Feenstra MG, de Bruin JP, Heinsbroek RP, Olivier B. Prefrontal dopamine is directly involved in the anxiogenic interoceptive cue of pentylenetetrazol but not in the interoceptive cue of chlordiazepoxide in the rat. Psychopharmacology (Berl). 2000;149(4):366–76.

    CAS  Google Scholar 

  177. Kawasaki H, Kaufman O, Damasio H, et al. Single-neuron responses to emotional visual stimuli recorded in human ventral prefrontal cortex. Nat Neurosci. 2001;4(1):15–6.

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA

    Dang Q. Dao Ph.D.

  2. Department of Psychiatry, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA

    Ramiro Salas Ph.D.

  3. Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, 415 Curie Boulevard, Clinical Research Building, Philadelphia, PA, 19104, USA

    Mariella De Biasi Ph.D.

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  1. Dang Q. Dao Ph.D.
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  1. Department of Neurobiology SHEL 1006, University of Alabama at Birmingham, Birmingham, Alabama, USA

    Robin A.J. Lester

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Dao, D.Q., Salas, R., De Biasi, M. (2014). Nicotinic Acetylcholine Receptors Along the Habenulo-Interpeduncular Pathway: Roles in Nicotine Withdrawal and Other Aversive Aspects. In: Lester, R. (eds) Nicotinic Receptors. The Receptors, vol 26. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-1167-7_18

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