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Habenular α5 nicotinic receptor subunit signalling controls nicotine intake

Abstract

Genetic variation in CHRNA5, the gene encoding the α5 nicotinic acetylcholine receptor subunit, increases vulnerability to tobacco addiction and lung cancer, but the underlying mechanisms are unknown. Here we report markedly increased nicotine intake in mice with a null mutation in Chrna5. This effect was ‘rescued’ in knockout mice by re-expressing α5 subunits in the medial habenula (MHb), and recapitulated in rats through α5 subunit knockdown in MHb. Remarkably, α5 subunit knockdown in MHb did not alter the rewarding effects of nicotine but abolished the inhibitory effects of higher nicotine doses on brain reward systems. The MHb extends projections almost exclusively to the interpeduncular nucleus (IPN). We found diminished IPN activation in response to nicotine in α5 knockout mice. Further, disruption of IPN signalling increased nicotine intake in rats. Our findings indicate that nicotine activates the habenulo-interpeduncular pathway through α5-containing nAChRs, triggering an inhibitory motivational signal that acts to limit nicotine intake.

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Figure 1: Increased nicotine intake in α5* knockout mice.
Figure 2: ‘Rescue’ of α5* nAChRs in the habenulo-interpeduncular tract normalizes nicotine intake.
Figure 3: α5* nAChRs in the habenulo-interpeduncular tract control nicotine intake and its reward-inhibiting effects in rats.
Figure 4: Nicotine-induced activation of the IPN in mice.
Figure 5: Disruption of IPN or MHb signalling increases nicotine intake in rats.

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References

  1. Mokdad, A. H., Marks, J. S., Stroup, D. F. & Gerberding, J. L. Actual causes of death in the United States, 2000. J. Am. Med. Assoc. 291, 1238–1245 (2004)

    Article  Google Scholar 

  2. Stolerman, I. P. & Jarvis, M. J. The scientific case that nicotine is addictive. Psychopharmacology 117, 2–10 (1995)

    Article  CAS  Google Scholar 

  3. Le Novère, N., Corringer, P. J. & Changeux, J. P. The diversity of subunit composition in nAChRs: evolutionary origins, physiologic and pharmacologic consequences. J. Neurobiol. 53, 447–456 (2002)

    Article  Google Scholar 

  4. Picciotto, M. R. et al. Acetylcholine receptors containing the β2 subunit are involved in the reinforcing properties of nicotine. Nature 391, 173–177 (1998)

    Article  ADS  CAS  Google Scholar 

  5. Tapper, A. R. et al. Nicotine activation of α4* receptors: sufficient for reward, tolerance, and sensitization. Science 306, 1029–1032 (2004)

    Article  ADS  CAS  Google Scholar 

  6. Corrigall, W. A., Franklin, K. B., Coen, K. M. & Clarke, P. B. The mesolimbic dopaminergic system is implicated in the reinforcing effects of nicotine. Psychopharmacology 107, 285–289 (1992)

    Article  CAS  Google Scholar 

  7. Ikemoto, S., Qin, M. & Liu, Z. H. Primary reinforcing effects of nicotine are triggered from multiple regions both inside and outside the ventral tegmental area. J. Neurosci. 26, 723–730 (2006)

    Article  CAS  Google Scholar 

  8. Maskos, U. et al. Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors. Nature 436, 103–107 (2005)

    Article  ADS  CAS  Google Scholar 

  9. Berrettini, W. et al. α-5/α-3 nicotinic receptor subunit alleles increase risk for heavy smoking. Mol. Psychiatry 13, 368–373 (2008)

    Article  CAS  Google Scholar 

  10. Saccone, S. F. et al. Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs. Hum. Mol. Genet. 16, 36–49 (2007)

    Article  CAS  Google Scholar 

  11. Liu, J. Z. et al. Meta-analysis and imputation refines the association of 15q25 with smoking quantity. Nature Genet. 42, 436–440 (2010)

    Article  CAS  Google Scholar 

  12. Bierut, L. J. et al. Variants in nicotinic receptors and risk for nicotine dependence. Am. J. Psychiatry 165, 1163–1171 (2008)

    Article  Google Scholar 

  13. Kuryatov, A., Berrettini, W. & Lindstrom, J. Acetylcholine receptor (AChR) α5 subunit variant associated with risk for nicotine dependence and lung cancer reduces (α4β2)2α5 AChR function. Mol. Pharmacol. 79, 119–125 (2011)

    Article  CAS  Google Scholar 

  14. Hung, R. J. et al. A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25. Nature 452, 633–637 (2008)

    Article  ADS  CAS  Google Scholar 

  15. Wang, Y., Broderick, P., Matakidou, A., Eisen, T. & Houlston, R. S. Role of 5p15.33 (TERT-CLPTM1L), 6p21.33 and 15q25.1 (CHRNA5-CHRNA3) variation and lung cancer risk in never-smokers. Carcinogenesis 31, 234–238 (2010)

    Article  Google Scholar 

  16. Amos, C. I. et al. Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nature Genet. 40, 616–622 (2008)

    Article  CAS  Google Scholar 

  17. Le Marchand, L. et al. Smokers with the CHRNA lung cancer-associated variants are exposed to higher levels of nicotine equivalents and a carcinogenic tobacco-specific nitrosamine. Cancer Res. 68, 9137–9140 (2008)

    Article  CAS  Google Scholar 

  18. Henningfield, J. E. & Goldberg, S. R. Nicotine as a reinforcer in human subjects and laboratory animals. Pharmacol. Biochem. Behav. 19, 989–992 (1983)

    Article  CAS  Google Scholar 

  19. Le Foll, B., Wertheim, C. & Goldberg, S. R. High reinforcing efficacy of nicotine in non-human primates. PLoS ONE 2, e230 (2007)

    Article  ADS  Google Scholar 

  20. Risner, M. E. & Goldberg, S. R. A comparison of nicotine and cocaine self-administration in the dog: fixed-ratio and progressive-ratio schedules of intravenous drug infusion. J. Pharmacol. Exp. Ther. 224, 319–326 (1983)

    CAS  PubMed  Google Scholar 

  21. Corrigall, W. A. & Coen, K. M. Nicotine maintains robust self-administration in rats on a limited-access schedule. Psychopharmacology 99, 473–478 (1989)

    Article  CAS  Google Scholar 

  22. Jackson, K. J. et al. Role of α5 nicotinic acetylcholine receptors in pharmacological and behavioral effects of nicotine in mice. J. Pharmacol. Exp. Ther. 334, 137–146 (2010)

    Article  CAS  Google Scholar 

  23. Matta, S. G. et al. Guidelines on nicotine dose selection for in vivo research. Psychopharmacology 190, 269–319 (2007)

    Article  CAS  Google Scholar 

  24. Russell, M. A., Wilson, C., Patel, U. A., Feyerabend, C. & Cole, P. V. Plasma nicotine levels after smoking cigarettes with high, medium, and low nicotine yields. BMJ 2, 414–416 (1975)

    Article  CAS  Google Scholar 

  25. Lynch, W. J. & Carroll, M. E. Regulation of drug intake. Exp. Clin. Psychopharmacol. 9, 131–143 (2001)

    Article  CAS  Google Scholar 

  26. Lynch, W. J. & Carroll, M. E. Regulation of intravenously self-administered nicotine in rats. Exp. Clin. Psychopharmacol. 7, 198–207 (1999)

    Article  CAS  Google Scholar 

  27. Marks, M. J. et al. Nicotine binding and nicotinic receptor subunit RNA after chronic nicotine treatment. J. Neurosci. 12, 2765–2784 (1992)

    Article  CAS  Google Scholar 

  28. Herkenham, M. & Nauta, W. J. Efferent connections of the habenular nuclei in the rat. J. Comp. Neurol. 187, 19–47 (1979)

    Article  CAS  Google Scholar 

  29. Grady, S. R. et al. Rodent habenulo-interpeduncular pathway expresses a large variety of uncommon nAChR subtypes, but only the α3β4* and α3β3β4* subtypes mediate acetylcholine release. J. Neurosci. 29, 2272–2282 (2009)

    Article  CAS  Google Scholar 

  30. London, E. D., Connolly, R. J., Szikszay, M., Wamsley, J. K. & Dam, M. Effects of nicotine on local cerebral glucose utilization in the rat. J. Neurosci. 8, 3920–3928 (1988)

    Article  CAS  Google Scholar 

  31. Donovick, P. J., Burright, R. G. & Zuromski, E. Localization of quinine aversion within the septum, habenula, and interpeduncular nucleus of the rat. J. Comp. Physiol. Psychol. 71, 376–383 (1970)

    Article  CAS  Google Scholar 

  32. 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. 29, 3014–3018 (2009)

    Article  CAS  Google Scholar 

  33. Glick, S. D., Ramirez, R. L., Livi, J. M. & Maisonneuve, I. M. 18-Methoxycoronaridine acts in the medial habenula and/or interpeduncular nucleus to decrease morphine self-administration in rats. Eur. J. Pharmacol. 537, 94–98 (2006)

    Article  CAS  Google Scholar 

  34. Matsumoto, M. & Hikosaka, O. Lateral habenula as a source of negative reward signals in dopamine neurons. Nature 447, 1111–1115 (2007)

    Article  ADS  CAS  Google Scholar 

  35. Brown, R. W., Collins, A. C., Lindstrom, J. M. & Whiteaker, P. Nicotinic α5 subunit deletion locally reduces high-affinity agonist activation without altering nicotinic receptor numbers. J. Neurochem. 103, 204–215 (2007)

    CAS  PubMed  Google Scholar 

  36. Kenny, P. J. & Markou, A. Nicotine self-administration acutely activates brain reward systems and induces a long-lasting increase in reward sensitivity. Neuropsychopharmacology 31, 1203–1211 (2006)

    Article  CAS  Google Scholar 

  37. Schaefer, G. J. & Michael, R. P. Task-specific effects of nicotine in rats: intracranial self-stimulation and locomotor activity. Neuropharmacology 25, 125–131 (1986)

    Article  CAS  Google Scholar 

  38. Kenny, P. J. Brain reward systems and compulsive drug use. Trends Pharmacol. Sci. 28, 135–141 (2007)

    Article  CAS  Google Scholar 

  39. Qin, C. & Luo, M. Neurochemical phenotypes of the afferent and efferent projections of the mouse medial habenula. Neuroscience 161, 827–837 (2009)

    Article  CAS  Google Scholar 

  40. Hussain, R. J., Taraschenko, O. D. & Glick, S. D. Effects of nicotine, methamphetamine and cocaine on extracellular levels of acetylcholine in the interpeduncular nucleus of rats. Neurosci. Lett. 440, 270–274 (2008)

    Article  CAS  Google Scholar 

  41. Girod, R., Barazangi, N., McGehee, D. & Role, L. W. Facilitation of glutamatergic neurotransmission by presynaptic nicotinic acetylcholine receptors. Neuropharmacology 39, 2715–2725 (2000)

    Article  CAS  Google Scholar 

  42. McGehee, D. S., Heath, M. J., Gelber, S., Devay, P. & Role, L. W. Nicotine enhancement of fast excitatory synaptic transmission in CNS by presynaptic receptors. Science 269, 1692–1696 (1995)

    Article  ADS  CAS  Google Scholar 

  43. Rauhut, A. S., Hawrylak, M. & Mardekian, S. K. Bupropion differentially alters the aversive, locomotor and rewarding properties of nicotine in CD-1 mice. Pharmacol. Biochem. Behav. 90, 598–607 (2008)

    Article  CAS  Google Scholar 

  44. Gavrilov, Y. V., Perekrest, S. V., Novikova, N. S. & Korneva, E. A. Stress-induced changes in cellular responses in hypothalamic structures to administration of an antigen (lipopolysaccharide) (in terms of c-Fos protein expression). Neurosci. Behav. Physiol. 38, 189–194 (2008)

    Article  Google Scholar 

  45. Laviolette, S. R., Alexson, T. O. & van der Kooy, D. Lesions of the tegmental pedunculopontine nucleus block the rewarding effects and reveal the aversive effects of nicotine in the ventral tegmental area. J. Neurosci. 22, 8653–8660 (2002)

    Article  CAS  Google Scholar 

  46. Kenny, P. J., Chartoff, E., Roberto, M., Carlezon, W. A., Jr & Markou, A. NMDA receptors regulate nicotine-enhanced brain reward function and intravenous nicotine self-administration: role of the ventral tegmental area and central nucleus of the amygdala. Neuropsychopharmacology 34, 266–281 (2009)

    Article  CAS  Google Scholar 

  47. Hong, L. E. et al. A genetically modulated, intrinsic cingulate circuit supports human nicotine addiction. Proc. Natl Acad. Sci. USA 107, 13509–13514 (2010)

    Article  ADS  CAS  Google Scholar 

  48. Schlaepfer, I. R. et al. The CHRNA5/A3/B4 gene cluster variability as an important determinant of early alcohol and tobacco initiation in young adults. Biol. Psychiatry 63, 1039–1046 (2008)

    Article  CAS  Google Scholar 

  49. Salas, R. et al. The nicotinic acetylcholine receptor subunit α5 mediates short-term effects of nicotine in vivo. Mol. Pharmacol. 63, 1059–1066 (2003)

    Article  CAS  Google Scholar 

  50. Paxinos, G. & Franklin, K. B. J. The Mouse Brain in Stereotaxic Coordinates 2nd edn (Academic, 2001)

    Google Scholar 

  51. Paxinos, G. & Watson, C. The Rat Brain in Stereotaxic Coordinates 3rd edn (Academic, 1997)

    Google Scholar 

  52. Lecourtier, L., Neijt, H. C. & Kelly, P. H. Habenula lesions cause impaired cognitive performance in rats: implications for schizophrenia. Eur. J. Neurosci. 19, 2551–2560 (2004)

    Article  Google Scholar 

  53. Kornetsky, C., Esposito, R. U., McLean, S. & Jacobson, J. O. Intracranial self-stimulation thresholds: a model for the hedonic effects of drugs of abuse. Arch. Gen. Psychiatry 36, 289–292 (1979)

    Article  CAS  Google Scholar 

  54. Huston-Lyons, D. & Kornetsky, C. Effects of nicotine on the threshold for rewarding brain stimulation in rats. Pharmacol. Biochem. Behav. 41, 755–759 (1992)

    Article  CAS  Google Scholar 

  55. Marks, M. J. et al. Two pharmacologically distinct components of nicotinic receptor-mediated rubidium efflux in mouse brain require the β2 subunit. J. Pharmacol. Exp. Ther. 289, 1090–1103 (1999)

    CAS  PubMed  Google Scholar 

  56. Shoaib, M. et al. The role of nicotinic receptor beta-2 subunits in nicotine discrimination and conditioned taste aversion. Neuropharmacology 42, 530–539 (2002)

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by the National Institute on Drug Abuse (DA020686 to P.J.K.; DA026693 to C.D.F.; P30DA015663 to M.J.M.) and The James and Esther King Biomedical Research Program, Florida Department of Health (07KN-06 to P.J.K.).

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C.D.F., Q.L., P.M.J. and M.J.M. performed all experiments; M.J.M. also provided essential reagents and assisted in manuscript editing; C.D.F. and P.J.K. designed the experiments, performed the statistical analyses and wrote the manuscript.

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Correspondence to Paul J. Kenny.

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The authors declare no competing financial interests.

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Fowler, C., Lu, Q., Johnson, P. et al. Habenular α5 nicotinic receptor subunit signalling controls nicotine intake. Nature 471, 597–601 (2011). https://doi.org/10.1038/nature09797

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