Acetylcholine receptors containing the β2 subunit are involved in the reinforcing properties of nicotine

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Release of the neurotransmitter dopamine in the mesolimbic system of the brain mediates the reinforcing properties of several drugs of abuse, including nicotine1. Here we investigate the contribution of the high-affinity neuronal nicotinic acetylcholine receptor2 to the effects of nicotine on the mesolimbic dopamine system in mice lacking the β2 subunit of this receptor3. We found that nicotine stimulates dopamine release in the ventral striatum of wild-type mice but not in the ventral striatum of β2-mutant mice. Using patch-clamp recording, we show that mesencephalic dopaminergic neurons from mice without the β2 subunit no longer respond to nicotine, and that self-administration of nicotine is attenuated in these mutant mice. Our results strongly support the idea that the β2-containing neuronal nicotinic acetylcholine receptor is involved in mediating the reinforcing properties of nicotine.

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Figure 1: Nicotine-elicited dopamine (DA) release in β2-mutant mice and their wild-type siblings.
Figure 2: Patch-clamp recording of nicotine-evoked currents in substantia nigra (SN) pars compacta and ventral tegmental area (VTA) of wild-type and.
Figure 3
Figure 4: Intravenous self-administration of cocaine and nicotine in β2−/− mice and their wild-type siblings with a history of cocaine self-administration.


  1. 1

    Dani, J. A. & Heinemann, S. Molecular and cellular aspects of nicotine abuse. Neuron 16, 905– 908 (1996).

  2. 2

    Role, L. W. & Berg, D. K. Nicotinic receptors in the development and modulation of CNS synapses. Neuron 16, 1077–1085 (1996).

  3. 3

    Picciotto, M. R. et al . Abnormal avoidance learning in mice lacking functional high-affinity nicotine receptor in the brain. Nature 374, 65–67 (1995).

  4. 4

    Koob, G. F. Drugs of abuse: anatomy, pharmacology and function of reward pathways. Trends Pharmacol. Sci. 13, 177–184 (1992).

  5. 5

    Stolerman, I. P., Mirza, N. R. & Shoaib, M. Nicotine psychopharmacology: Addiction, cognition and neuroadaptation. Med. Res. Rev. 15, 47– 72 (1995).

  6. 6

    Pontieri, F. E., Tanda, G., Orzi, F. & Di Chiara, G. Effects of nicotine on the nucleus accumbens and similarity to those of addictive drugs. Nature 382, 255–257 ( 1996).

  7. 7

    Grady, S., Marks, M. J., Wonnacott, S. & Collins, A. C. Characterization of nicotinic receptor-mediated [3H]dopamine release form synaptosomes prepared from mouse striatum. J. Neurochem. 59, 848–856 (1992).

  8. 8

    Clarke, P. B., Fu, D. S., Jakubovic, A. & Fibiger, H. C. Evidence that mesolimbic dopaminergic activation underlies the locomotor stimulant action of nicotine in rats. J. Pharmacol. Exp. Ther. 246, 701–708 (1988).

  9. 9

    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 (Berlin) 107, 285–289 (1992).

  10. 10

    Le Novère, N., Zoli, M. & Changeux, J.-P. Neuronal nicotinic receptor α6 subunit mRNA is selectively concentrated in catecholaminergic nuclei of the rat brain. Eur. J. Neurosci. 8, 2428– 2439 (1996).

  11. 11

    Reavill, C., Walther, B., Stolerman, I. P. & Testa, B. Behavioural and pharmacokinetic studies on nicotine, cytisine and lobeline. Neuropharmacology 29, 619– 624 (1990).

  12. 12

    Risinger, F. O. & Oakes, R. A. Nicotine-induced conditioned place preference and conditioned place aversion in mice. Pharmacol. Biochem. Behav. 51, 457– 461 (1995).

  13. 13

    Nisell, M., Nomikos, G. G. & Svensson, T. H. Systemic nicotine-induced dopamine release in the rat nucleus accumbens is regulated by nicotinic receptors in the ventral tegmental area. Synapse 16, 36–44 (1994).

  14. 14

    Henningfield, J. E., Miyasato, K. & Jasinski, D. R. Cigarette smokers self-administer intravenous nicotine. Pharmacol. Biochem. Behav. 19, 887– 890 (1983).

  15. 15

    Reavill, C., Walther, B., Stolerman, I. P. & Testa, B. Behavioural and pharmacokinetic studies on nicotine, cytisine and lobeline. Neuropharmacology 29, 619– 624 (1990).

  16. 16

    Grace, A. A. & Onn, S. P. Morphology and electrophysiological properties of immunocytochemically identified rat dopamine neurons recorded in vitro. J. Neurosci. 9, 3463– 3481 (1989).

  17. 17

    Luetje, C. W. & Patrick, J. Both α- and β-subunits contribute to the agonist sensitivity of neuronal nicotinic acetylcholine receptors. J. Neurosci. 11, 837– 845 (1991).

  18. 18

    Izenwasser, S., Jacocks, H. M., Rosenberger, J. G. & Cox, B. M. Nicotine indirectly inhibits [3H]dopamine uptake at concentrations that do not directly promote [3H]dopamine release in rat striatum. J. Neurochem. 56, 603– 610 (1991).

  19. 19

    Kaufman, M. J., Spealman, R. D. & Madras, B. K. Distribution of cocaine recognition sites in monkey brain: I. In vitro autoradiography with [3H]CFT. Synapse 9, 177–187 ( 1991).

  20. 20

    Dawson, T. M., Gehlert, D. R., McCabe, R. T., Barnett, A. & Wamsley, J. K. D1 dopamine receptors in the rat brain: a quantitative autoradiographic analysis. J. Neurosci. 6, 2352–2365 ( 1986).

  21. 21

    Mansour, A. et al. Localization of dopamine D2 receptor mRNA and D1 and D2 receptor binding in the rat brain and pituitary: an in situ hybridization-receptor autoradiographic analysis. J. Neurosci. 10, 2587–2600 (1990).

  22. 22

    Memo, M. et al. Dopaminergic inhibition of prolactin release and calcium influx induced by neurotensin in anterior pituitary is independent of cyclic AMP system. J. Neurochem. 47, 1689– 1695 (1986).

  23. 23

    Rheinhard, J. F., Smith, G. K. & Nichol, C. A. Arapid and sensitive assay for tyrosine-3-monooxygenase based upon the release of [3H]-H2O and adsorption of [3H]-tyrosine by charcoal. Life Sci. 39, 2185–2189 (1986).

  24. 24

    Blaha, C. D. et al. Modulation of dopamine efflux in the nucleus accumbens after cholinergic stimulation of the ventral tegmental area in intact, pedunculopontine tegmental nucleus-lesioned, and laterodorsal tegmental nucleus-lesioned rats. J. Neurosci. 16, 714–722 (1996).

  25. 25

    Calabresi, P., Lacey, M. G. & North, R. A. Nicotinic excitation of rat ventral tegmental neurones in vitro studies by intracellular recording. Br. J. Pharmacol. 98, 135–140 ( 1989).

  26. 26

    Merlo Pich, E. et al . Common neural substrates for the addictive properties of nicotine and cocaine. Science 275, 83– 86 (1997).

  27. 27

    Grahame, N. J., Phillips, T. J., Burkhart-Kasch, S. & Cunningham, C. L. Intravenous cocaine self-administration in the C57BL/6J mouse. Pharmacol. Biochem. Behav. 51, 827– 834 (1995).

  28. 28

    Tessari, M., Valerio, E., Chiamulera, C. & Beardsley, P. M. Nicotine reinforcement in rats with histories of cocaine self-administration. Psychopharmacology 121, 282– 283 (1995).

  29. 29

    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).

  30. 30

    Rimondini, R. et al . PEC-60 increases dopamine but not GABA release in the dorsolateral neostriatum of the halothane anaesthetized rat. An in vivo microdialysis study. Neurosci. Lett. 177, 53– 57 (1994).

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We thank M. Memo and D. Uberti for help and advice with DA-stimulated cyclase assays; M. Epping-Jordan for help with self-administration experiments; P. Sattonnet-Roche for technical assistance; L. Gold, F. Caine and C. Chiamulera for discussing the behavioural results; and E. Ratti, D. Trist and A. North (GlaxoWellcome) for supporting part of the project. This work was supported by the Collège de France, the Centre National de la Recherche Scientifique, the Association Française contre la Myopathie, the Council for Tobacco Research, Biomed and Biotech contract from the Commission of the European Communities, a grant from the Human Frontiers Science Program, a Roux grant from the Institut Pasteur for C.L., a young investigator award from NARSAD and a grant from NIDA to M.R.P.

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Correspondence to Jean-Pierre Changeux.

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