Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors

Abstract

Worldwide, 100 million people are expected to die this century from the consequences of nicotine addiction1, but nicotine is also known to enhance cognitive performance2. Identifying the molecular mechanisms involved in nicotine reinforcement and cognition is a priority and requires the development of new in vivo experimental paradigms. The ventral tegmental area (VTA) of the midbrain is thought to mediate the reinforcement properties of many drugs of abuse. Here we specifically re-expressed the β2-subunit of the nicotinic acetylcholine receptor (nAChR) by stereotaxically injecting a lentiviral vector into the VTA of mice carrying β2-subunit deletions3,4. We demonstrate the efficient re-expression of electrophysiologically responsive, ligand-binding nicotinic acetylcholine receptors in dopamine-containing neurons of the VTA, together with the recovery of nicotine-elicited dopamine release and nicotine self-administration. We also quantified exploratory behaviours of the mice, and showed that β2-subunit re-expression restored slow exploratory behaviour (a measure of cognitive function) to wild-type levels, but did not affect fast navigation behaviour. We thus demonstrate the sufficient role of the VTA in both nicotine reinforcement and endogenous cholinergic regulation of cognitive functions.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Lentivector-mediated expression of eGFP and nAChR β2-subunit in the VTA.
Figure 2: Effects of nicotine in vivo on dopamine neuron firing and dopamine release.
Figure 3: Intra-VTA nicotine self-administration.
Figure 4: VTA β2-subunit re-expression and behaviours in open fields.

Similar content being viewed by others

References

  1. Peto, R. et al. Mortality from smoking worldwide. Br. Med. Bull. 52, 12–21 (1996)

    Article  CAS  Google Scholar 

  2. Levin, E. D. & Rezvani, A. H. Nicotinic treatment for cognitive dysfunction. Curr. Drug Targets CNS Neurol. Disord. 1, 423–431 (2002)

    Article  CAS  Google Scholar 

  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)

    Article  ADS  CAS  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. Corringer, P. J., Le Novere, N. & Changeux, J. P. Nicotinic receptors at the amino acid level. Annu. Rev. Pharmacol. Toxicol. 40, 431–458 (2000)

    Article  CAS  Google Scholar 

  6. McGehee, D. S. & Role, L. W. Physiological diversity of nicotinic acetylcholine receptors expressed by vertebrate neurons. Annu. Rev. Physiol. 57, 521–546 (1995)

    Article  CAS  Google Scholar 

  7. Laviolette, S. R. & van der Kooy, D. The neurobiology of nicotine addiction: bridging the gap from molecules to behaviour. Nature Rev. Neurosci. 5, 55–65 (2004)

    Article  CAS  Google Scholar 

  8. Granon, S., Faure, P. & Changeux, J. P. Executive and social behaviors under nicotinic receptor regulation. Proc. Natl Acad. Sci. USA 100, 9596–9601 (2003)

    Article  ADS  CAS  Google Scholar 

  9. Maskos, U., Kissa, K., St Cloment, C. & Brulet, P. Retrograde trans-synaptic transfer of green fluorescent protein allows the genetic mapping of neuronal circuits in transgenic mice. Proc. Natl Acad. Sci. USA 99, 10120–10125 (2002)

    Article  ADS  CAS  Google Scholar 

  10. Naldini, L. et al. In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science 272, 263–267 (1996)

    Article  ADS  CAS  Google Scholar 

  11. Zoli, M., Lena, C., Picciotto, M. R. & Changeux, J. P. Identification of four classes of brain nicotinic receptors using β2 mutant mice. J. Neurosci. 18, 4461–4472 (1998)

    Article  CAS  Google Scholar 

  12. Swanson, L. W. The projections of the ventral tegmental area and adjacent regions: a combined fluorescent retrograde tracer and immunofluorescence study in the rat. Brain Res. Bull. 9, 321–353 (1982)

    Article  CAS  Google Scholar 

  13. Grace, A. A. & Bunney, B. S. Intracellular and extracellular electrophysiology of nigral dopaminergic neurons–1. Identification and characterization. Neuroscience 10, 301–315 (1983)

    Article  CAS  Google Scholar 

  14. Grenhoff, J., Aston-Jones, G. & Svensson, T. H. Nicotinic effects on the firing pattern of midbrain dopamine neurons. Acta Physiol. Scand. 128, 351–358 (1986)

    Article  CAS  Google Scholar 

  15. Mansvelder, H. D., De Rover, M., McGehee, D. S. & Brussaard, A. B. Cholinergic modulation of dopaminergic reward areas: upstream and downstream targets of nicotine addiction. Eur. J. Pharmacol. 480, 117–123 (2003)

    Article  CAS  Google Scholar 

  16. Klink, R., de Kerchove d'Exaerde, A., Zoli, M. & Changeux, J. P. Molecular and physiological diversity of nicotinic acetylcholine receptors in the midbrain dopaminergic nuclei. J. Neurosci. 21, 1452–1463 (2001)

    Article  CAS  Google Scholar 

  17. 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)

    Article  ADS  CAS  Google Scholar 

  18. David, V., Durkin, T. P. & Cazala, P. Differential effects of the dopamine D2/D3 receptor antagonist sulpiride on self-administration of morphine into the ventral tegmental area or the nucleus accumbens. Psychopharmacology (Berl.) 160, 307–317 (2002)

    Article  CAS  Google Scholar 

  19. Bardo, M., Donohew, R. & Harrington, N. Psychobiology of novelty seeking and drug seeking behavior. Behav. Brain Res. 77, 23–43 (1996)

    Article  CAS  Google Scholar 

  20. Robbins, T. W. Chemical neuromodulation of frontal-executive functions in humans and other animals. Exp. Brain Res. 133, 130–138 (2000)

    Article  CAS  Google Scholar 

  21. Renner, M. J. Neglected aspects of exploratory behavior and investigatory behavior. Psychobiology 18, 16–22 (1990)

    Google Scholar 

  22. Thinus-Blanc, C. Animal Spatial Cognition: Behavioural and Neural Approaches (World Scientific, Singapore, 1996)

    Book  Google Scholar 

  23. Faure, P., Neumeister, H., Faber, D. & Korn, H. Symbolic analysis of swimming trajectories reveals scale invariance and provides a model for fish locomotion. Fractals 11, 233–243 (2003)

    Article  MathSciNet  Google Scholar 

  24. Zoli, M., Picciotto, M. R., Ferrari, R., Cocchi, D. & Changeux, J. P. Increased neurodegeneration during ageing in mice lacking high-affinity nicotine receptors. EMBO J. 18, 1235–1244 (1999)

    Article  CAS  Google Scholar 

  25. Poucet, B. & Benhamou, S. The neuropsychology of spatial cognition in the rat. Crit. Rev. Neurobiol. 11, 101–120 (1997)

    Article  CAS  Google Scholar 

  26. Mesulam, M. M., Mufson, E. J., Wainer, B. H. & Levey, A. I. Central cholinergic pathways in the rat: an overview based on an alternative nomenclature (Ch1-Ch6). Neuroscience 10, 1185–1201 (1983)

    Article  CAS  Google Scholar 

  27. Carr, D. B. & Sesack, S. R. GABA-containing neurons in the rat ventral tegmental area project to the prefrontal cortex. Synapse 38, 114–123 (2000)

    Article  CAS  Google Scholar 

  28. Dehaene, S., Kerszberg, M. & Changeux, J. P. A neuronal model of a global workspace in effortful cognitive tasks. Proc. Natl Acad. Sci. USA 95, 14529–14534 (1998)

    Article  ADS  CAS  Google Scholar 

  29. Schultz, W., Dayan, P. & Montague, P. R. A neural substrate of prediction and reward. Science 275, 1593–1599 (1997)

    Article  CAS  Google Scholar 

  30. Cunningham, M. G. & McKay, R. D. A hypothermic miniaturized stereotaxic instrument for surgery in newborn rats. J. Neurosci. Methods 47, 105–114 (1993)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This research was supported by the Institut Pasteur, Collège de France, Centre National de la Recherche Scientifique CNRS URA 2182 and UMR 5106, Association de Recherche sur le Cancer, European Commission Contracts ‘NIDE’ and ‘Nicotine and Ageing’, Mission Interministérielle de Lutte contre la Drogue et la Toxicomanie (MILDT), a National Research Service Award Fellowship from the NIH (to B. E. M.), a Scholarship from the Letten F. Saugstad Foundation (to M. B.), and an ATER from Collège de France (to A. E.). We are grateful to L. Prado for the electrophysiological characterization of expression plasmids, and to C. Reperant and M. Soudant for technical assistance. We would like to thank J.-P. Bourgeois, B. Gutkin, H. Korn, P.-M. Lledo and R. McKay for comments on the manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to J.-P. Changeux.

Ethics declarations

Competing interests

Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Supplementary information

Supplementary Methods

Contains detailed information on the lentiviral vector constructed and all analysis methods used in the study, and Supplementary Figures S1-S6 (DOC 2407 kb)

Supplementary Figure S7

Anxiety measures of WT and KO mice (PDF 26 kb)

Supplementary Figure S8

Quantitative analysis of exploratory mouse behaviour in the open field (PDF 108 kb)

Supplementary Figure S9

State transitions in the open field behaviour (PDF 20 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Maskos, U., Molles, B., Pons, S. et al. Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors. Nature 436, 103–107 (2005). https://doi.org/10.1038/nature03694

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature03694

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing