Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors

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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.

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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.

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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.

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Correspondence to J.-P. Changeux.

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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)

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

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