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

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Abstract

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.

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Acknowledgements

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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