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The Journal of Neuroscience, November 19, 2008, 28(47):12318-12327; doi:10.1523/JNEUROSCI.3918-08.2008

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Behavioral/Systems/Cognitive
Crucial Role of 4 and 6 Nicotinic Acetylcholine Receptor Subunits from Ventral Tegmental Area in Systemic Nicotine Self-Administration

S. Pons,^1,2 * L. Fattore,^3,4 * G. Cossu,⁵ S. Tolu,^1,2 E. Porcu,⁵ J. M. McIntosh,⁶ J. P. Changeux,² U. Maskos,^1,2 and W. Fratta^3,4,5

¹Unité ‘Neurobiologie intégrative des systèmes cholinergiques’, Institut Pasteur, 75724 Paris Cedex 15, France, ²Centre National de la Recherche Scientifique, Unité de Recherche Associée 2182, Institut Pasteur, 75724 Paris Cedex 15, France, ³Institute of Neuroscience, Consiglio Nazionale delle Ricerche, Sezione di Cagliari, 09042 Monserrato, Italy, ⁴Centre of Excellence ‘Neurobiology of Dependence’ and ⁵Department of Neuroscience, Cittadella Universitaria di Monserrato, University of Cagliari, 09042 Monserrato, Italy, and ⁶Departments of Biology and Psychiatry, University of Utah, Salt Lake City, Utah 84112

Correspondence should be addressed to either of the following: U. Maskos, Email: uwe.maskos{at}pasteur.fr, or W. Fratta, E-mail: Email: wfratta{at}unica.it, at the above addresses.

The identification of the molecular mechanisms involved in nicotine addiction and its cognitive consequences is a worldwide priority for public health. Novel in vivo paradigms were developed to match this aim. Although the β2 subunit of the neuronal nicotinic acetylcholine receptor (nAChR) has been shown to play a crucial role in mediating the reinforcement properties of nicotine, little is known about the contribution of the different subunit partners of β2 (i.e., 4 and 6), the homo-pentameric 7, and the brain areas other than the ventral tegmental area (VTA) involved in nicotine reinforcement. In this study, nicotine (8.7–52.6 µg free base/kg/inf) self-administration was investigated with drug-naive mice deleted (KO) for the β2, 4, 6 and 7 subunit genes, their wild-type (WT) controls, and KO mice in which the corresponding nAChR subunit was selectively re-expressed using a lentiviral vector (VEC mice). We show that WT mice, β2-VEC mice with the β2 subunit re-expressed exclusively in the VTA, 4-VEC mice with selective 4 re-expression in the VTA, 6-VEC mice with selective 6 re-expression in the VTA, and 7-KO mice promptly self-administer nicotine intravenously, whereas β2-KO, β2-VEC in the substantia nigra, 4-KO and 6-KO mice do not respond to nicotine. We thus define the necessary and sufficient role of 4β2- and 6β2-subunit containing nicotinic receptors (4β2*- and 6β2*-nAChRs), but not 7*-nAChRs, present in cell bodies of the VTA, and their axons, for systemic nicotine reinforcement in drug-naive mice.

Key words: nicotinic acetylcholine receptor (nAChR); ventral tegmental area (VTA); lentiviral vector; nicotine; intravenous self-administration; drug-naive mice

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Received Aug. 8, 2008; revised Sept. 22, 2008; accepted Oct. 9, 2008.

Correspondence should be addressed to either of the following: U. Maskos, Email: uwe.maskos{at}pasteur.fr, or W. Fratta, E-mail: Email: wfratta{at}unica.it, at the above addresses.

This article has been cited by other articles:

				K. J. Jackson, J. M. McIntosh, D. H. Brunzell, S. S. Sanjakdar, and M. I. Damaj The Role of {alpha}6-Containing Nicotinic Acetylcholine Receptors in Nicotine Reward and Withdrawal J. Pharmacol. Exp. Ther., November 1, 2009; 331(2): 547 - 554. [Abstract] [Full Text] [PDF]

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