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*NICOTINE
*NICOTINE TARTRATE

Vol. 294, Issue 3, 1112-1119, September 2000

Evidence That Nicotinic alpha 7 Receptors Are Not Involved in the Hyperlocomotor and Rewarding Effects of Nicotine1

Andrew J. Grottick, Gerhard Trube, William A. Corrigall, Joerg Huwyler, Parichehr Malherbe, Rene Wyler and Guy A. Higgins

PRBN, F. Hoffmann-La Roche Ltd., Basel, Switzerland (A.J.G., G.T., J.H., P.M., R.W., G.A.H.); and Centre for Addiction and Mental Health, ARF Division, Toronto, Canada (W.A.C.)

Neuronal nicotinic receptors are comprised of combinations of alpha 2-9 and beta 2-4 subunits arranged to form a pentameric receptor. Currently, the principal central nervous system (CNS) subtypes are believed to be alpha 4beta 2 and a homomeric alpha 7 receptor, although other combinations almost certainly exist. The identity of the nicotinic receptor subtype(s) involved in the rewarding effects of nicotine are unknown. In the present study, using some recently described subtype selective nicotinic agonists and antagonists, we investigated the role of the alpha 7 nicotinic receptor in the mediation of nicotine-induced hyperactivity and self-administration in rats. The alpha 7 receptor agonists AR-R 17779 and DMAC failed to stimulate locomotor activity in both nicotine-nontolerant and -sensitized rats. In contrast, nicotine and the putative alpha 4beta 2 subtype selective agonist SIB1765F increased activity in both experimental conditions. In nicotine-sensitized rats, the high affinity (including the alpha 4beta 2 subtype) nicotinic antagonist dihydro-beta -erythroidine (DHbeta E), but not the selective alpha 7 antagonist methyllycaconitine (MLA), antagonized a nicotine-induced hyperactivity. Similarly, DHbeta E, but not MLA, pretreatment reduced nicotine self-administration. Electrophysiology experiments using Xenopus oocytes expressing the human alpha 7 receptor confirmed AR-R 17779 and DMAC to be potent agonists at this site, and further studies demonstrated the ability of systemically administered AR-R 17779 to penetrate into the CNS. Taken together, these results indicate a negligible role of alpha 7 receptors in nicotine-induced hyperlocomotion and reward in the rat, and support the view for an involvement of a member from the high-affinity nicotinic receptor subclass, possibly alpha 4beta 2. Issues such as drug potency, CNS penetration, and desensitization of the alpha 7 receptor are discussed.

1 Funding for this work was provided by F. Hoffman-La Roche AG. We would like to thank Kathy Coen and Laurie Adamson for their contribution to the nicotine self-administration experiments and Eva Pflugfelder for assistance with the oocyte experiments.

0022-3565/00/2943-1112$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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