Evidence that nicotinic 7 receptors are not involved in the hyperlocomotor and rewarding effects of nicotine.

Abstract

ABSTRACT Neuronal nicotinic receptors are comprised of combinations of ␣ 2-9 and ␤ 2-4 subunits arranged to form a pentameric receptor. Currently, the principal central nervous system (CNS) subtypes are believed to be ␣ 4 ␤ 2 and a homomeric ␣ 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 ␣ 7 nicotinic receptor in the mediation of nicotine-induced hyperactivity and selfadministration in rats. The ␣ 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 ␣ 4 ␤ 2 subtype selective agonist SIB1765F increased activity in both experimental conditions. In nicotinesensitized rats, the high affinity (including the ␣ 4 ␤ 2 subtype) nicotinic antagonist dihydro-␤-erythroidine (DH␤E), but not the selective ␣ 7 antagonist methyllycaconitine (MLA), antagonized a nicotine-induced hyperactivity. Similarly, DH␤E, but not MLA, pretreatment reduced nicotine self-administration. Electrophysiology experiments using Xenopus oocytes expressing the human ␣ 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 ␣ 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 ␣ 4 ␤ 2 . Issues such as drug potency, CNS penetration, and desensitization of the ␣ 7 receptor are discussed