title: Evidence that nicotinic alpha(7) receptors are not involved in the hyperlocomotor and rewarding effects of nicotine.
abstract: 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(4)beta(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(4)beta(2) subtype selective agonist SIB1765F increased activity in both experimental conditions. In nicotine-sensitized rats, the high affinity (including the alpha(4)beta(2) subtype) nicotinic antagonist dihydro-beta-erythroidine (DHbetaE), but not the selective alpha(7) antagonist methyllycaconitine (MLA), antagonized a nicotine-induced hyperactivity. Similarly, DHbetaE, 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(4)beta(2). Issues such as drug potency, CNS penetration, and desensitization of the alpha(7) receptor are discussed.
authors.affiliation: PRBN, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: A J
authors.initials: AJ
authors.lastname: Grottick
authors.forename: G
authors.initials: G
authors.lastname: Trube
authors.forename: W A
authors.initials: WA
authors.lastname: Corrigall
authors.forename: J
authors.initials: J
authors.lastname: Huwyler
authors.forename: P
authors.initials: P
authors.lastname: Malherbe
authors.forename: R
authors.initials: R
authors.lastname: Wyler
authors.forename: G A
authors.initials: GA
authors.lastname: Higgins
mesh_terms: D000818:Animals; D001952:Bridged-Ring Compounds / Q000134:cerebrospinal fluid / Q000494:pharmacology; D004594:Electrophysiology; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D009043:Motor Activity / Q000502:physiology*; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology; D009865:Oocytes / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000502:physiology*; D012201:Reward; D012646:Self Administration; D013141:Spiro Compounds / Q000134:cerebrospinal fluid / Q000494:pharmacology; D014162:Transfection; D014982:Xenopus laevis; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C412895:4-((3-(5,6-dihydro-4H-(2,3')bipyridinyl-3-ylidene)propenyl)phenyl)dimethylamine; C408128:AR-R 17779; D001952:Bridged-Ring Compounds; C579167:Chrna7 protein, human; C579165:Chrna7 protein, rat; D008024:Ligands; D018722:Nicotinic Agonists; D011725:Pyridines; D011759:Pyrrolidines; D011978:Receptors, Nicotinic; D013141:Spiro Compounds; D064569:alpha7 Nicotinic Acetylcholine Receptor; D009538:Nicotine; C100989:altinicline maleate