title: Negative allosteric modulation of nicotinic acetylcholine receptors blocks nicotine self-administration in rats.
abstract: Drugs that antagonize nicotinic acetylcholine receptors (nAChRs) can be used to inhibit nicotine-induced behavior in both humans and animals. The aim of our experiments is to establish a proof-of-principle that antagonism of nAChRs by negative allosteric modulation can alter behavior in a relevant animal model of addiction, nicotine self-administration. We have identified a novel, negative allosteric modulator of nAChRs, UCI-30002 [N-(1,2,3,4-tetrahydro-1-naphthyl)-4-nitroaniline], with selectivity for the major neuronal nAChR subtypes over muscle-type nAChRs. After systemic administration, UCI-30002 significantly reduces nicotine self-administration in rats on both fixed ratio and progressive ratio schedules of reinforcement. The minimum effective dose that significantly alters nicotine self-administration corresponds to brain concentrations of UCI-30002 that produce at least 30% inhibition of the major neuronal nAChR subtypes measured in vitro. UCI-30002 has no effect on responding for food reinforcement in rats on either type of schedule, indicating that there is no effect on general responding or natural reward. UCI-30002 represents validation of the concept that negative allosteric modulators may have significant benefits as a strategy for treating nicotine addiction and encourages the development of subtype-selective modulators.
authors.affiliation: Department of Pharmacology, School of Medicine, University of California, Irvine, CA 92697, USA.
authors.forename: Ryan F
authors.initials: RF
authors.lastname: Yoshimura
authors.forename: Derk J
authors.initials: DJ
authors.lastname: Hogenkamp
authors.forename: Wen Y
authors.initials: WY
authors.lastname: Li
authors.forename: Minhtam B
authors.initials: MB
authors.lastname: Tran
authors.forename: James D
authors.initials: JD
authors.lastname: Belluzzi
authors.forename: Edward R
authors.initials: ER
authors.lastname: Whittemore
authors.forename: Frances M
authors.initials: FM
authors.lastname: Leslie
authors.forename: Kelvin W
authors.initials: KW
authors.lastname: Gee
mesh_terms: D000495:Allosteric Site; D000814:Aniline Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D005247:Feeding Behavior / Q000187:drug effects / Q000208:ethnology; D008024:Ligands; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009281:Naphthalenes / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D009538:Nicotine / Q000008:administration & dosage* / Q000009:adverse effects; D018733:Nicotinic Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control; D012646:Self Administration; D014029:Tobacco Use Disorder / Q000188:drug therapy / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: D000814:Aniline Compounds; D008024:Ligands; C524978:N-(1,2,3,4-tetrahydro-1-naphthyl)-4-nitroaniline; D009281:Naphthalenes; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D009538:Nicotine