PT - JOURNAL ARTICLE AU - Ryan F. Yoshimura AU - Derk J. Hogenkamp AU - Wen Y. Li AU - Minhtam B. Tran AU - James D. Belluzzi AU - Edward R. Whittemore AU - Frances M. Leslie AU - Kelvin W. Gee TI - Negative Allosteric Modulation of Nicotinic Acetylcholine Receptors Blocks Nicotine Self-Administration in Rats AID - 10.1124/jpet.107.128751 DP - 2007 Dec 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 907--915 VI - 323 IP - 3 4099 - http://jpet.aspetjournals.org/content/323/3/907.short 4100 - http://jpet.aspetjournals.org/content/323/3/907.full SO - J Pharmacol Exp Ther2007 Dec 01; 323 AB - 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. The American Society for Pharmacology and Experimental Therapeutics