Negative Allosteric Modulation of Nicotinic Acetylcholine Receptors Blocks Nicotine Self-Administration in Rats

  1. Ryan F. Yoshimura,
  2. Derk J. Hogenkamp,
  3. Wen Y. Li,
  4. Minhtam B. Tran,
  5. James D. Belluzzi,
  6. Edward R. Whittemore,
  7. Frances M. Leslie and
  8. Kelvin W. Gee
  1. Department of Pharmacology, School of Medicine, University of California, Irvine, California
  1. Address correspondence to:
    Dr. Kelvin W. Gee, Department of Pharmacology, University of California, Medical Surge I, Room 110C, Irvine, CA 92697. E-mail: kwgee{at}uci.edu

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.

Footnotes

  • This work was supported in part by University of California Discovery Grant Bio04-10469 (to K.W.G.).

  • Parts of this work were previously presented at the following conference: Yoshimura RF, Hogenkamp DJ, Li WY, and Gee KW (2006) Negative allosteric modulators of neuronal nicotinic acetylcholine receptors as potential smoking cessation therapeutics. 2006 Society for Neuroscience; 2006 Oct 14–18; Atlanta, GA. Session no. 591.7, Society for Neuroscience, Washington, DC.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.107.128751.

  • ABBREVIATIONS: DHβE, dihydro-β-erythroidine; nACHR, nicotinic acetylcholine receptor; UCI-30002, N-(1,2,3,4-tetrahydro-1-naphthyl)-4-nitroaniline; NMDA, N-methyl-d-aspartate; PEG, polyethylene glycol 400; D5W, 5% dextrose in water; DMSO, dimethyl sulfoxide; FR, fixed ratio; TO20, 20-s dark time-out period; BP, break point; ANOVA, analysis of variance.

    • Received July 19, 2007.
    • Accepted September 13, 2007.
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  1. Published online before print September 14, 2007, doi: 10.1124/jpet.107.128751 JPET December 2007 vol. 323 no. 3 907-915
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