Received for publication July 23, 2007.
Revised September 10, 2007.
Accepted for publication September 13, 2007.

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, N-(1,2,3,4-tetrahydro-1-naphthyl)-4-nitroaniline (UCI-30002), with selectivity for the major neuronal nAChR subtypes over muscle-type nAChRs. Following 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.

Key words: allosteric, electrophysiology, nAChR, nicotine, pharmacokinetics, self-administration