Unexpected loss of sensitivity to the nicotinic acetylcholine receptor antagonist activity of mecamylamine and dihydro-β-erythroidine in nicotine-tolerant mice.

Fernando B De Moura,Lance R Mcmahon,Jenny L Wilkerson

doi:10.1002/brb3.1581

Abstract

ObjectivesThere is a long‐standing interest in developing nicotinic acetylcholine receptor (nAChR) antagonists for concomitant use with nAChR agonists (e.g., nicotine replacement) as complementary smoking cessation aids. Previous studies demonstrate that daily nicotine treatment confers tolerance to some effects of nicotine, as well as cross‐tolerance to other nAChR agonists. The current study assessed the extent to which antagonism of nicotine varies as a function of daily nicotine treatment.MethodsSchedule‐controlled responding and hypothermia were selected for study because they have been previously used to examine the pharmacology of nicotine, and both are sensitive to the development nicotine tolerance. The rate‐decreasing and hypothermic effects of nicotine, as well as antagonism of those effects, were examined in C57BL/6J mice before, during treatment with, and after discontinuation of three daily injections of 1.78 mg/kg nicotine. The nonselective nAChR antagonist mecamylamine and the β2 nAChR antagonist dihydro‐β‐erythroidine (DHβE) were studied in combination with nicotine.ResultsThe ED50 values of nicotine to produce rate‐decreasing and hypothermic effects were, respectively, 0.44 and 0.82 mg/kg prior, 1.6 and 3.2 mg/kg during, and 0.74 and 1.1 mg/kg after discontinuation of daily nicotine treatment. Prior to daily nicotine treatment, mecamylamine decreased response rate and rectal temperature. However, during daily nicotine, mecamylamine (up to 5.6 mg/kg) only decreased rectal temperature. DHβE (up to 5.6 mg/kg) when studied prior to daily nicotine decreased rectal temperature, but that decrease was abolished during chronic nicotine treatment. Mecamylamine and DHβE antagonized the rate‐decreasing and hypothermic effects of nicotine before and after daily nicotine; however, during daily nicotine, mecamylamine and DHβE antagonized only the hypothermic effects of nicotine.ConclusionsThe differential antagonism of rate‐decreasing and hypothermic effects implicates differential involvement of nAChR subtypes. The decreased capacity of mecamylamine and DHβE to antagonize nicotine during chronic nicotine treatment may indicate that their effectiveness as smoking cessations might vary as a function of nicotine tolerance and dependence.

Highlights

Tobacco use is the leading cause of preventable death (World Health Organization, 2011)
This study identified whether exposure to nicotine under conditions that produce tolerance but are unlikely to be sensitive to antagonist-induced precipitated withdrawal (Damaj et al, 2003; de Moura & McMahon, 2016) disrupts the ability of the nicotinic acetylcholine receptor (nAChR) antagonists mecamylamine and DHβE to block the in vivo effects of nicotine
Simple schedule-controlled responding and hypothermia were selected for study because they have been previously used to examine the pharmacology of nicotine, and both are sensitive to the development of nicotine tolerance (Cunningham & McMahon, 2011; de Moura & McMahon, 2016; Rodriguez et al, 2014; Rosecrans et al, 1989)

Summary

| INTRODUCTION

Tobacco use is the leading cause of preventable death (World Health Organization, 2011). A potential strategy previously considered but not yet formally approved is the use of nicotinic acetylcholine receptor (nAChR) antagonists, which have been demonstrated to attenuate the reinforcing effects of nicotine as well as nicotine-induced increases in mesolimbic dopamine (Corrigall, Franklin, Coen, & Clarke, 1992; Crooks, Bardo, & Dwoskin, 2014; Nisell, Nomikos, & Svensson, 1994). One such antagonist is the nonselective, noncompetitive nAChR ligand mecamylamine (Frishman, Mitta, Kupersmith, & Ky, 2006; Lancaster & Stead, 2000). Simple schedule-controlled responding and hypothermia were selected for study because they have been previously used to examine the pharmacology of nicotine, and both are sensitive to the development of nicotine tolerance (Cunningham & McMahon, 2011; de Moura & McMahon, 2016; Rodriguez et al, 2014; Rosecrans et al, 1989)

| MATERIALS AND METHODS

| Experimental procedure

33 Mecamylamine

Findings

| DISCUSSION