Discriminative stimulus and hypothermic effects of some derivatives of the nAChR agonist epibatidine in mice

Abstract

Rationale Receptor mechanisms underlying the in vivo effects of nicotinic acetylcholine receptor (nAChR) drugs need to be determined to better understand possible differences in therapeutic potential. Objective This study compared the effects of agonists that are reported either to differ in intrinsic activity (i.e., efficacy) at α4β2 nAChR in vitro or to have in vivo effects consistent with differences in efficacy. The drugs included nicotine, varenicline, cytisine, epibatidine, and three novel epibatidine derivatives 2′-fluoro-(4-nitrophenyl) deschloro-epibatidine (RTI-7527-102), 2′-fluorodeschloroepibatidine (RTI-7527-36), and 3′-(3″-dimethylaminophenyl)-epibatidine (RTI-7527-76). Methods Mice discriminated nicotine base (1 mg/kg base) from saline; other mice were used to measure rectal temperature. Results In the nicotine discrimination assay, the maximum percentage of nicotine-appropriate responding varied: 92% for nicotine, 84% for epibatidine, 77% for RTI-7527-36, 71% for varenicline, and significantly less for RTI-7527-76 (58%), RTI-7527-102 (46%), and cytisine (33%). Each drug markedly decreased rectal temperature by as much as 12 °C. The rank order potency in the discrimination and hypothermia assays was epibatidine > RTI-7527-36 > nicotine > RTI-7527-102 > varenicline = cytisine = RTI-7527-76. The nAChR antagonist mecamylamine (3.2 mg/kg) antagonized the discriminative stimulus effects of epibatidine and RTI-7527-102, as well as the hypothermic effects of every drug except cytisine. The β2-subunit selective nAChR antagonist dihydro-β-erythroidine (DHβE; up to 10 mg/kg) antagonized hypothermic effects, but less effectively so than mecamylamine. Conclusions The marked hypothermic effects of all drugs except cytisine are due in part to agonism at nAChR containing β2 subunits. Differential substitution for the nicotine discriminative stimulus is consistent with differences in α4β2 nAChR efficacy; however, these results suggest that multiple nAChR receptor subtypes mediate the effects of the agonists.

Differential antagonism and tolerance/cross-tolerance among nicotinic acetylcholine receptor agonists

“…However, varenicline has also been demonstrated to have agonist activity at α7 nAChRs, α3β4 nAChRs, and 5HT 3 receptors (Grady et al, 2010; Lummis et al, 2011). Actions at multiple receptors including nAChR and non-nAChR are consistent with studies suggesting that low efficacy at α4β2 nAChRs cannot account for all of the behavioral effects of varenicline (Cunningham and McMahon, 2011; Cunningham and McMahon, 2013; Rodriguez et al, 2014). …”

“…The present study was conducted to measure both in vivo effects and had two main objectives: 1) identify the extent to which α4β2 nAChRs mediate the rate-decreasing and hypothermic effects of nicotine, varenicline, cytisine, and epibatidine; and 2) examine the extent to which differential antagonism by the selective α4β2 nAChR antagonist dihydro-β-erythroidine (DHβE) predicts the degree of cross-tolerance that develops from nicotine to varenicline, cytisine, and epibatidine. Epibatidine was previously demonstrated to fully substitute for a nicotine discriminative stimulus in C57BL/6J mice (Rodriguez et al, 2014), consistent with similar mechanisms at nAChRs. Therefore, the expectation was that tolerance to nicotine would be accompanied by cross-tolerance from nicotine to epibatidine.…”

“…Operant responding (Cunningham and McMahon, 2011) and hypothermia in C57BL/6J mice (Rodriguez et al, 2014) have been used to examine the receptor pharmacology of nicotine and other nAChR agonists, as well as tolerance to nicotine (Rosecrans et al, 1989). The present study was conducted to measure both in vivo effects and had two main objectives: 1) identify the extent to which α4β2 nAChRs mediate the rate-decreasing and hypothermic effects of nicotine, varenicline, cytisine, and epibatidine; and 2) examine the extent to which differential antagonism by the selective α4β2 nAChR antagonist dihydro-β-erythroidine (DHβE) predicts the degree of cross-tolerance that develops from nicotine to varenicline, cytisine, and epibatidine.…”

Effects of nicotine in combination with drugs described as positive allosteric nicotinic acetylcholine receptor modulators in vitro: discriminative stimulus and hypothermic effects in mice

“…Nicotine was chosen because it is used widely from tobacco products and in the form of nicotine replacement therapy, and the effects of the novel compounds were studied both alone and in combination with nicotine. The discriminative stimulus effects and hypothermic effects of nicotine were both studied because there is evidence that nAChR subtypes differentially mediate these effects (Rodriguez et al, 2014), which was expected to confer drug- and effect-dependent differences in their modulation. Drug discrimination appears to be mediated by the α4β2 nAChR subtype (Gommans et al, 2000; Shoaib et al, 2002).…”

“…Drug discrimination appears to be mediated by the α4β2 nAChR subtype (Gommans et al, 2000; Shoaib et al, 2002). However, published data suggest that the hypothermic effects of nicotine are mediated by not only the α4β2 nAChR subtype (Rodriguez et al, 2014), but also perhaps the α7 nAChR subtype (Freitas et al, 2013a). Therefore, the nicotinic antagonists mecamylamine, dihydro-β-erythroidine (DHβE), and methyllycaconitine (MLA) were used to further characterize the nAChR mechanism underlying the hypothermic effects of nicotine.…”