The effects of nicotine, varenicline, and cytisine on schedule-controlled responding in mice: Differences in α4β2 nicotinic receptor activation

Cunningham, Colin S.; McMahon, Lance R.

doi:10.1016/j.ejphar.2010.12.003

Cited by 25 publications

(25 citation statements)

References 22 publications

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“…However, mecamylamine was less effective at blocking the small cardiovascular changes produced by cytisine. Although previous findings have reported that the in vitro and in vivo effects of cytisine were partially or fully attenuated by mecamylamine (Stolerman et al, 1983; Hall et al, 1993; Chandler and Stolerman, 1997; Cunningham and McMahon et al, 2011; Cunningham et al, 2012), the current data suggest that the large doses of cytisine used in the present study have some non-nicotinic receptor-mediated effects.…”

Section: Discussioncontrasting

confidence: 90%

Patterns of nicotinic receptor antagonism II: Cardiovascular effects in rats

Jutkiewicz

Rice

Carroll

et al. 2013

Drug and Alcohol Dependence

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Background Tobacco cessation pharmacotherapies currently are limited to nicotine itself, the partial nicotine agonists varenicline and cytisine, and the antidepressant bupropion. Compared with agonists, nicotinic antagonists such as the noncompetitive, nonselective compound mecamylamine, and the competitive, α4β2-preferring antagonist dihydro-β-erythroidine (DHβE) may be a novel approach to the treatment of tobacco smoking as both are effective antagonists of nicotine’s central effects. Considering nicotinic acetylcholine receptors mediate critical peripheral effects of acetylcholine, such as cardiovascular effects, it is important to study how nicotinic antagonists would alter the cardiovascular system and the cardiovascular changes induced by nicotine. Methods The effects of several nicotinic agonists and antagonists on blood pressure and heart rate were measured in conscious, unrestrained rats following parenteral administration using a telemetry system. Results Nicotine and other nicotinic receptor agonists (epibatidine, varenicline, and cytisine) produced similar increases in blood pressure, whereas their effects on heart rate were biphasic. The cardiovascular changes were attenuated by the nonselective nicotine antagonist, mecamylamine, but the peripherally-restricted antagonist hexamethonium blocked only the agonist-induced changes in blood pressure. The α7-preferring antagonist, MLA, and the α4β2-preferring antagonist, DHβE, were much less effective in blocking the agonist-induced cardiovascular changes, indicating that nicotine’s cardiovascular effects, are due to activation at autonomic ganglia involving nicotinic receptor subtypes other than α4, α7, or β2. Conclusions The data indicate that the cardiovascular effects of nicotine and nicotine-like agents are mediated through receptor mechanisms that are distinct from those that mediate the central effects of nicotine.

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Section: Discussioncontrasting

confidence: 90%

Patterns of nicotinic receptor antagonism II: Cardiovascular effects in rats

Jutkiewicz

Rice

Carroll

et al. 2013

Drug and Alcohol Dependence

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“…4). Overall, the actions of varenicline at low doses, as an antagonist of ␤2* nAChRs, and at higher doses, as an agonist of ␣3␤4* nAChRs as seen in the formalin test, seem consistent with varenicline's effects on body temperature, locomotion (Ortiz et al, 2012), and responding for food in mice (Cunningham and McMahon, 2011). In contrast, the agonist effects of sazetidine-A in the formalin test seems to be mediated largely by ␤2* nAChR subtypes.…”

Section: Discussionmentioning

confidence: 60%

The Antinociceptive Effects of Nicotinic Partial Agonists Varenicline and Sazetidine-A in Murine Acute and Tonic Pain Models

AlSharari

Carroll

McIntosh

et al. 2012

J Pharmacol Exp Ther

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Nicotinic agonists display a wide-range profile of antinociceptive activity in acute, tonic, and chronic pain models. However, their effectiveness is limited by their unacceptable side effects. We investigated the antinociceptive effects of two new ␣4␤2* nicotinic partial agonists, varenicline and sazetidine-A, in acute thermal and tonic pain mouse models. Both drugs failed to induce significant effects in the tail-flick and hot-plate tests after subcutaneous administration. However, they blocked nicotine's effects in these tests at very low doses. In contrast to acute pain tests, varenicline and sazetidine-A dose-dependently induced an analgesic effect in the mouse formalin test after systemic administration. Their antinociceptive effects were mediated, however, by different nicotinic acetylcholine receptor (nAChR) subtypes. Sazetidine-A effects were mediated by ␤2* nAChR subtypes, whereas varenicline actions were attributed to ␣3␤4 nAChRs. Moreover, low inactive doses of varenicline blocked nicotine's actions in phase II of the formalin test. Overall, our results suggest that the antagonistic actions of varenicline at low doses are mediated by ␤2*-nAChRs and at higher doses as an agonist by ␣3␤4*-nAChRs. In contrast, both actions of sazetidine-A are mediated by ␤2*-nAChR subtypes. These results suggest that nicotinic partial agonists possess analgesic effects in a rodent tonic pain model and may provide a potential treatment for the treatment of chronic pain disorders.

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“…The relative potency of cytisine to produce discriminative stimulus, rate-decreasing, and hypothermic effects was the same as that for all of the other nAChR agonists studied here. Moreover, mecamylamine was demonstrated previously to antagonize both the discriminative stimulus and rate-decreasing effects of cytisine (Cunningham and McMahon 2011; 2013). The mechanism responsible for the hypothermic effects of cytisine could be of some interest inasmuch as non-nicotinic mechanisms are involved in the effectiveness of cytisine as a smoking cessation aid.…”

Section: Discussionmentioning

confidence: 92%

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

et al. 2014

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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.

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The effects of nicotine, varenicline, and cytisine on schedule-controlled responding in mice: Differences in α4β2 nicotinic receptor activation

Cited by 25 publications

References 22 publications

Patterns of nicotinic receptor antagonism II: Cardiovascular effects in rats

Patterns of nicotinic receptor antagonism II: Cardiovascular effects in rats

The Antinociceptive Effects of Nicotinic Partial Agonists Varenicline and Sazetidine-A in Murine Acute and Tonic Pain Models

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

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