Discriminative stimulus properties of the nicotinic agonist cytisine

Chandler, Carol J.; Stolerman, I. P.

doi:10.1007/s002130050188

Cited by 48 publications

(22 citation statements)

References 25 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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“…However, the current findings highlight the importance of nAChRs besides α4β2* in the behavioral effects of varenicline, which is the most effective smoking cessation aid on the market today (Hays et al 2008). Previous studies using either multiple nicotine training doses (Jutkiewicz et al 2011; Cunningham and McMahon 2013) or cytisine as a training drug (Chandler and Stolerman 1997) have strongly implicated a role for multiple nAChR subtypes in the discriminative stimulus effects of nicotine, and failure of DHβE to antagonize varenicline in the nicotine discrimination is consistent with a possible contribution of non-α4β2* nAChRs to the discriminative stimulus effects of nicotine.…”

Section: Discussionmentioning

confidence: 85%

The contribution of α4β2 and non-α4β2 nicotinic acetylcholine receptors to the discriminative stimulus effects of nicotine and varenicline in mice

Moura

McMahon

2016

Psychopharmacology

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Rationale The extent to which non-α4β2 versus α4β2* nAChRs contribute to the behavioral effects of varenicline and other nAChR agonists is unclear. Objectives The purpose of this study was to characterize the discriminative stimulus effects of varenicline and nicotine using various nAChR agonists and antagonists to elucidate possible non-α4β2 nAChR mechanisms. Methods Separate groups of male C57BL/6J mice were trained to discriminate varenicline (3.2 mg/kg) or nicotine (1 mg/kg). Test drugs included mecamylamine, the nAChR agonists epibatidine, nicotine, cytisine, varenicline, RTI-102, the β2-containing nAChR antagonist dihydro-β-erythroidine (DHβE), the α7 nAChR agonist PNU-282987, the α7 antagonist methyllycaconitine (MLA), the α3β4 antagonist 18-methoxycoronaridine (18-MC), and the non-nAChR drugs midazolam and cocaine. Results In nicotine-trained mice, maximum nicotine-appropriate responding was: 95% nicotine, 94% epibatidine; 63% varenicline; 58% cytisine; and less than 50% for RTI-102, PNU-282987, midazolam, and cocaine. In varenicline-trained mice, maximum varenicline-appropriate responding was: 90% varenicline, 86% epibatidine; 74% cytisine; 80% RTI-102; 50% cocaine; and 50% or less for nicotine, PNU-282987, and midazolam. Drugs were studied to doses that abolished operant responding. Mecamylamine antagonized the discriminative stimulus effects, but not the rate-decreasing effects, of nicotine and varenicline. DHβE antagonized the discriminative stimulus and rate-decreasing effects of nicotine, but not varenicline in either the nicotine or varenicline discrimination assays. The discriminative stimulus, but not rate-decreasing, effects of epibatidine were antagonized by DHβE regardless of the training drug. Conclusions These results suggest that α4β2* nAChRs differentially mediate the discriminative stimulus effects of nicotine and varenicline, and suggest that varenicline has substantial non-α4β2 nAChR activity.

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“…However, unlike varenicline, cross-tolerance failed to develop from nicotine to cytisine. While differences in the receptor pharmacology of nicotine and cytisine have been previously observed in vivo (Chandler and Stolerman, 1997), antagonism of cytisine by mecamylamine suggests that nAChRs mediate the rate-decreasing effects of cytisine. The lack of cross-tolerance from nicotine to cytisine could indicate that the current parameters of chronic nicotine dosing do not produce loss of function at the nAChR subtypes that mediate the effects of cytisine.…”

Section: Discussionmentioning

confidence: 86%

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

Moura

McMahon²

2016

Behavioural Pharmacology

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The tobacco dependence pharmacotherapies varenicline and cytisine act as partial α4β2 nAChR agonists. However, the extent to which α4β2 nAChRs mediate their in vivo effects remains unclear. Nicotine, varenicline, cytisine, and epibatidine were studied in male C57BL/6J mice for their effects on rates of fixed ratio responding and rectal temperature, alone and in combination with the nonselective nAChR antagonist mecamylamine and the α4β2 nAChR antagonist DHβE. The effects of nicotine, varenicline, cytisine, epibatidine, and cocaine were assessed before and during chronic nicotine treatment. The rate-decreasing and hypothermic effects of nicotine, varenicline, cytisine, and epibatidine were antagonized by mecamylamine (1 mg/kg), but only the effects of nicotine and epibatidine were antagonized by DHβE (3.2 mg/kg). Chronic nicotine produced 4.7 and 5.1 fold rightward shifts in the nicotine dose-effect functions to decrease response rate and rectal temperature, respectively. Nicotine treatment decreased the potency of epibatidine to decrease response rate and rectal temperature 2.2 and 2.9 fold, respectively, and shifted the varenicline dose-effect functions 2.0 and 1.7 fold rightward, respectively. Cross-tolerance did not develop from nicotine to cytisine. These results suggest that the in vivo pharmacology of tobacco cessation aids cannot be attributed to a single nAChR subtype; instead, multiple receptor subtypes differentially mediate their effects.

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Discriminative stimulus properties of the nicotinic agonist cytisine

Cited by 48 publications

References 25 publications

Patterns of nicotinic receptor antagonism II: Cardiovascular effects in rats

Patterns of nicotinic receptor antagonism II: Cardiovascular effects in rats

The contribution of α4β2 and non-α4β2 nicotinic acetylcholine receptors to the discriminative stimulus effects of nicotine and varenicline in mice

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

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