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

Moura, Fernando B. de; McMahon, Lance R.

doi:10.1097/fbp.0000000000000233

Cited by 10 publications

(26 citation statements)

References 22 publications

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Section: Discussioncontrasting

confidence: 90%

“…Mecamylamine failed to antagonize the rate-decreasing effects of nicotine and varenicline, which contradicts previous studies demonstrating that the rate-decreasing effects of nicotine and varenicline were antagonized by mecamylamine (de Moura and McMahon 2016). However, this current study and the de Moura and McMahon (2016) study differed in the amount of nicotine and varenicline exposure the mice received. Repeated exposure to nicotine and varenicline in the current study, which was greater than in the de Moura and McMahon (2016) experiment prior to chronic nicotine treatment, may have diminished the capacity of mecamylamine to antagonize the rate-decreasing effects of nicotine and varenicline.…”

Section: Discussioncontrasting

confidence: 90%

“…However, this current study and the de Moura and McMahon (2016) study differed in the amount of nicotine and varenicline exposure the mice received. Repeated exposure to nicotine and varenicline in the current study, which was greater than in the de Moura and McMahon (2016) experiment prior to chronic nicotine treatment, may have diminished the capacity of mecamylamine to antagonize the rate-decreasing effects of nicotine and varenicline. Furthermore, 3.2 mg/kg mecamylamine has significant rate-decreasing effects on its own which may have limited its ability to antagonize the rate-decreasing effects of nicotine and varenicline.…”

Section: Discussionmentioning

confidence: 92%

“…However, it has also been demonstrated that the β2 selective nAChR antagonist dihydro-β-erythroidine (DHβE; Papke et al 2008) will not antagonize the discriminative stimulus effects of varenicline in nicotine-trained animals (Cunningham and McMahon 2013). In another study, the rate-decreasing effects and hypothermic effects of nicotine and varenicline were differentially antagonized by DHβE, and cross-tolerance to these effects of varenicline from nicotine treatment was significantly less than tolerance to nicotine (de Moura and McMahon, 2016). These results suggested that varenicline and nicotine differ in their pharmacology to produce in vivo effects.…”

Section: Introductionmentioning

confidence: 97%

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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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Section: Discussioncontrasting

confidence: 90%

Section: Discussioncontrasting

confidence: 90%

Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 97%

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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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“…However, extremely high level of nicotine results in hypotension and reduced heart rate intermediated by peripheral ganglionic blockade or central nervous system (N. L. Benowitz, 1988). In addition, the tolerance of nicotine is developed after repeated doses, which may cause adverse effects of nausea, vomiting and pallor and so on (Moura & McMahon, 2016).…”

Section: Historical Backgroundmentioning

confidence: 99%

Development of Nicotine Loaded Chitosan Nanoparticles for Lung Delivery

Wang¹

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Cigarette smoking has become one of the leading causes of preventable deaths all over the world, causing a serious threat to human wellbeing and a tremendous economic burden to governments. The currently available treatment options for smoking cessation are not efficient. The pulmonary delivery of drugs by methods such as dry powder inhaler (DPI) has been recognized as one of the most efficient routes of drug delivery to the targeted area. The lung delivery of nicotine in this way would be expected to mimic the effects of tobacco smoking and could significantly reduce the negative health effects of smoking that result from nicotine addiction.The aim of this study is to develop nanoparticles with controlled physicochemical properties using biodegradable polymer of chitosan (CS) loaded with nicotine salt for pulmonary delivery as DPI formulations. The outcomes of this project are expected to be a safe and effective CS-based nicotine formulation for pulmonary delivery to treat nicotine dependence. This thesis specially addresses the research questions: (1) how to develop a feasible process to manufacture the nanoparticles suitable for pulmonary drug delivery using biodegradable polymer of CS containing nicotine salt; (2) how to develop an animal model for pulmonary drug delivery from DPI formulation using a nose-only inhalation device.The current therapeutic options for treatment of smoking addiction have been reviewed, and current advancements of technology in pulmonary drug delivery are summarised. Buccal administration of drugs exhibits a low oral bioavailability, and sublingual tablets and chewing gums can be swallowed before being absorbed.Although nasal spray of nicotine is a fast way to deliver nicotine into the bloodstream, Development of Nicotine Loaded Chitosan Nanoparticles for Lung Delivery iii the rate of absorption is still not as rapid as cigarette smoking. Therefore, it is proposed that delivery of nicotine with sustained drug release profile direct into the deep lung is likely to more effectively mimic the rapid effects of cigarette smoking on a physiological level, which could eliminate patient craving and allow the tapering of nicotine level over time to improve patients' compliance.Water in oil (w/o) emulsion crosslinking method has been used to fabricate nicotine hydrogen tartrate (NHT)-loaded CS nanoparticles which separate as solid microaggregates. The physicochemical properties of particles are characterized by a series of techniques. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) shows that the prepared particles are spherical in morphology with rough surface after loading CS particles with NHT. Dynamic Light Scattering (DLS)by Zetasizer determined nanoparticle size ranging from 167.6 nm to 411 nm, while DLS by Mastersizer demonstrated that the microaggregates of these nanoparticles are in the respirable range (<5µm). The surface positive charge as measured by zeta potential tends to decrease with increase of mass ratios of NHT to CS, which is in contr...

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

2020

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Objectives: There 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.Methods: 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 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. Results:The ED 50 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. Conclusions:The 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

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

Cited by 10 publications

References 22 publications

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

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

Development of Nicotine Loaded Chitosan Nanoparticles for Lung Delivery

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

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