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Nicotine & Tobacco Research : Official... Feb 2022Ingestion of nicotine by smoking, vaping, or other means elicits various effects including reward, antinociception, and aversion due to irritation, bitter taste, and... (Review)
Review
INTRODUCTION
Ingestion of nicotine by smoking, vaping, or other means elicits various effects including reward, antinociception, and aversion due to irritation, bitter taste, and unpleasant side effects such as nausea and dizziness.
AIMS AND METHODS
Here we review the sensory effects of nicotine and the underlying neurobiological processes.
RESULTS AND CONCLUSIONS
Nicotine elicits oral irritation and pain via the activation of neuronal nicotinic acetylcholine receptors (nAChRs) expressed by trigeminal nociceptors. These nociceptors excite neurons in the trigeminal subnucleus caudalis (Vc) and other brainstem regions in a manner that is significantly reduced by the nAChR antagonist mecamylamine. Vc neurons are excited by lingual application of nicotine and exhibit a progressive decline in firing to subsequent applications, consistent with desensitization of peripheral sensory neurons and progressively declining ratings of oral irritation in human psychophysical experiments. Nicotine also elicits a nAChR-mediated bitter taste via excitation of gustatory afferents. Nicotine solutions are avoided even when sweeteners are added. Studies employing oral self-administration have yielded mixed results: Some studies show avoidance of nicotine while others report increased nicotine intake over time, particularly in adolescents and females. Nicotine is consistently reported to increase human pain threshold and tolerance levels. In animal studies, nicotine is antinociceptive when delivered by inhalation of tobacco smoke or systemic infusion, intrathecally, and by intracranial microinjection in the pedunculopontine tegmentum, ventrolateral periaqueductal gray, and rostral ventromedial medulla. The antinociception is thought to be mediated by descending inhibition of spinal nociceptive transmission. Menthol cross-desensitizes nicotine-evoked oral irritation, reducing harshness that may account for its popularity as a flavor additive to tobacco products.
IMPLICATIONS
Nicotine activates brain systems underlying reward and antinociception, but at the same time elicits aversive sensory effects including oral irritation and pain, bitter taste, and other unpleasant side effects mediated largely by nicotinic acetylcholine receptors (nAChRs). This review discusses the competing aversive and antinociceptive effects of nicotine and exposure to tobacco smoke, and the underlying neurobiology. An improved understanding of the interacting effects of nicotine will hopefully inform novel approaches to mitigate nicotine and tobacco use.
Topics: Adolescent; Animals; Female; Humans; Mecamylamine; Nicotine; Receptors, Nicotinic; Nicotiana; Tobacco Products; Tobacco Use
PubMed: 33955474
DOI: 10.1093/ntr/ntab086 -
Expert Review of Clinical Pharmacology Mar 2019Green tobacco sickness occurs from transdermal absorption of chemicals from freshly harvested, green tobacco leaves. Signs and symptoms include nausea, vomiting,... (Review)
Review
Green tobacco sickness occurs from transdermal absorption of chemicals from freshly harvested, green tobacco leaves. Signs and symptoms include nausea, vomiting, headache, and abdominal cramps. Prevalence has shifted from the United States and Europe to China, India, and Brazil. Worldwide 8 million individuals are afflicted, including women and children. Areas covered: Mecamylamine (Inversine®, Vecamyl®), a nicotinic acetylcholine receptor (nAChR) antagonist, should be tested as a remedy for green tobacco sickness. Mecamylamine is approved as an oral tablet for the treatment of hypertension, is safe, and is off-patent. Mecamylamine attenuates many of the effects of nicotine and tobacco including seizures, thereby supporting its use as an effective pharmacotherapy for tobacco dependence. Varenicline (Chantix®) and cytisine (Tabex®) are low efficacy (i.e. intrinsic activity) nAChR agonists, are used as smoking cessation aids, and are viable options to test as remedies against green tobacco sickness. Nicotine immunization strategies may provide further options for future testing. Expert commentary: Efforts to demonstrate reversal and/or prevention of green tobacco sickness by mecamylamine will underscore the importance of nicotine in this illness and highlight a new medication for effective treatment of tobacco poisoning.
Topics: Agricultural Workers' Diseases; Humans; Mecamylamine; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Plant Leaves; Nicotiana; Vaccines; Varenicline
PubMed: 30650314
DOI: 10.1080/17512433.2019.1570844 -
Pharmacology, Biochemistry, and Behavior Jul 2013Mecamylamine (3-methylaminoisocamphane hydrochloride) is a nicotinic parasympathetic ganglionic blocker, originally utilized as a therapeutic agent to treat... (Review)
Review
Mecamylamine (3-methylaminoisocamphane hydrochloride) is a nicotinic parasympathetic ganglionic blocker, originally utilized as a therapeutic agent to treat hypertension. Mecamylamine administration produces several deleterious side effects at therapeutically relevant doses. As such, mecamylamine's use as an antihypertensive agent was phased out, except in severe hypertension. Mecamylamine easily traverses the blood-brain barrier to reach the central nervous system (CNS), where it acts as a nicotinic acetylcholine receptor (nAChR) antagonist, inhibiting all known nAChR subtypes. Since nAChRs play a major role in numerous physiological and pathological processes, it is not surprising that mecamylamine has been evaluated for its potential therapeutic effects in a wide variety of CNS disorders, including addiction. Importantly, mecamylamine produces its therapeutic effects on the CNS at doses 3-fold lower than those used to treat hypertension, which diminishes the probability of peripheral side effects. This review focuses on the pharmacological properties of mecamylamine, the differential effects of its stereoisomers, S(+)- and R(-)-mecamylamine, and the potential for effectiveness in treating CNS disorders, including nicotine and alcohol addiction, mood disorders, cognitive impairment and attention deficit hyperactivity disorder.
Topics: Animals; Drug Evaluation, Preclinical; Humans; Mecamylamine; Nicotinic Antagonists; Stereoisomerism
PubMed: 23603417
DOI: 10.1016/j.pbb.2013.04.005 -
Neuroscience Letters Jun 2023L-theanine, 2-amino-4-(ethylcarbamoyl) butyric acid, an amino acid detected in green tea leaves, is used as a dietary supplement to attenuate stress and enhance mood and...
BACKGROUND
L-theanine, 2-amino-4-(ethylcarbamoyl) butyric acid, an amino acid detected in green tea leaves, is used as a dietary supplement to attenuate stress and enhance mood and cognition. Furthermore, L-theanine induces anxiolytic effects in humans. Recently, L-theanine was reported to reduce morphine physical dependence in primates, suggesting the potential usefulness of L-theanine for drug dependence intervention.
OBJECTIVE
The aim of this study is to determine whether L-theanine attenuates nicotine-withdrawal (somatic and affective signs) and nicotine reward in mice. We also investigated the effects of L-theanine on nicotinic receptors binding and function.
METHODS
ICR male mice rendered dependent to nicotine through implanted subcutaneous osmotic minipumps for 14 days undertook precipitated nicotine withdrawal by mecamylamine on day 15. Anxiety-like behaviors using LDB, somatic signs observation and hot plate latency were assessed consecutively after treatment with L-theanine. Furthermore, we examined the effect of L-theanine on acute nicotine responses and nicotine conditioned reward in mice and on expressed nicotinic receptors in oocytes.
KEY FINDINGS
L-theanine reduced in a dose-dependent manner anxiety-like behavior, hyperalgesia and somatic signs during nicotine withdrawal. Also, L-theanine decreased the nicotine CPP, but it did not affect the acute responses of nicotine. Finally, L-theanine did not alter the binding or the function of expressed α4β2 and α7 nAChRs.
CONCLUSION
Our results support the potential of L-theanine as a promising candidate for treating nicotine dependence.
Topics: Humans; Male; Mice; Animals; Nicotine; Mice, Inbred ICR; Substance Withdrawal Syndrome; Receptors, Nicotinic; Mecamylamine; Reward; Nicotinic Antagonists
PubMed: 37105354
DOI: 10.1016/j.neulet.2023.137279 -
Pharmacology, Biochemistry, and Behavior Apr 2019Mecamylamine is a non-competitive nicotinic acetylcholine receptor (nAChR) antagonist that has been prescribed for hypertension and as an off-label smoking cessation...
Mecamylamine is a non-competitive nicotinic acetylcholine receptor (nAChR) antagonist that has been prescribed for hypertension and as an off-label smoking cessation aid. Here, we examined pharmacological mechanisms underlying the interoceptive effects (i.e., discriminative stimulus effects) of mecamylamine (5.6 mg/kg s.c.) and compared the effects of nAChR antagonists in this discrimination assay to their capacity to block a nicotine discriminative stimulus (1.78 mg/kg s.c.) in rhesus monkeys. Central (pempidine) and peripherally restricted nAChR antagonists (pentolinium and chlorisondamine) dose-dependently substituted for the mecamylamine discriminative stimulus in the following rank order potency (pentolinium > pempidine > chlorisondamine > mecamylamine). In contrast, at equi-effective doses based on substitution for mecamylamine, only mecamylamine antagonized the discriminative stimulus effects of nicotine, i.e., pentolinium, chlorisondamine, and pempidine did not. NMDA receptor antagonists produced dose-dependent substitution for mecamylamine with the following rank order potency (MK-801 > phencyclidine > ketamine). In contrast, behaviorally active doses of smoking cessation aids including nAChR agonists (nicotine, varenicline, and cytisine), the smoking cessation aid and antidepressant bupropion, and the benzodiazepine midazolam did not substitute for the discriminative stimulus effects of mecamylamine. These data suggest that peripheral nAChRs and NMDA receptors may contribute to the interoceptive stimulus effects produced by mecamylamine. Based on the current results, the therapeutic use of mecamylamine (i.e., for smoking or to alleviate green tobacco sickness) should be weighed against the potential for mecamylamine to produce interoceptive effects that overlap with another class of abused drugs (i.e., NMDA receptor agonists).
Topics: Animals; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Female; Macaca mulatta; Male; Mecamylamine; Nicotine; Nicotinic Agonists
PubMed: 30738085
DOI: 10.1016/j.pbb.2019.02.002 -
Pharmacology, Biochemistry, and Behavior Aug 2011Attention can be readily measured in experimental animal models. Animal models of attention have been used to better understand the neural systems involved in attention,... (Review)
Review
Attention can be readily measured in experimental animal models. Animal models of attention have been used to better understand the neural systems involved in attention, how attention is impaired, and how therapeutic treatments can ameliorate attentional deficits. This review focuses on the ways in which animal models are used to better understand the neuronal mechanism of attention and how to develop new therapeutic treatments for attentional impairment. Several behavioral test methods have been developed for experimental animal studies of attention, including a 5-choice serial reaction time task (5-CSRTT), a signal detection task (SDT), and a novel object recognition (NOR) test. These tasks can be used together with genetic, lesion, pharmacological and behavioral models of attentional impairment to test the efficacy of novel therapeutic treatments. The most prominent genetic model is the spontaneously hypertensive rat (SHR). Well-characterized lesion models include frontal cortical or hippocampal lesions. Pharmacological models include challenge with the NMDA glutamate antagonist dizocilpine (MK-801), the nicotinic cholinergic antagonist mecamylamine and the muscarinic cholinergic antagonist scopolamine. Behavioral models include distracting stimuli and attenuated target stimuli. Important validation of these behavioral tests and models of attentional impairments for developing effective treatments for attentional dysfunction is the fact that stimulant treatments effective for attention deficit hyperactivity disorder (ADHD), such as methylphenidate (Ritalin®), are effective in the experimental animal models. Newer lines of treatment including nicotinic agonists, α4β2 nicotinic receptor desensitizers, and histamine H₃ antagonists, have also been found to be effective in improving attention in these animal models. Good carryover has also been seen for the attentional improvement caused by nicotine in experimental animal models and in human populations. Animal models of attention can be effectively used for the development of new treatments of attentional impairment in ADHD and other syndromes in which have attentional impairments occur, such as Alzheimer's disease and schizophrenia.
Topics: Animals; Attention; Attention Deficit Disorder with Hyperactivity; Behavior, Animal; Disease Models, Animal; Dizocilpine Maleate; Humans; Mecamylamine; Nootropic Agents; Rats; Rats, Inbred SHR; Scopolamine
PubMed: 21334367
DOI: 10.1016/j.pbb.2011.02.008 -
The Journal of Pharmacology and... Mar 2021Nicotine is the major addictive component in tobacco. Cotinine is the major metabolite of nicotine and a weak agonist for nicotinic acetylcholine receptors (nAChRs).... (Comparative Study)
Comparative Study
Nicotine is the major addictive component in tobacco. Cotinine is the major metabolite of nicotine and a weak agonist for nicotinic acetylcholine receptors (nAChRs). Nicotine supports self-administration in rodents. However, it remains undetermined whether cotinine can be self-administered. This study aimed to characterize cotinine self-administration in rats, to compare effects of cotinine to those of nicotine, and to determine potential involvement of nAChRs in cotinine's effects. Adult Wistar rats were trained to self-administer cotinine or nicotine (0.0075, 0.015, 0.03, or 0.06 mg/kg per infusion) under fixed-ratio (FR) and progressive-ratio (PR) schedules. Blood nicotine and cotinine levels were determined after the last FR session. Effects of mecamylamine, a nonselective nAChR antagonist, and varenicline, a partial agonist for 42* nAChRs, on cotinine and nicotine self-administration were determined. Rats readily acquired cotinine self-administration, responded more on active lever, and increased motivation to self-administer cotinine when the reinforcement requirement increased. Blood cotinine levels ranged from 77 to 792 ng/ml. Nicotine induced more infusions at lower doses during FR schedules and greater breakpoints at higher doses during the PR schedule than cotinine. There was no difference in cotinine self-administration between male and female rats. Mecamylamine and varenicline attenuated nicotine but not cotinine self-administration. These results indicate that cotinine was self-administered by rats. These effects of cotinine were less robust than nicotine and exhibited no sex difference. nAChRs appeared to be differentially involved in self-administration of nicotine and cotinine. These results suggest cotinine may play a role in the development of nicotine use and misuse. SIGNIFICANCE STATEMENT: Nicotine addiction is a serious public health problem. Cotinine is the major metabolite of nicotine, but its involvement in nicotine reinforcement remains elusive. Our findings indicate that cotinine, at doses producing clinically relevant blood cotinine levels, supported intravenous self-administration in rats. Cotinine self-administration was less robust than nicotine. Mecamylamine and varenicline attenuated nicotine but not cotinine self-administration. These results suggest cotinine may play a role in the development of nicotine use and misuse.
Topics: Animals; Cotinine; Dose-Response Relationship, Drug; Drug Interactions; Female; Male; Mecamylamine; Nicotine; Rats; Rats, Wistar; Receptors, Nicotinic; Self Administration; Varenicline
PubMed: 33361363
DOI: 10.1124/jpet.120.000367 -
The Cochrane Database of Systematic... 2000Mecamylamine is a nicotine antagonist (that is it blocks the effect of nicotine). The rationale for its use in smoking cessation is that it may block the rewarding... (Comparative Study)
Comparative Study Review
BACKGROUND
Mecamylamine is a nicotine antagonist (that is it blocks the effect of nicotine). The rationale for its use in smoking cessation is that it may block the rewarding effect of nicotine and thus reduce the urge to smoke.
OBJECTIVES
The objective of this review was to determine the effectiveness of mecamylamine in promoting smoking cessation, either alone or in combination with nicotine replacement therapy.
SEARCH STRATEGY
We searched the Cochrane Tobacco Addiction Group trials register.
SELECTION CRITERIA
Randomised trials of mecamylamine, either alone or in combination with nicotine replacement therapy, which reported smoking cessation rates at least six months after intervention.
DATA COLLECTION AND ANALYSIS
We extracted data in duplicate on the type of subjects, the dose and duration of the mecamylamine and nicotine treatments, side-effects of treatment, the outcome measures, method of randomisation, and completeness of follow-up. The main outcome measure was sustained abstinence from smoking (biochemically validated) after at least six months follow-up in patients smoking at baseline. Smokers lost to follow-up were regarded as being continuing smokers. Because of the preliminary nature of available data, we did not perform meta-analysis but report the results narratively.
MAIN RESULTS
We identified two studies, both from the same investigators. In a study of 48 volunteers, a combination of mecamylamine plus nicotine patch was more effective than nicotine patch alone (abstinence rate at one year 37.5% vs 4.2%). In a second study, 80 volunteers were treated for four weeks prior to cessation with one of four treatments: 1. Nicotine patch plus mecamylamine capsules 2. Nicotine alone 3. Mecamylamine alone 4. No active drug. All four groups received combination treatment with nicotine and mecamylamine after the scheduled quit date. The abstinence rates in these four groups were respectively 40%, 20%, 15% and 15%. The higher abstinence rate in the group treated with combination therapy was not statistically significant. The authors reported a statistically significant benefit of mecamylamine using Kaplan-Meier survival analysis. In the doses used, mecamylamine was well tolerated, although up to 40% of subjects required reductions in dose, usually because of constipation.
REVIEWER'S CONCLUSIONS
Data from two small studies suggest that the combination of nicotine and mecamylamine may be superior to nicotine alone in promoting smoking cessation. However, these results require confirmation in larger studies before the treatment can be recommended clinically.
Topics: Administration, Cutaneous; Drug Therapy, Combination; Humans; Mecamylamine; Nicotine; Nicotinic Antagonists; Smoking Cessation; Smoking Prevention
PubMed: 10796584
DOI: 10.1002/14651858.CD001009 -
Psychopharmacology Feb 2014Nicotinic acetylcholine receptors (nAChRs) have been implicated in the pathophysiology of cognitive deficits in the domains of attention and memory in schizophrenia.... (Randomized Controlled Trial)
Randomized Controlled Trial
RATIONALE
Nicotinic acetylcholine receptors (nAChRs) have been implicated in the pathophysiology of cognitive deficits in the domains of attention and memory in schizophrenia. While nicotinic agonists and antagonists have been proposed as smoking cessation aids, few comparisons have been made of these agents on cognitive performance in individuals with schizophrenia.
OBJECTIVES
This study investigated the acute effects of a nAChR antagonist, mecamylamine, and partial agonist, varenicline, on cognitive function in non-smokers with and without schizophrenia.
METHODS
Single oral doses of mecamylamine 10 mg, varenicline 1 mg, and placebo were administered 1 week apart in random order to adults with schizophrenia (n = 30) and to healthy volunteers (n = 41) in a double-blind, crossover design. The primary outcome of interest was sustained attention as assessed with hit reaction time variability (HRT-SD) on the identical pairs continuous performance test (CPT-IP).
RESULTS
Mecamylamine worsened performance on CPT-IP HRT-SD, a measure of attention, compared to varenicline in both groups. Performance on mecamylamine was worse than performance on both placebo and varenicline on several additional measures of attention, including CPT-IP hit reaction time (HRT) and random errors at various levels of task difficulty. There was a treatment by diagnosis interaction, such that mecamylamine worsened performance on CPT-IP 2-digit HRT, 3-digit random errors, and 4-digit hit rate compared to placebo and varenicline in participants with schizophrenia; effects not observed in controls.
CONCLUSIONS
These findings support a role for nAChRs in attention and suggest that those with schizophrenia may be particularly sensitive to nAChR blockade.
Topics: Adult; Antipsychotic Agents; Attention; Benzazepines; Cognition; Cross-Over Studies; Double-Blind Method; Female; Humans; Male; Mecamylamine; Middle Aged; Neuropsychological Tests; Nicotinic Agonists; Nicotinic Antagonists; Quinoxalines; Reaction Time; Schizophrenia; Schizophrenic Psychology; Smoking Cessation; Task Performance and Analysis; Varenicline
PubMed: 24114425
DOI: 10.1007/s00213-013-3286-3 -
Physiology & Behavior Dec 2012The early development of novel nicotinic drugs for Tourette's and depression was a very long journey in discovery, which began with basic behavioral neuroscience studies... (Review)
Review
The early development of novel nicotinic drugs for Tourette's and depression was a very long journey in discovery, which began with basic behavioral neuroscience studies aimed at understanding how cholinergic and dopaminergic systems interact in the basal ganglia to control goal directed movement. These early rodent studies with nicotine and dopamine antagonists formed the basis for investigating a potentially improved treatment for children suffering from Tourette's syndrome (TS). Clinically, the research trajectory first focused on studies employing the use of nicotine gum to potentiate the therapeutic effect of the dopamine receptor antagonist, haloperidol, in patients with TS. These projects led to the discovery of a new use for a decades-old blood pressure medication, mecamylamine, a nicotine antagonist, which also appeared to provide symptomatic relief in some TS patients when used clinically and was found to reduce symptoms of mood instability and depression. This unexpected discovery led to a new hypothesis regarding the mechanism of action of antidepressants as well as a series of successful independent trials employing mecamylamine, and its active enantiomer, TC5214, as an augmenting agent in the treatment of major depression. This article is a chronological mini review of these basic and clinical translational studies on nicotinic therapeutics for Tourette's syndrome and depression over the past 25 years.
Topics: Animals; Basal Ganglia; Depression; Humans; Mecamylamine; Nicotine; Tourette Syndrome; Translational Research, Biomedical
PubMed: 22776623
DOI: 10.1016/j.physbeh.2012.06.023