-
Nicotine & Tobacco Research : Official... Apr 2012Src kinase is reported to regulate neuronal nicotinic acetylcholine receptor activity, which is among the principal receptor systems acted upon by nicotine. Src kinase...
INTRODUCTION
Src kinase is reported to regulate neuronal nicotinic acetylcholine receptor activity, which is among the principal receptor systems acted upon by nicotine. Src kinase is documented to mediate the pathogenesis of substance dependence. Therefore, the present study has been designed to investigate the effect of SU-6656, selective src kinase inhibitor, on the development of nicotine dependence in a mouse model of mecamylamine-induced nicotine withdrawal syndrome.
METHODS
Our experimental protocol consisted of administration of nicotine (2.5 mg/kg, subcutaneously), 4 times daily for 7 days. In order to precipitate nicotine withdrawal, mice were given 1 injection of mecamylamine (3 mg/kg, intraperitoneally), 1 hr after the last nicotine injection on the test day (Day 8). Behavioral observations were made for a period of 30 min immediately after mecamylamine treatment. Withdrawal syndrome was quantitated in terms of a composite withdrawal severity score (WSS), and withdrawal syndrome-related anxiety was assessed by elevated plus maze test results.
RESULTS
SU-6656 markedly and dose dependently (p < .01) attenuated mecamylamine-induced experimental nicotine withdrawal syndrome in mice measured in terms of WSS and anxiety score.
CONCLUSIONS
Thus, it is suggested that src kinase is involved in the development of nicotine dependence-induced precipitation of its withdrawal syndrome and thus may serve as a viable pharmacological target to tackle the problem of nicotine addiction.
Topics: Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Indoles; Injections, Intraperitoneal; Injections, Subcutaneous; Male; Mecamylamine; Mice; Narcotic Antagonists; Nicotine; Substance Withdrawal Syndrome; Sulfonamides; Tobacco Use Disorder; src-Family Kinases
PubMed: 22102627
DOI: 10.1093/ntr/ntr228 -
Lancet (London, England) Aug 1998
Topics: Adolescent; Adult; Female; Humans; Male; Mecamylamine; Nicotinic Antagonists; Retrospective Studies; Tourette Syndrome; Treatment Outcome
PubMed: 9728992
DOI: 10.1016/S0140-6736(05)60822-7 -
British Medical Journal Nov 1957
Topics: Administration, Intravenous; Administration, Oral; Autonomic Agents; Body Fluids; Humans; Mecamylamine
PubMed: 13472094
DOI: 10.1136/bmj.2.5055.1219 -
Experimental and Clinical... Feb 2002Clinical and preclinical evidence suggests that mecamylamine, a nicotinic receptor antagonist, may have anxiolytic properties. The purpose of this study was to further... (Comparative Study)
Comparative Study
Clinical and preclinical evidence suggests that mecamylamine, a nicotinic receptor antagonist, may have anxiolytic properties. The purpose of this study was to further investigate the anxiolytic properties of mecamylamine in rats as measured by the Elevated Plus Maze and the Social Interaction models of anxiety and to determine if manipulation of the testing environment (either brightly lit or dimly lit conditions) influenced the results. Results indicated that mecamylamine had significant anxiolytic effects in both the Elevated Plus Maze and Social Interaction Tests and that these effects were dependent on dose administered and the level of anxiety produced under different testing conditions. If confirmed by further clinical research, nicotinic receptor antagonists like mecamylamine may represent a novel class of anxiolytics.
Topics: Animals; Anti-Anxiety Agents; Anxiety; Behavior, Animal; Interpersonal Relations; Lighting; Male; Mecamylamine; Models, Psychological; Rats; Rats, Wistar
PubMed: 11866248
DOI: 10.1037//1064-1297.10.1.18 -
Life Sciences 1997The effect of ondansetron (0.01-0.1 mg/kg, s.c.), a selective 5-HT3 receptor antagonist, on mecamylamine-precipitated nicotine-withdrawal aversion was examined in the...
The effect of ondansetron (0.01-0.1 mg/kg, s.c.), a selective 5-HT3 receptor antagonist, on mecamylamine-precipitated nicotine-withdrawal aversion was examined in the conditioned place preference paradigm. Male Sprague-Dawley rats were chronically treated subcutaneously with 9 mg/kg/day (-)-nicotine tartrate using an osmotic minipump. After nicotine treatment for 7 days, mecamylamine (1 mg/kg, s.c.), a nicotinic receptor antagonist, produced place aversion in nicotine-dependent rats. This aversive effect was dose-dependently antagonized by pretreatment with ondansetron 30 min prior to the conditioning. These results suggest that ondansetron may attenuate the place aversion associated with nicotine withdrawal, and may be useful for the treatment of nicotine dependence.
Topics: Animals; Conditioning, Psychological; Male; Mecamylamine; Nicotine; Nicotinic Antagonists; Ondansetron; Rats; Rats, Sprague-Dawley; Serotonin Antagonists; Substance Withdrawal Syndrome
PubMed: 9353175
DOI: 10.1016/s0024-3205(97)00745-5 -
Psychopharmacology Mar 1979Male Sprague-Dawley rats weighing 116--241 g were injected i.p. with ketamine hydrochloride, 80 mg per kilo of body weight. Immediately after loss of righting reflex,...
Male Sprague-Dawley rats weighing 116--241 g were injected i.p. with ketamine hydrochloride, 80 mg per kilo of body weight. Immediately after loss of righting reflex, scopolamine, physostigmine, and mecamylamine were administered i.p. to different groups of rats. Control animals received sterile saline by the same route. The ketamine-induced sleeping time was significantly prolonged by physostigmine and scopolamine, but not by mecamylamine. After the delayed injection of physostigmine, the ketamine sleeping time was longer. These results, although too preliminary for a mechanistic interpretation, suggest that multiple neurotransmitter systems, probably including the cholinergic system, are involved in the mechanism of action of ketamine-induced narcosis.
Topics: Animals; Drug Interactions; Ketamine; Male; Mecamylamine; Physostigmine; Rats; Scopolamine; Sleep; Time Factors
PubMed: 108720
DOI: 10.1007/BF00426811 -
Expert Opinion on Emerging Drugs Jun 2014Tobacco dependence remains a global epidemic and the largest preventable cause of morbidity and mortality around the world. Smoking cessation has benefits at all ages... (Review)
Review
INTRODUCTION
Tobacco dependence remains a global epidemic and the largest preventable cause of morbidity and mortality around the world. Smoking cessation has benefits at all ages but remains challenging for several reasons, among which are the complexities of nicotine addiction and limitations of available pharmacotherapies.
AREAS COVERED
This review summarizes current and emerging pharmacotherapies for the treatment of tobacco dependence, including first- and second-line recommended agents. Medications with alternative primary indications that have been investigated as potential treatments for tobacco dependence are also discussed. Articles reviewed were obtained through searches of PubMed, Ovid MEDLINE, ClinicalTrials.gov and the Pharmaprojects database.
EXPERT OPINION
Current evidence suggests that the two most effective pharmacotherapies to treat tobacco dependence are varenicline and combination nicotine replacement therapy. Alternative agents investigated demonstrate mixed rates of success in achieving long-term abstinence from smoking. No single pharmacotherapy will serve as a universally successful treatment given the complex underpinnings of tobacco dependence and individuality of smokers. The ultimate goal of tobacco research with respect to pharmacotherapeutic development continues to be providing clinicians with an armamentarium of drugs to choose from allowing for tailoring of treatment for smokers.
Topics: Atomoxetine Hydrochloride; Benzazepines; Bupropion; Clinical Trials as Topic; Clonidine; Humans; Mecamylamine; Nicotine; Nortriptyline; Propylamines; Quinoxalines; Tobacco Use Cessation Devices; Tobacco Use Disorder; Varenicline
PubMed: 24654737
DOI: 10.1517/14728214.2014.899580 -
Pharmacology, Biochemistry, and Behavior Feb 2001Separate and combined effects of nicotine and the nicotinic antagonist mecamylamine were studied in 32 healthy volunteer smokers after overnight abstinence from smoking.... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
Separate and combined effects of nicotine and the nicotinic antagonist mecamylamine were studied in 32 healthy volunteer smokers after overnight abstinence from smoking. Subjects participated in three sessions (3 h each), during which they wore skin patches delivering either 0 mg/24 h, 21 mg/24 h or 42 mg/24 h nicotine. Thirty-two subjects were randomly assigned to two groups receiving oral mecamylamine hydrochloride (10 mg) vs. placebo capsules. Two and one-half hours after drug administration, subjects were allowed to smoke ad lib, rating the cigarettes for rewarding and aversive effects. Transdermal nicotine produced a dose-related reduction in the subjective rewarding qualities of smoking. Nicotine also reduced craving for cigarettes and this effect was attenuated, but not eliminated, by mecamylamine. Mecamylamine blocked the discriminability of high vs. low nicotine puffs of smoke, and increased nicotine intake substantially during the ad lib smoking period. Some of the psychophysiological effects of each drug (elevation in blood pressure from nicotine, sedation and decreased blood pressure from mecamylamine) were offset by the other drug. The results supported the hypothesis that nicotine replacement can alleviate tobacco withdrawal symptoms even in the presence of an antagonist such as mecamylamine. Mecamylamine did not precipitate withdrawal beyond the level associated with overnight cigarette deprivation, suggesting its effects were primarily due to offsetting the action of concurrently administered nicotine as opposed to blocking endogenous cholinergic transmission.
Topics: Administration, Cutaneous; Adolescent; Adult; Analysis of Variance; Arousal; Behavior, Addictive; Blood Pressure; Dizziness; Drug Therapy, Combination; Female; Heart Rate; Humans; Male; Mecamylamine; Middle Aged; Nausea; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Smoking; Substance Withdrawal Syndrome
PubMed: 11267622
DOI: 10.1016/s0091-3057(00)00465-2 -
Neuropsychopharmacology : Official... Mar 1999We have previously shown that nicotine enhances cue-induced cocaine craving. In the present study, the effects of a nicotine antagonist, mecamylamine, on cue-induced... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
We have previously shown that nicotine enhances cue-induced cocaine craving. In the present study, the effects of a nicotine antagonist, mecamylamine, on cue-induced cocaine craving were investigated. Twenty-three cocaine-dependent patients, all cigarette smokers, were randomly assigned to mecamylamine (2.5 mg tablet) or placebo in a single-dose, placebo-controlled, crossover, double-blind study. Craving and anxiety were measured before and after cocaine cues with visual analog scales for desire to use cocaine and mood. Skin conductance, skin temperature and heart rate were recorded before and during cocaine cues. Following exposure to cocaine cues, all patients reported an increase in cocaine craving and anxiety relative to the precue measures. Cue exposure also produced an increase in skin conductance and decrease in skin temperature. The cue-induced increase in cocaine craving was reduced, while the cue-induced skin conductance and temperature responses were unaffected, by mecamylamine. These findings show that cue-induced cocaine craving is attenuated by mecamylamine. Further study on the use of mecamylamine in relapse prevention programs are suggested.
Topics: Adolescent; Adult; Aged; Behavior, Addictive; Cocaine-Related Disorders; Cross-Over Studies; Cues; Double-Blind Method; Female; Humans; Male; Mecamylamine; Middle Aged; Nicotinic Antagonists; Smoking
PubMed: 10063490
DOI: 10.1016/S0893-133X(98)00076-1 -
The Journal of Pharmacology and... Jan 2004Chlorisondamine and mecamylamine are nicotinic antagonists that produce both ganglionic and central blockade. Chlorisondamine, when administered as a large systemic...
Chlorisondamine and mecamylamine are nicotinic antagonists that produce both ganglionic and central blockade. Chlorisondamine, when administered as a large systemic dose, produces a persistent central block, despite being charged. The present study evaluated the cardiovascular effects of chlorisondamine. Shortly after administration, chlorisondamine (0.10, 1, and 10 mg/kg i.m.) lowered blood pressure significantly and decreased heart rate at the low dose (0.1 mg/kg i.m.) and increased heart rate at the high dose (10 mg/kg i.m.). Mecamylamine (1 and 10 mg/kg i.m.) also lowered blood pressure and heart rate. After both antagonists, heart rate returned to baseline values within 90 min and blood pressure within 24 h. Low doses of nicotine (0.01-0.03 mg/kg i.m.) lowered blood pressure but did not affect heart rate. Higher doses (0.10-3.2 mg/kg i.m.) transiently increased blood pressure and heart rate. Subsequent to antagonist administration, nicotine was administered to determine whether either drug blocked the cardiovascular effects of nicotine. Chlorisondamine (0.1, 1, and 10 mg/kg i.m.) administered 30 min before nicotine blocked the increases in blood pressure and heart rate. Only the high dose (10 mg/kg i.m.) of chlorisondamine administered 24 h before nicotine produced a blockade of nicotine's pressor effect. This block diminished within 3 days. Mecamylamine (1 mg/kg i.m.) antagonized only nicotine's tachycardic effect. Longer pretreatment with mecamylamine (10 mg/kg, 24 h before nicotine challenge) did not antagonize the cardiovascular effects of nicotine. Thus, chlorisondamine produces a longer lasting blockade of nicotine's cardiovascular effects than mecamylamine.
Topics: Animals; Blood Pressure; Chlorisondamine; Columbidae; Drug Interactions; Heart Rate; Mecamylamine; Nicotine; Nicotinic Antagonists
PubMed: 14566012
DOI: 10.1124/jpet.103.057307