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The American Journal of the Medical... Aug 1956
Topics: Camphor; Mecamylamine
PubMed: 13339785
DOI: 10.1097/00000441-195608000-00002 -
Psychopharmacology Oct 1996Mecamylamine is an antihypertensive that acts via nicotinic antagonism and has been suggested as an aid in smoking cessation. Nicotine dependent patients may not accept... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
Mecamylamine is an antihypertensive that acts via nicotinic antagonism and has been suggested as an aid in smoking cessation. Nicotine dependent patients may not accept mecamylamine if it precipitates withdrawal, as it does in nicotine dependent rats. This study examined mecamylamine's effects using procedures designed to measure precipitated withdrawal symptoms in humans. Ten cigarette smokers (mean of 37.5 cigarettes/day) and ten non tobacco-using subjects participated in three 6-h sessions. After a 2-h baseline period in which smokers smoked one cigarette every 30 min, oral mecamylamine (0, 10, or 20 mg randomly ordered across sessions) was administered (double-blind). No smoking was allowed for the remainder of the session. Mecamylamine reduced blood pressure and increased heart rate relative to placebo in both the smokers and the non-tobacco users. No reliable direct subjective effects of mecamylamine were observed. Smokers' subjective reports of cigarette craving and tobacco withdrawal increased, and DSST performance was disrupted over the last 4 h of each session. Effects were independent of dose (placebo versus active). These results suggest that up to 20 mg mecamylamine will not precipitate nicotine withdrawal and that this medication would be acceptable for use in smoking cessation.
Topics: Adult; Blood Pressure; Carbon Monoxide; Female; Heart Rate; Humans; Male; Mecamylamine; Middle Aged; Nicotinic Antagonists; Smoking; Smoking Cessation; Stimulation, Chemical; Substance Withdrawal Syndrome
PubMed: 8923568
DOI: 10.1007/s002130050094 -
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 -
Brain Research Bulletin Nov 2020Previous studies showed that mecamylamine a noncompetitive and nonspecific blocker of nicotinic acetylcholine receptors (nAChRs), stimulates the activity of the dorsal...
Previous studies showed that mecamylamine a noncompetitive and nonspecific blocker of nicotinic acetylcholine receptors (nAChRs), stimulates the activity of the dorsal raphe nucleus (DRN) serotonergic neurons and DRN serotonin (5-HT) release. In the present study, the mechanisms involved in these mecamylamine-induced effects were examined using electrophysiology and calcium-imaging studies, both performed in Wistar rat midbrain slices. Mecamylamine (0.5-9 μM), bath administered, increased the firing frequency of identified 5-HT DRN neurons by a maximum of 5% at 3 μM. This effect was accompanied by a 112 % increase in the frequency of spontaneous excitatory postsynaptic currents of 5-HT DRN neurons. It was blocked by the AMPA/kainate receptor blocker CNQX (10 μM) and by the specific α4β2 nAChRs blocker dihydro-β-erythroidine (100 nM) but was not affected by tetrodotoxin (TTX, 500 nM). Simultaneously, mecamylamine produced a 58 % decrease in the frequency of GABAergic spontaneous inhibitory postsynaptic currents, an effect that was not influenced by TTX. Calcium-imaging studies support the results obtained with the electrophysiological studies by showing that mecamylamine (3 μM) increases the activity of a cell population located in the midline of the DRN, which was sensitive to the inhibitory effects of 8-OH-DPAT, an agonist at 5-HT receptors. It is assumed that mecamylamine, in low concentrations, acts as an agonist of α4β2 nAChRs present on the glutamatergic DRN terminals, thus increasing intra-raphe glutamate release. This stimulatory effect is reinforced by the decrease in DRN GABA release, which is dependent on the mecamylamine-induced blockade of α7 nAChRs located on DRN GABAergic terminals. We hypothesize that at least a part of mecamylamine antidepressant effects described in animal models of depression are mediated by an increase in DRN 5-HT release.
Topics: Action Potentials; Animals; Calcium; Dorsal Raphe Nucleus; Ganglionic Blockers; Male; Mecamylamine; Patch-Clamp Techniques; Rats; Rats, Wistar; Serotonergic Neurons
PubMed: 32910991
DOI: 10.1016/j.brainresbull.2020.08.031 -
Bollettino Chimico Farmaceutico Apr 1957
Topics: Autonomic Agents; Chlorides; Ions; Mecamylamine
PubMed: 13436596
DOI: No ID Found -
ACS Chemical Neuroscience Aug 2010
Topics: Animals; Antidepressive Agents; Citalopram; Clinical Trials, Phase III as Topic; Depressive Disorder, Major; Double-Blind Method; Drug Evaluation, Preclinical; Drug Therapy, Combination; Humans; Mecamylamine; Molecular Structure; Multicenter Studies as Topic; Nicotinic Antagonists; Patient Selection; Randomized Controlled Trials as Topic; Receptors, Nicotinic; Selective Serotonin Reuptake Inhibitors; Stereoisomerism
PubMed: 22778844
DOI: 10.1021/cn100070s -
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 -
Investigative Ophthalmology & Visual... Apr 2008Nicotinic acetylcholine receptors (nAChR) are best known for their role in neurotransmission, but they have recently been demonstrated on vascular endothelial cells....
PURPOSE
Nicotinic acetylcholine receptors (nAChR) are best known for their role in neurotransmission, but they have recently been demonstrated on vascular endothelial cells. Acetylcholine is their endogenous ligand, but they are also stimulated by nicotine. By stimulating nAChR, nicotine promotes tumor angiogenesis as well as atherosclerotic plaque neovascularization. In this study, the authors investigated the role of nAChR in the pathogenesis of choroidal neovascularization (CNV).
METHODS
The effect of the nonselective nAChR antagonist mecamylamine was tested on human retinal and choroidal endothelial cells in vitro and in a murine model of CNV.
RESULTS
Several nAChR isoforms were identified in retinal and choroidal microvascular endothelial cells, and the ability of these cells to form tubules when grown in growth factor-reduced basement membrane matrix and supplemented with VEGF was suppressed by the nAChR antagonist mecamylamine. Supplementation of the drinking water of mice with nicotine increased the size of CNV lesions at Bruch membrane rupture sites, an effect that was blocked by subcutaneous administration of mecamylamine (50 mg/kg/d) by an osmotic pump. In the absence of nicotine, CNV formation was suppressed by the infusion of 50 mg/kg/d mecamylamine or by topical application 0.1 or 1% mecamylamine to the cornea.
CONCLUSIONS
These data suggest that endogenous activation of nAChR promotes CNV and that activation of nAChR by nicotine may contribute to the increased incidence of CNV seen in smokers with age-related macular degeneration (AMD). Topically administered mecamylamine could provide an appealing new treatment approach for CNV.
Topics: Animals; Cells, Cultured; Choroid; Choroidal Neovascularization; Disease Models, Animal; Endothelium, Vascular; Female; Humans; Immunoblotting; Mecamylamine; Mice; Mice, Inbred C57BL; Nicotine; Nicotinic Antagonists; Protein Isoforms; RNA, Messenger; Receptors, Nicotinic; Retinal Vessels
PubMed: 18385094
DOI: 10.1167/iovs.07-0089 -
IDrugs : the Investigational Drugs... Mar 2006Targacept Inc, under license from the University of South Florida, is developing a low-dose, liquid gel capsule formulation of the nicotinic acetylcholine antagonist...
Targacept Inc, under license from the University of South Florida, is developing a low-dose, liquid gel capsule formulation of the nicotinic acetylcholine antagonist mecamylamine, as a potential treatment for various neuropsychiatric disorders.
Topics: Adolescent; Adult; Animals; Attention Deficit Disorder with Hyperactivity; Child; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Evaluation, Preclinical; Humans; Mecamylamine; Nicotinic Antagonists; Randomized Controlled Trials as Topic; Smoking Cessation; Substance-Related Disorders; Tourette Syndrome
PubMed: 16523387
DOI: No ID Found -
Experimental and Clinical... Aug 1998The nicotinic antagonist mecamylamine was evaluated in a randomized smoking cessation trial. Four groups of participants (n = 20 per group) received nicotine plus... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
The nicotinic antagonist mecamylamine was evaluated in a randomized smoking cessation trial. Four groups of participants (n = 20 per group) received nicotine plus mecamylamine, nicotine alone, mecamylamine alone, or no drug for 4 weeks before cessation. After the quit-smoking date, all subjects received nicotine plus mecamylamine treatment for 6 weeks. Nicotine skin patches (21 mg/24 hr) and mecamylamine capsules (2.5-5.0 mg twice per day) were used. Precessation mecamylamine significantly prolonged the duration of continuous smoking abstinence; abstinence rates at the end of treatment were 47.5% with mecamylamine and 27.5% without mecamylamine. Nicotine + mecamylamine reduced ad lib smoking, smoking satisfaction, and craving more than either drug alone. Moreover, the orthostatic decrease in blood pressure caused by mecamylamine was offset by nicotine. Mecamylamine before smoking cessation may be an effective adjunct to nicotine patch therapy.
Topics: Adult; Affect; Behavior Therapy; Drug Therapy, Combination; Female; Humans; Male; Mecamylamine; Nicotine; Nicotinic Agonists; North Carolina; Smoking Cessation; Time Factors; Tobacco Use Disorder
PubMed: 9725117
DOI: 10.1037//1064-1297.6.3.331