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El Dia Medico May 1957
Topics: Autonomic Agents; Hypertension; Mecamylamine
PubMed: 13447685
DOI: No ID Found -
Progress in Neuro-psychopharmacology &... Apr 20011. The available evidence suggests that stress induced release of acetylcholine (ACh) in the brain has a significant role in mediating neuroendocrine, emotional, and...
1. The available evidence suggests that stress induced release of acetylcholine (ACh) in the brain has a significant role in mediating neuroendocrine, emotional, and physiological responses to stress. Recent findings also suggest that stress indirectly (via acetylcholine) and nicotine directly stimulates the HPA axis through activation of nAChRs. 2. Our working hypothesis is that under stressful conditions, nicotinic receptor antagonists, such as mecamylamine, should act to attenuate the activation of the HPA axis and exhibit anxiolytic behavioral effects. The purpose of this study was to determine whether or not mecamylamine would: a) produce anxiolytic effects in rats on the elevated plus maze and b) blunt the plasma corticosterone response to predator stress in rats. 3. Results suggested that mecamylamine has anxiolytic properties under stressful conditions. In the EPM experiment, mecamylamine (0.3 mg/kg) produced increased time spent in the open arms. Similarly, in the predator stressor experiment, mecamylamine blunted the stress-induced plasma corticosterone response, with the lowest dose of mecamylamine (0.1 mg/kg). 4. These findings may have important therapeutic implications since clinical observations have shown that low doses of mecamylamine reduce tension and anxiety in patients with Tourette syndrome.
Topics: Animals; Anti-Anxiety Agents; Anxiety; Cats; Corticosterone; Dose-Response Relationship, Drug; Hypothalamo-Hypophyseal System; Male; Mecamylamine; Nicotinic Antagonists; Pituitary-Adrenal System; Rats; Rats, Sprague-Dawley; Stress, Psychological
PubMed: 11371000
DOI: 10.1016/s0278-5846(00)00178-0 -
British Medical Journal May 1959
Topics: Autonomic Agents; Gastrointestinal Hemorrhage; Hemorrhage; Humans; Intestinal Diseases; Jejunum; Mecamylamine
PubMed: 13638660
DOI: 10.1136/bmj.1.5130.1167 -
Lancet (London, England) Sep 1957
Topics: Autonomic Agents; Hypertension; Mecamylamine; Monitoring, Physiologic; Professional Practice
PubMed: 13476665
DOI: 10.1016/s0140-6736(57)91941-4 -
Behavioural Pharmacology Aug 2014The extent to which chronic nicotine treatment can alter the effects of the nicotinic acetylcholine receptor antagonist mecamylamine, and whether those effects can be...
The extent to which chronic nicotine treatment can alter the effects of the nicotinic acetylcholine receptor antagonist mecamylamine, and whether those effects can be attenuated by nicotine have not been clearly established in the literature. Here, the discriminative stimulus effects of mecamylamine were compared between one group of rhesus monkeys receiving a continuous infusion of nicotine base (5.6 mg/kg/day subcutaneously) and another group of monkeys not receiving nicotine treatment. Both groups responded under a fixed ratio 5 schedule of stimulus-shock termination. Stimulus control was obtained at doses of 1.78 mg/kg mecamylamine in monkeys receiving continuous nicotine and 5.6 mg/kg mecamylamine in monkeys not receiving continuous nicotine treatment. Nicotine did not attenuate the discriminative stimulus effects of mecamylamine in either group. Discontinuation of continuous nicotine produced responding on the mecamylamine lever within 24 h in some but not all monkeys. This may indicate a qualitative difference in the discriminative stimulus effects of mecamylamine between groups, perhaps reflecting antagonism of nicotine and nicotine withdrawal in monkeys receiving continuous nicotine. The failure of nicotine to reverse the effects of mecamylamine is consistent with a noncompetitive interaction at nicotinic acetylcholine receptors and indicates that mecamylamine-induced withdrawal cannot be readily modified by nicotine.
Topics: Animals; Discrimination Learning; Female; Macaca mulatta; Male; Mecamylamine; Neuropsychological Tests; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Receptors, Nicotinic; Substance Withdrawal Syndrome
PubMed: 24978703
DOI: 10.1097/FBP.0000000000000054 -
Brain and Behavior Apr 2020There is a long-standing interest in developing nicotinic acetylcholine receptor (nAChR) antagonists for concomitant use with nAChR agonists (e.g., nicotine replacement)...
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 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 may indicate that their effectiveness as smoking cessations might vary as a function of nicotine tolerance and dependence.
Topics: Animals; Dihydro-beta-Erythroidine; Dose-Response Relationship, Drug; Drug Tolerance; Male; Mecamylamine; Mice; Mice, Inbred C57BL; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Smoking Cessation
PubMed: 32092237
DOI: 10.1002/brb3.1581 -
Journal of Pharmaceutical and... Sep 2000The nicotine receptor antagonist mecamylamine has been shown to increase the efficacy of transdermal nicotine as a pharmacotherapy for tobacco addiction. A product for...
The nicotine receptor antagonist mecamylamine has been shown to increase the efficacy of transdermal nicotine as a pharmacotherapy for tobacco addiction. A product for simultaneous transdermal administration of nicotine and mecamylamine is undergoing clinical trials. In order to carry out pharmacokinetic studies, quantitation of low nanogram per milliliter levels of mecamylamine and nicotine was required. This paper describes a method for simultaneous determination of mecamylamine, nicotine, and the nicotine metabolite, cotinine, in human plasma using gas chromatography-mass spectrometry (GC-MS). Limits of quantitation for mecamylamine, nicotine and cotinine are 2, 1 and 2 ng/ml, respectively.
Topics: Cotinine; Gas Chromatography-Mass Spectrometry; Humans; Indicators and Reagents; Mecamylamine; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Reference Standards; Reproducibility of Results; Solutions
PubMed: 10975241
DOI: 10.1016/s0731-7085(00)00343-5 -
Journal of the American Academy of... Sep 2001The safety and efficacy of mecamylamine as a monotherapy in children and adolescents with Tourette's disorder (TD) was investigated in an 8-week multicenter,... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
OBJECTIVE
The safety and efficacy of mecamylamine as a monotherapy in children and adolescents with Tourette's disorder (TD) was investigated in an 8-week multicenter, double-blind, placebo-controlled study.
METHOD
Eligible subjects included subjects with TD (DSM-IV), with a naturalistic mix of comorbid diagnoses, nonsmokers, aged 8 to 17 years, whose behavioral and emotional symptoms (according to parents) were more disturbing than tics. After a washout period of all psychotropic medication, subjects were randomly assigned to either mecamylamine (n = 29) or placebo (n = 32). Mecamylamine doses ranged from 2.5 to 7.5 mg/day. Primary efficacy measures included the Tourette's Disorder Scale-Clinician Rated (TODS-CR) and 21-point Clinical Global Improvement scale; secondary efficacy measures included the Yale Global Tic Severity Scale and a rage-attack scale (RAScal).
RESULTS
Of the 61 subjects who were randomized, 50 (82%) completed at least 3 weeks on medication and 38 (62%) completed the full 8-week trial. Study withdrawals included 12/29 on mecamylamine and 11/32 on placebo. For the total sample, mecamylamine was no more effective than placebo on any of the outcome measures. However, an item analysis of the TODS-CR suggested that mecamylamine may have reduced sudden mood changes and depression in moderately to severely affected subjects. Except for a slight increase in heart rate during the 1st week in both the mecamylamine and the placebo groups, there where no significant mecamylamine-related changes in vital signs, electrocardiogram, complete blood cell count, or blood chemistry values.
CONCLUSIONS
Mecamylamine, in doses up to 7.5 mg/day, is well tolerated in children and adolescents, but as a monotherapy it does not appear to be an effective treatment for tics or for the total spectrum of symptoms associated with TD. However, further studies should be conducted to investigate its possible therapeutic effects in subjects with comorbid mood disorders and as an adjunct to neuroleptic medication.
Topics: Adolescent; Child; Comorbidity; Depression; Double-Blind Method; Female; Ganglionic Blockers; Heart Rate; Humans; Male; Mecamylamine; Mood Disorders; Placebos; Severity of Illness Index; Tourette Syndrome; Treatment Outcome
PubMed: 11556635
DOI: 10.1097/00004583-200109000-00020 -
Psychopharmacology May 1997Nefiracetam is undergoing preclinical and clinical tests as a cognition-enhancing drug in Alzheimer's disease (AD). Nicotinic cholinergic receptors are lost in AD, and...
Nefiracetam is undergoing preclinical and clinical tests as a cognition-enhancing drug in Alzheimer's disease (AD). Nicotinic cholinergic receptors are lost in AD, and nicotinic as well as muscarinic cholinergic receptors are involved in the modulation of eyeblink conditioning. Experiments were carried out using young rabbits to examine the effect of nefiracetam on cholinergic antagonists to nicotinic (mecamylamine) and muscarinic (scopolamine) receptors. Rabbits were tested for 15 days in the 750 ms delay eyeblink classical conditioning paradigm in paired and explicitly unpaired conditions. Nefiracetam at a dose of 15 mg/kg significantly ameliorated the effects of 0.5 mg/kg mecamylamine, and nefiracetam at a dose of 10 mg/kg significantly ameliorated the effect of 1.5 mg/kg scopolamine. The vehicle alone and nefiracetam alone groups performed similarly to the groups treated with mecamylamine or scopolamine and nefiracetam. Reversal by nefiracetam of a nicotinic as well as a muscarinic cholinergic antagonist indicates that the drug may affect deficits specific to AD.
Topics: Animals; Dose-Response Relationship, Drug; Female; Learning; Mecamylamine; Nootropic Agents; Pyrrolidinones; Rabbits; Reaction Time; Scopolamine
PubMed: 9201800
DOI: 10.1007/s002130050275 -
The Journal of Pharmacology and... Feb 2009(+/-)-Mecamylamine is a racemic mixture of a widely used brain-permeant noncompetitive inhibitor of muscle-type and neuronal nicotinic receptors (NNRs). The present...
(+/-)-Mecamylamine is a racemic mixture of a widely used brain-permeant noncompetitive inhibitor of muscle-type and neuronal nicotinic receptors (NNRs). The present studies evaluated whether the stereoisomers of this drug show different profiles for inhibition of the high-sensitivity (HS) and low-sensitivity (LS) isoforms of the human alpha4beta2 NNR subtype expressed in subclonal human epithelial 1 cells. We found that at low concentrations (micromolar range), TC-5214 [S-(+)-mecamylamine] was more effective than TC-5213 [R-(-)-mecamylamine] in inhibiting the LS alpha4beta2 NNRs. In addition, we demonstrated that TC-5214 potentiated and TC-5213 inhibited agonist-induced activation of HS alpha4beta2 NNRs. The stereoselectivity of mecamylamine enantiomers at HS and LS alpha4beta2 receptors demonstrates that TC-5214 is the preferred stereoisomer for selective activation of HS, whereas it is more effective in suppressing LS receptor function. This feature could be relevant to therapeutic applications where such a selective mechanism of action is required.
Topics: Allosteric Regulation; Biophysical Phenomena; Cells, Cultured; Dose-Response Relationship, Drug; Epithelial Cells; Humans; Mecamylamine; Muscles; Neurons; Receptors, Nicotinic; Stereoisomerism
PubMed: 18957576
DOI: 10.1124/jpet.108.146910