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British Medical Journal Feb 1957
Topics: Autonomic Agents; Disease Management; Hypertension; Mecamylamine
PubMed: 13396275
DOI: 10.1136/bmj.1.5016.422 -
Neurobiology of Learning and Memory Jul 2006The nicotinic antagonist mecamylamine has been widely shown to cause cognitive impairment. However, these effects are mainly seen with high doses. There have been... (Comparative Study)
Comparative Study
The nicotinic antagonist mecamylamine has been widely shown to cause cognitive impairment. However, these effects are mainly seen with high doses. There have been scattered findings that low doses of mecamylamine can have the opposite effect. This may be due to opposite effects of low doses of mecamylamine. In the current study, an extensive dose-effect function of mecamylamine was characterized in the low-dose range. Adult female Sprague-Dawley rats were trained on a repeated acquisition procedure on an automated 8-arm radial maze. Three of the eight arms were designated as correct for any particular session. Five trials per session were run. The number of errors per trial to find the three correct arms was determined. The rats were trained on the repeated acquisition procedure for at least 18 sessions at which time they showed reliable learning each session. Then, the effect of low doses of mecamylamine between 0 and 1 mg/kg were assessed in a repeated measures counterbalanced design. This dose range of mecamylamine did not affect performance on the first trial when the rats were naïve to the array to be learned. On trials 2-5 a significant (p<.025) quadratic dose-effect function was seen over this dose range. The most substantial effect was seen with 0.125 mg/kg of mecamylamine, which caused a significant (p<.05) improvement relative to the saline control condition. The effect diminished with increasing mecamylamine doses and with the 1 mg/kg dose choice accuracy was back to control levels. This study showed that low doses of mecamylamine can effectively improve learning. A U-shaped dose-effect curve was documented. This suggests possible low-dose nicotinic antagonist lines of treatment for cognitive impairment.
Topics: Animals; Dose-Response Relationship, Drug; Exploratory Behavior; Female; Maze Learning; Mecamylamine; Nicotine; Nicotinic Antagonists; Rats; Rats, Sprague-Dawley; Reaction Time; Statistics, Nonparametric
PubMed: 16632386
DOI: 10.1016/j.nlm.2006.01.007 -
European Biophysics Journal : EBJ Apr 2008The blocking action of mecamylamine on different types of nicotinic acetylcholine receptors (nAChRs) has been extensively studied and used as a tool to characterize the...
The blocking action of mecamylamine on different types of nicotinic acetylcholine receptors (nAChRs) has been extensively studied and used as a tool to characterize the nAChRs from different synapses. However, mechanism of mecamylamine action was not fully explored for all types of nAChRs. In the present study, we provide brief description of the mecamylamine action on muscle nAChRs expressed at the frog neuromuscular junction. In this preparation mecamylamine block of nAChRs was accompanied by a use-dependent block relief induced by membrane depolarization combined with the activation of nAChRs by endogenous agonist acetylcholine (ACh). Further, three kinetic models of possible mecamylamine interaction with nAChRs were analyzed including simple open channel block, symmetrical trapping block and asymmetrical trapping block. This analysis suggested that mecamylamine action could be described on the basis of trapping mechanism, when the antagonist remained inside the channel even in the absence of bound agonist. Such receptors with trapped mecamylamine inside were predicted to have a closing rate constant about three times faster than resting one and a fast voltage-dependent unblocking rate constant. Specific experimental conditions and morphological organization of the neuromuscular synapses were considered to simulate time course of the mecamylamine block development. Thus, likewise for the neuronal nAChRs, the trapping mechanism determined the action of mecamylamine on synaptic neuromuscular currents evoked by the endogenous agonist acetylcholine (ACh), however specific morphological organization of the synaptic transmission delayed time development of the currents block.
Topics: Animals; Biophysics; Computer Simulation; Kinetics; Mecamylamine; Models, Biological; Models, Chemical; Models, Theoretical; Muscles; Neuromuscular Junction; Nicotinic Antagonists; Probability; Ranidae; Receptors, Nicotinic; Time Factors
PubMed: 17938901
DOI: 10.1007/s00249-007-0224-5 -
Psychopharmacology Jan 2017The beneficial effects of nicotinic acetylcholine receptor (nAChR) agonists on cognitive performance have been widely shown. Paradoxically, recent preclinical studies...
RATIONALE
The beneficial effects of nicotinic acetylcholine receptor (nAChR) agonists on cognitive performance have been widely shown. Paradoxically, recent preclinical studies employing extremely low doses of nAChR antagonists have also found cognitive enhancement, perhaps pointing to a novel treatment mechanism for cognitive deficits.
OBJECTIVES
The aim was to test whether low doses of the nAChR antagonist mecamylamine would benefit performance in human volunteers.
METHODS
The study employed a double-blind within-subject design. Over four separate days, healthy adult non-smokers (n = 23) were tested with placebo and three trace doses of mecamylamine (0.25-1 mg, p.o.), adjusted for body weight. Participants performed three computerized tasks: a task of spatial selective attention and stimulus detection, the rapid visual information processing task (RVIPT) taxing sustained attention and working memory, and a change detection short-term memory task. Subjective state and vital signs were assessed repeatedly.
RESULTS
Mecamylamine did not improve performance in any of the tasks. Any trends that were observed instead pointed toward performance impairment. Mecamylamine also had no effects on subjective state or vital signs.
CONCLUSIONS
The present results do not support the hypothesized cognitive-enhancing potential of low doses of mecamylamine. Contrary to preclinical reports, these findings speak against low-dose nAChR antagonism as a novel avenue for treating cognitive deficits.
Topics: Adult; Attention; Cognition; Double-Blind Method; Female; Humans; Male; Mecamylamine; Memory, Short-Term; Middle Aged; Neuropsychological Tests; Nicotinic Antagonists; Nootropic Agents; Young Adult
PubMed: 27678550
DOI: 10.1007/s00213-016-4443-2 -
Journal of Psychopharmacology (Oxford,... Feb 2017A pharmacologic challenge model with a nicotinic antagonist could be an important tool not only to understand the complex role of the nicotinic cholinergic system in...
Pharmacokinetics and pharmacodynamics of oral mecamylamine - development of a nicotinic acetylcholine receptor antagonist cognitive challenge test using modelling and simulation.
A pharmacologic challenge model with a nicotinic antagonist could be an important tool not only to understand the complex role of the nicotinic cholinergic system in cognition, but also to develop novel compounds acting on the nicotinic acetylcholine receptor. The objective was to develop a pharmacokinetic-pharmacodynamic (PKPD) model using nonlinear mixed effects (NLME) methods to quantitate the pharmacokinetics of three oral mecamylamine doses (10, 20 and 30 mg) and correlate the plasma concentrations to the pharmacodynamic effects on a cognitive and neurophysiologic battery of tests in healthy subjects. A one-compartment linear kinetic model best described the plasma concentrations of mecamylamine. Mecamylamine's estimated clearance was 0.28 ± 0.015 L min. The peripheral volume of distribution (291 ± 5.15 L) was directly related to total body weight. Mecamylamine impaired the accuracy and increased the reaction time in tests evaluating short term working memory with a steep increase in the concentration-effect relationship at plasma concentrations below 100 μg L. On the other hand, mecamylamine induced a decrease in performance of tests evaluating visual and fine motor coordination at higher plasma concentrations (EC 97 μg L). Systolic and diastolic blood pressure decreased exponentially after a plasma mecamylamine concentration of 80 μg L, a known effect previously poorly studied in healthy subjects. The developed mecamylamine PKPD model was used to quantify the effects of nicotinic blockade in a set of neurophysiological tests in humans with the goal to provide insight into the physiology and pharmacology of the nicotinic system in humans and the possibility to optimize future trials that use mecamylamine as a pharmacological challenge.
Topics: Adult; Blood Pressure; Cognition; Humans; Male; Mecamylamine; Memory, Short-Term; Nicotine; Nicotinic Antagonists; Reaction Time; Receptors, Nicotinic; Young Adult
PubMed: 27927703
DOI: 10.1177/0269881116681417 -
Human Psychopharmacology Jun 2009Nicotinic cholinergic stimulation has known beneficial effects in attention-deficit/hyperactivity disorder (ADHD). Mecamylamine is a non-competitive nicotinic antagonist... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Nicotinic cholinergic stimulation has known beneficial effects in attention-deficit/hyperactivity disorder (ADHD). Mecamylamine is a non-competitive nicotinic antagonist which is reported in several animal studies to have paradoxical positive effects on cognition at ultra-low doses. Comparable studies in humans have not been conducted. The aim of this study was to determine the effects of acute ultra-low doses of mecamylamine on cognition in adult ADHD.
METHODS
Fifteen (6 female) non-smokers with ADHD completed this acute, within subjects, double blind study of 0.2, 0.5, 1.0 mg of oral mecamylamine and placebo. Behavioral inhibition, recognition memory, and delay aversion were assessed at each dose.
RESULTS
The 0.5 mg dose of mecamylamine significantly improved recognition memory and reduced tolerance for delay. Mecamylamine increased participant rated irritability and investigator rated restlessness. There were no effects on vital signs or physical side effects.
CONCLUSION
This is the first study to find measurable effects of ultra-low doses of mecamylamine in humans. Mecamylamine did not improve core ADHD cognitive symptoms, but significantly improved recognition memory. These effects may represent mixed receptor activity (activation and blockade) at the doses tested. The finding of beneficial effects on memory processes has important clinical implications and further exploration of this effect is warranted.
Topics: Adolescent; Affect; Attention Deficit Disorder with Hyperactivity; Behavior; Choice Behavior; Cognition; Discrimination, Psychological; Double-Blind Method; Female; Humans; Male; Mecamylamine; Memory; Neuropsychological Tests; Nicotinic Antagonists; Psychiatric Status Rating Scales; Psychomotor Performance; Recognition, Psychology; Young Adult
PubMed: 19475630
DOI: 10.1002/hup.1026 -
Behavioural Pharmacology Jun 2011A conjunctive variable-interval differential-reinforcement-of-low-rate (VI-DRL, n=18) responding schedule and a stop-signal task (n=18) were used to evaluate the...
A conjunctive variable-interval differential-reinforcement-of-low-rate (VI-DRL, n=18) responding schedule and a stop-signal task (n=18) were used to evaluate the disinhibiting effects of nicotine on response withholding in rats. Sucrose solution was used to reinforce responding, and after a stable baseline was achieved under saline-administration conditions, 0.3 mg/kg nicotine was delivered before each session. Experiment 1 showed that repeated, but not the initial, administration of nicotine decreased performance on both tasks, and the effect of sensitization followed a similar timeline; 10 consecutive doses resulted in poorer proportion-correct VI-DRL trials and percent correct stop trials than the initial dose of nicotine. Furthermore, sensitization to 0.3 mg/kg nicotine decreased performance regardless of whether a spaced or consecutive-dosing regimen was followed. Experiment 2 was designed to test whether mecamylamine hydrochloride (0.1-1.0 mg/kg) could attenuate the effects of repeated 0.3 mg/kg nicotine administration, and the degree to which mecamylamine attenuation of the effect of nicotine to produce impulsive action was relative to dose. Results from experiment 2 showed that response disinhibition, as evaluated using the VI-DRL and stop-signal tasks, is related in a systematic manner to nicotinic-acetylcholine receptor activation.
Topics: Animals; Dose-Response Relationship, Drug; Impulsive Behavior; Male; Mecamylamine; Nicotine; Rats; Rats, Sprague-Dawley; Reinforcement Schedule
PubMed: 21448062
DOI: 10.1097/FBP.0b013e328345ca1c -
Journal of Child and Adolescent... Jun 2012To explore possible benefits of a nicotinic acetylcholine receptor (nAChR) agent for autistic symptoms based on postmortem observation of nAChR abnormalities (deficient... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To explore possible benefits of a nicotinic acetylcholine receptor (nAChR) agent for autistic symptoms based on postmortem observation of nAChR abnormalities (deficient α4β2 nAChRs, excess α7 nAChRs) in brains of patients with autism.
METHOD
Mecamylamine, because of its safety record in children with other disorders, was chosen for this first exploration. Twenty children with autism spectrum disorder age 4-12 years were randomly assigned for 14 weeks to placebo (n=8) or mecamylamine (n=12) in ascending fixed doses: 0.5 mg/day for 6 weeks, 2.5 mg for 2 weeks, then 5 mg/day for 6 weeks. Improvement was rated by a blinded independent evaluator. Because of small sample, data analysis was descriptive.
RESULTS
Eighteen participants (10 mecamylamine, 8 placebo) completed the study. All doses were well tolerated; the only side effect of note was constipation (50% compared with 25% of placebo group). Three children had clinically nonsignificant electrocardiographic QT prolongation. Both groups showed modest to moderate improvement, but differences between groups were negligible. On the primary outcome measure, the Ohio Autism Clinical Impressions Scale, 90% of the active treatment group showed improvement at some point (but only 40% sustained it), compared with 62% on placebo. Of the four in active treatment that sustained improvement, three had a maximum dose of 0.13-0.15 mg/kg/day, while those who regressed had doses ≥0.18 mg/kg/day. Graphed means suggested better outcome with lower mg/kg and longer medication duration. Four parents spontaneously reported reduced hyperactivity and irritability and better verbalization and continued mecamylamine at their own expense.
CONCLUSION
Mecamylamine appeared to be safe, but not very effective in autism. The suggestion of better results at lower doses and longer exposure warrants consideration for future trials. The next step would be exploration of a more specific α4β2 nAChR agonist, such as varenicline.
Topics: Child; Child Development Disorders, Pervasive; Child, Preschool; Constipation; Dose-Response Relationship, Drug; Double-Blind Method; Female; Ganglionic Blockers; Humans; Male; Mecamylamine; Pilot Projects; Treatment Outcome
PubMed: 22537359
DOI: 10.1089/cap.2011.0056 -
Neuroscience Letters Nov 1988The nicotinic acetylcholine channel blockers mecamylamine (MECA) and pempidine (PEMP) blocked voltage-clamped isolated catfish retina cone horizontal responses to...
The nicotinic acetylcholine channel blockers mecamylamine (MECA) and pempidine (PEMP) blocked voltage-clamped isolated catfish retina cone horizontal responses to aspartate (Asp) and N-methyl-D-aspartate (NMDA) but had little effect on currents induced by kainate and quisqualate. Concentration response curves for NMDA and Asp in the presence of MECA suggested that MECA was a non-competitive inhibitor of NMDA and Asp responses. Further, the MECA and PEMP block of NMDA and Asp-induced currents was highly voltage-sensitive. The non-competitive and voltage-sensitive block of NMDA and Asp-induced currents by MECA suggest that MECA (and PEMP) block the NMDA receptor ion channel.
Topics: Animals; Aspartic Acid; Catfishes; Electric Conductivity; In Vitro Techniques; Mecamylamine; Membrane Potentials; N-Methylaspartate; Retina
PubMed: 3071750
DOI: 10.1016/0304-3940(88)90276-5 -
Psychopharmacology Jun 1994Recently, a rodent model of nicotine abstinence syndrome has been developed based on observing the frequency of spontaneous behavioral signs following termination of...
Recently, a rodent model of nicotine abstinence syndrome has been developed based on observing the frequency of spontaneous behavioral signs following termination of continuous subcutaneous infusion of nicotine tartrate. In the present study, the nicotinic antagonist mecamylamine precipitated an abstinence syndrome in nicotine-dependent rats. Twelve rats were each infused for 7 days with 9 mg/kg per day nicotine tartrate in saline via Alzet osmotic minipumps; another 12 rats were sham-operated and remained nicotine-naive. Six rats from each group received 1 mg/kg mecamylamine in saline SC immediately before a 30-min observation, while the remaining six rats from each group received saline alone. Nicotine-infused rats receiving mecamylamine exhibited significantly more (P < 0.01), overall abstinence signs than all other groups. In terms of categories of signs, they displayed significantly more gasps/writhes, teeth chatter/chews, shakes/tremors and ptosis. In a second experiment utilizing only nicotine-naive rats, a far higher dose of mecamylamine (5 mg/kg sc) induced a quasi-nicotine abstinence syndrome. The results provide further validation for this rodent model of nicotine abstinence syndrome.
Topics: Animals; Behavior, Animal; Male; Mecamylamine; Nicotine; Nicotinic Antagonists; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome; Substance-Related Disorders
PubMed: 7862893
DOI: 10.1007/BF02244770