The Experts below are selected from a list of 294 Experts worldwide ranked by ideXlab platform
Paul R. Sanberg - One of the best experts on this subject based on the ideXlab platform.
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Anxiolytic effects of Mecamylamine in two animal models of anxiety.
Experimental and clinical psychopharmacology, 2002Co-Authors: Mary B. Newman, Paul R. Sanberg, John J. Manresa, R. Douglas ShytleAbstract: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.
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Nicotine induced seizures blocked by Mecamylamine and its stereoisomers.
Life sciences, 2001Co-Authors: Mary B. Newman, Paul R. Sanberg, John J. Manresa, R. Douglas ShytleAbstract:Abstract Recent genetic research has shown that certain forms of epilepsy may arise from mutations in the genes encoding for the α7 and α4 neuronal nicotinic acetylcholine receptor (nAChR) ion channels. These receptors are also involved with the induction of nicotine-induced seizures. (±)-Mecamylamine (Inversine®), a classic nAChR antagonist, potently inhibits nicotine-induced seizures. The purpose of the present study was to assess the inhibitory effects of (±)-Mecamylamine and its stereoisomers on nicotine-induced seizures in male Sprague-Dawley rats. Rats received saline, (±)-Mecamylamine, R-(−)-Mecamylamine, or S-(+)-Mecamylamine (s.c.) at doses of 0.1, 0.3, or 1.0 mg/kg 15 minutes prior to nicotine injection, 3.6 mg/kg (s.c.), an optimal dose for seizure induction. Rats were observed for 30 minutes with seizure latency, duration, and severity as primary measures and locomotor activity recorded as a secondary measure at 5-minute intervals. The results indicate that Mecamylamine and each of its stereoisomers block nicotine-induced seizures in a dose–related manner and suggest that the S-(+)– Mecamylamine isomer has inhibitory properties more similar to the racemic than to the R-(−)–Mecamylamine isomer. The results of this study may be clinically important for the future design of novel anti-seizure medications.
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Mecamylamine new therapeutic uses and toxicity risk profile
Clinical Therapeutics, 2001Co-Authors: John M. Young, Paul R. Sanberg, Douglas R Shytle, Tony P. GeorgeAbstract:Abstract Background: Mecamylamine hydrochloride was initially developed for its ganglion-blocking activity and has been marketed as an antihypertensive agent in the United States for > 40 years. Several other potential therapeutic applications are being investigated, most of them focusing on the drug's ability to cross the blood-brain barrier and selectively antagonize neuronal nicotinic acetylcholine receptors. This central activity of Mecamylamine is demonstrable at much lower doses than the effective antihypertensive dose, thus avoiding many of the bothersome side effects associated with the drug's inhibition of parasympathetic activity. Objective: Because investigations are being conducted in new patient populations, including pediatric patients, an update of the toxicity/risk profile of Mecamylamine is timely. This review describes nonclinical and clinical data pertaining to the pharmacology, toxicity, and tolerability of Mecamylamine, including some previously unpublished toxicology and clinical pharmacokinetics data. Potential new therapeutic applications are discussed, including the use of Mecamylamine in treating autonomic dysreflexia; dependencies on nicotine, cocaine, and other substances of abuse; Tourette's syndrome; and other neuropsychiatric disorders. Methods: Information for this review of Mecamylamine was identified through a search of MEDLINE ® from 1966 to the present, as well as from the master files of Merck & Co, Inc, the drug's original manufacturer, and Layton BioScience, Inc, its present manufacturer. Conclusions: The available data concerning potential new applications of Mecamylamine, although sparse, suggest that the drug's toxicity/risk profile may be much improved at lower doses.
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Analysis of Mecamylamine Stereoisomers on Human Nicotinic Receptor Subtypes
The Journal of pharmacology and experimental therapeutics, 2001Co-Authors: Roger L. Papke, Paul R. Sanberg, R. Douglas ShytleAbstract:Because Mecamylamine, a nicotinic receptor antagonist, is used so often in nicotine research and because Mecamylamine may have important therapeutic properties clinically, it is important to fully explore and understand its pharmacology. In the present study, the efficacy and potency of Mecamylamine and its stereoisomers were evaluated as inhibitors of human α3β4, α3β2, α7, and α4β2 nicotinic acetylcholine receptors (nAChRs), as well as mouse adult type muscle nAChRs and rat N -methyl-d-aspartate (NMDA) receptors expressed in Xenopus oocytes. The selectivity of Mecamylamine for neuronal nAChR was manifested primarily in terms of slow recovery rates from Mecamylamine-induced inhibition. Neuronal receptors showed a prolonged inhibition after exposure to low micromolar concentrations of Mecamylamine. Muscle-type receptors showed a transient inhibition by similar concentrations of Mecamylamine, and NMDA receptors were only transiently inhibited by higher micromolar concentrations. Mecamylamine inhibition of neuronal nAChR was noncompetitive and voltage dependent. Although there was little difference between S -(+)-Mecamylamine and R -(−)-Mecamylamine in terms of 50% inhibition concentration values for a given receptor subtype, there appeared to be significant differences in the off-rates for the Mecamylamine isomers from the receptors. Specifically, S -(+)-Mecamylamine appeared to dissociate more slowly from α4β2 and α3β4 receptors than did R- (−)-Mecamylamine. In addition, it was found that muscle-type receptors appeared to be somewhat more sensitive to R- (−)-Mecamylamine than to S- (+)-Mecamylamine. Together, these findings suggest that in chronic (i.e., therapeutic) application, S- (+)-Mecamylamine might be preferable to R- (−)-Mecamylamine in terms of equilibrium inactivation of neuronal receptors with decreased side effects associated with muscle-type receptors.
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Mecamylamine effects on haloperidol-induced catalepsy and defecation.
The International journal of neuroscience, 2001Co-Authors: Paul R. Sanberg, Mary B. Newman, John J. Manresa, Sarah E. Potts, Franco Alvarez, David W. Cahill, R. Douglas ShytleAbstract:Recent clinical experience with Tourette syndrome (TS) patients suggests that the nicotinic receptor antagonist, Mecamylamine (Inversine®), may be a useful adjunct to neuroleptic therapy for controlling tic symptom. This is consistent with previous preclinical findings demonstrating that Mecamylamine can potentiate the cataleptic effects of neuroleptics in rats. However, these earlier preclinical studies employed high doses (1–2.5 mg/kg) of Mecamylamine that may not be clinically relevant since human doses of Mecamylamine used to treat TS have been much lower (0.03–0.1 mg/kg). In order to test the potential therapeutic properties of Mecamylamine preclinically, we conducted catalepsy experiments in rats employing both a low and high dose of Mecamylamine in combination with haloperidol. Sixty-four male Sprague Dawley rats were randomized into four treatment groups (n equals; 16/group). Each rat received an injection of either saline or Mecamylamine (0.1 or 3.0 mg/kg sc) followed one hour later with a second...
Jed E Rose - One of the best experts on this subject based on the ideXlab platform.
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Mecamylamine moderates cue-induced emotional responses in smokers.
Addictive behaviors, 2005Co-Authors: F. Joseph Mcclernon, Jed E RoseAbstract:The nicotinic antagonist, Mecamylamine, has been shown to reduce cue-elicited cocaine craving and to aid in smoking cessation. In a within-subjects design, 16 dependent smokers received Mecamylamine (10 mg) or placebo capsules on two different days. Subjects imagined smoking urge and non-urge scenarios after smoking their usual brand vs. denicotinized cigarettes. Smoking usual-brand cigarettes produced greater positive effects and Mecamylamine blocked heart rate (HR) boost and cigarette sensory impact. Mecamylamine also resulted in greater craving and less calmness, regardless of cigarette smoked. Urge script imagination in the Mecamylamine+denicotinized condition resulted in calmness similar to usual-brand conditions and higher than the placebo+denicotinized condition. A similar trend was observed for negative affect. These results suggest that Mecamylamine can moderate smoking cue-induced emotional responses in smokers.
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Mecamylamine acutely increases human intravenous nicotine self-administration.
Pharmacology biochemistry and behavior, 2003Co-Authors: Jed E Rose, Frederique M Behm, Eric C. Westman, James E BatesAbstract:Previous studies of human cigarette smoking have shown that administration of the nicotinic acetylcholine receptor antagonist Mecamylamine produces acute increases in smoking behavior. In contrast, studies of intravenous nicotine self-administration in animals typically show an immediate decrease in self-administration behavior following Mecamylamine administration. To investigate whether this discrepancy might be due in part to the mode of nicotine self-administration (intravenous vs. cigarette smoke), we measured the rate of intravenous nicotine self-administration in tobacco-dependent human smokers. After being trained in a preliminary session to self-administer puff-sized bolus doses of nicotine, 16 subjects were exposed to two sessions (4 h duration) in which they could self-administer intravenous nicotine ad lib. Two hours prior to one session, subjects swallowed a capsule containing 10 mg Mecamylamine, and before the other session they took a placebo capsule. Rates of responding for nicotine were assessed, as were subjective reports of withdrawal symptoms and plasma nicotine levels. There was a significantly higher rate of nicotine self-administration in the Mecamylamine condition, and Mecamylamine attenuated the reduction in craving over the session that occurred during nicotine self-administration. These results indicate that route of administration is not likely the major source of the discrepancy between findings from animal and human studies of nicotine administration. Instead, it is likely that the higher rates of nicotine self-administration induced by Mecamylamine were due to an attenuation of the effects of nicotine (e.g., alleviation of withdrawal symptoms) in nicotine-dependent subjects. Thus, animal models of nicotine dependence may need to be employed in conjunction with self-administration procedures in order to duplicate the effects of Mecamylamine observed in studies of human smokers.
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Mecamylamine Modifies the Pharmacokinetics and Reinforcing Effects of Alcohol
Alcoholism clinical and experimental research, 2002Co-Authors: Ola Blomqvist, Jed E Rose, Carlos A. Hernandez-avila, Jeffrey Van Kirk, Henry R. KranzlerAbstract:Background: Central nicotinic cholinergic receptors modify alcohol-induced mesolimbic dopamine activation, which seems to be important in the reinforcing properties of alcohol. Consistent with this model, acute administration to rats of the tertiary nicotinic receptor antagonist Mecamylamine blocks both alcohol consumption and alcohol-induced dopamine release in the nucleus accumbens. This study was conducted to test the hypothesis that, during the ascending limb of the blood alcohol concentration curve, Mecamylamine would reduce the stimulating and pleasurable effects of an intoxicating dose of alcohol in humans. Methods: Ten female and 10 male volunteers with no history of alcohol or substance use disorders, including nicotine dependence, completed the study. During two laboratory sessions, subjects consumed three aliquots of an alcohol-containing drink, with a total ethanol content of 0.7 g/kg (in women) or 0.8 g/kg (in men), over a 30-min period. Two hours before the first drink, subjects were pretreated with Mecamylamine or placebo, with the order of sessions counterbalanced. Primary outcome measures included the Drug Effect Questionnaire, the central stimulation subscale of the Alcohol Sensation Scale, and the stimulant subscale of the Biphasic Alcohol Effects Scale. Breath alcohol level (BAL) was examined to identify the ascending and descending limbs of the blood alcohol curve and to assess pharmacokinetic interactions between alcohol and Mecamylamine. Results: Significant effects of time, study drug, and their interaction were observed. Compared with placebo, Mecamylamine reduced BAL. After controlling for BAL at each time point, Mecamylamine also reduced the Drug Effect Questionnaire and Alcohol Sensation Scale stimulant subscale scores, with a trend for a similar effect on the Biphasic Alcohol Effects Scale score. Conclusions: Mecamylamine seems to modify both the pharmacokinetic profile of alcohol and the rewarding effects of alcohol in healthy volunteers.
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Acute effects of nicotine and Mecamylamine on tobacco withdrawal symptoms, cigarette reward and ad lib smoking.
Pharmacology biochemistry and behavior, 2001Co-Authors: Jed E Rose, Frederique M Behm, Eric C. WestmanAbstract: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.
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The nicotinic antagonist Mecamylamine preferentially inhibits cocaine vs. food self-administration in rats
Physiology & Behavior, 2000Co-Authors: Edward D. Levin, Jed E Rose, Amir H Rezvani, Tonya Mead, Camille Gallivan, Rita GrossAbstract:Abstract Nicotinic acetylcholine systems play important roles in addiction, and nicotinic receptor stimulation stimulates dopamine release while the nicotinic antagonist Mecamylamine reduces it. Reid et al. [Neuropsychopharmacology 20 (1999) 297.] recently found in human cocaine addicts that Mecamylamine reduced cue-elicited cocaine craving. The current study assessed the impact of Mecamylamine on cocaine self-administration in rats. Female Sprague–Dawley rats ( N =7) were implanted with intravenous (iv) catheters and trained to lever press for cocaine (0.32 mg/kg/infusion FR-1 with a 60-s timeout) in 45-min sessions. After 2 weeks of training, the rats were injected with saline or Mecamylamine (1, 2, or 4 mg/kg sc) 10 min before the session. They received the same dose for 1 week with 1 week of uninjected testing between doses. Mecamylamine, compared to saline, significantly ( P N =8) were trained to lever press for food reinforcement. In these rats, the 1 and 2-mg/kg Mecamylamine doses had no effect on food self-administration. Significant reductions in food self-administration were not seen unless the high dose of 4-mg/kg Mecamylamine was used. Nicotinic antagonist treatment reduces cocaine self-administration in rats at doses that do not cause generalized effects on food-reinforced responding. Nicotinic antagonistic treatment may be a useful new approach to treat cocaine addiction.
Tony P. George - One of the best experts on this subject based on the ideXlab platform.
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Mecamylamine a nicotinic acetylcholine receptor antagonist with potential for the treatment of neuropsychiatric disorders
Expert Opinion on Pharmacotherapy, 2009Co-Authors: Ingrid Bacher, Douglas Shytle, Tony P. GeorgeAbstract:Mecamylamine (Inversine®), the first orally available antihypertensive agent launched in the 1950s, is rarely used today for hypertension because of its widespread ganglionic side effects at antihypertensive doses (25 – 90 mg/day). However, more recent clinical studies suggest that Mecamylamine is effective at much lower doses for blocking the central and peripheral effects of nicotine. Pharmacologically, Mecamylamine has been well characterized as a nonselective and noncompetitive antagonist of nicotinic acetylcholine receptors (nAChRs). Because Mecamylamine easily crosses the blood – brain barrier at relatively low doses (2.5 – 10 mg), it has been used by several research groups over the past two decades investigating the role of central nAChRs in the etiology and treatment of various neuropsychiatric disorders, including addiction disorders, Tourette's syndrome, schizophrenia and various cognitive and mood disorders. Two independent Phase II clinical trials recently confirmed Mecamylamine's hypothesize...
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Mecamylamine – a nicotinic acetylcholine receptor antagonist with potential for the treatment of neuropsychiatric disorders
Expert opinion on pharmacotherapy, 2009Co-Authors: Ingrid Bacher, Douglas Shytle, Tony P. GeorgeAbstract:Mecamylamine (Inversine®), the first orally available antihypertensive agent launched in the 1950s, is rarely used today for hypertension because of its widespread ganglionic side effects at antihypertensive doses (25 – 90 mg/day). However, more recent clinical studies suggest that Mecamylamine is effective at much lower doses for blocking the central and peripheral effects of nicotine. Pharmacologically, Mecamylamine has been well characterized as a nonselective and noncompetitive antagonist of nicotinic acetylcholine receptors (nAChRs). Because Mecamylamine easily crosses the blood – brain barrier at relatively low doses (2.5 – 10 mg), it has been used by several research groups over the past two decades investigating the role of central nAChRs in the etiology and treatment of various neuropsychiatric disorders, including addiction disorders, Tourette's syndrome, schizophrenia and various cognitive and mood disorders. Two independent Phase II clinical trials recently confirmed Mecamylamine's hypothesize...
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Mecamylamine new therapeutic uses and toxicity risk profile
Clinical Therapeutics, 2001Co-Authors: John M. Young, Paul R. Sanberg, Douglas R Shytle, Tony P. GeorgeAbstract:Abstract Background: Mecamylamine hydrochloride was initially developed for its ganglion-blocking activity and has been marketed as an antihypertensive agent in the United States for > 40 years. Several other potential therapeutic applications are being investigated, most of them focusing on the drug's ability to cross the blood-brain barrier and selectively antagonize neuronal nicotinic acetylcholine receptors. This central activity of Mecamylamine is demonstrable at much lower doses than the effective antihypertensive dose, thus avoiding many of the bothersome side effects associated with the drug's inhibition of parasympathetic activity. Objective: Because investigations are being conducted in new patient populations, including pediatric patients, an update of the toxicity/risk profile of Mecamylamine is timely. This review describes nonclinical and clinical data pertaining to the pharmacology, toxicity, and tolerability of Mecamylamine, including some previously unpublished toxicology and clinical pharmacokinetics data. Potential new therapeutic applications are discussed, including the use of Mecamylamine in treating autonomic dysreflexia; dependencies on nicotine, cocaine, and other substances of abuse; Tourette's syndrome; and other neuropsychiatric disorders. Methods: Information for this review of Mecamylamine was identified through a search of MEDLINE ® from 1966 to the present, as well as from the master files of Merck & Co, Inc, the drug's original manufacturer, and Layton BioScience, Inc, its present manufacturer. Conclusions: The available data concerning potential new applications of Mecamylamine, although sparse, suggest that the drug's toxicity/risk profile may be much improved at lower doses.
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Mecamylamine: new therapeutic uses and toxicity/risk profile.
Clinical therapeutics, 2001Co-Authors: John M. Young, Paul R. Sanberg, R. Douglas Shytle, Tony P. GeorgeAbstract:Abstract Background: Mecamylamine hydrochloride was initially developed for its ganglion-blocking activity and has been marketed as an antihypertensive agent in the United States for > 40 years. Several other potential therapeutic applications are being investigated, most of them focusing on the drug's ability to cross the blood-brain barrier and selectively antagonize neuronal nicotinic acetylcholine receptors. This central activity of Mecamylamine is demonstrable at much lower doses than the effective antihypertensive dose, thus avoiding many of the bothersome side effects associated with the drug's inhibition of parasympathetic activity. Objective: Because investigations are being conducted in new patient populations, including pediatric patients, an update of the toxicity/risk profile of Mecamylamine is timely. This review describes nonclinical and clinical data pertaining to the pharmacology, toxicity, and tolerability of Mecamylamine, including some previously unpublished toxicology and clinical pharmacokinetics data. Potential new therapeutic applications are discussed, including the use of Mecamylamine in treating autonomic dysreflexia; dependencies on nicotine, cocaine, and other substances of abuse; Tourette's syndrome; and other neuropsychiatric disorders. Methods: Information for this review of Mecamylamine was identified through a search of MEDLINE ® from 1966 to the present, as well as from the master files of Merck & Co, Inc, the drug's original manufacturer, and Layton BioScience, Inc, its present manufacturer. Conclusions: The available data concerning potential new applications of Mecamylamine, although sparse, suggest that the drug's toxicity/risk profile may be much improved at lower doses.
R. Douglas Shytle - One of the best experts on this subject based on the ideXlab platform.
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Anxiolytic effects of Mecamylamine in two animal models of anxiety.
Experimental and clinical psychopharmacology, 2002Co-Authors: Mary B. Newman, Paul R. Sanberg, John J. Manresa, R. Douglas ShytleAbstract: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.
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Nicotine induced seizures blocked by Mecamylamine and its stereoisomers.
Life sciences, 2001Co-Authors: Mary B. Newman, Paul R. Sanberg, John J. Manresa, R. Douglas ShytleAbstract:Abstract Recent genetic research has shown that certain forms of epilepsy may arise from mutations in the genes encoding for the α7 and α4 neuronal nicotinic acetylcholine receptor (nAChR) ion channels. These receptors are also involved with the induction of nicotine-induced seizures. (±)-Mecamylamine (Inversine®), a classic nAChR antagonist, potently inhibits nicotine-induced seizures. The purpose of the present study was to assess the inhibitory effects of (±)-Mecamylamine and its stereoisomers on nicotine-induced seizures in male Sprague-Dawley rats. Rats received saline, (±)-Mecamylamine, R-(−)-Mecamylamine, or S-(+)-Mecamylamine (s.c.) at doses of 0.1, 0.3, or 1.0 mg/kg 15 minutes prior to nicotine injection, 3.6 mg/kg (s.c.), an optimal dose for seizure induction. Rats were observed for 30 minutes with seizure latency, duration, and severity as primary measures and locomotor activity recorded as a secondary measure at 5-minute intervals. The results indicate that Mecamylamine and each of its stereoisomers block nicotine-induced seizures in a dose–related manner and suggest that the S-(+)– Mecamylamine isomer has inhibitory properties more similar to the racemic than to the R-(−)–Mecamylamine isomer. The results of this study may be clinically important for the future design of novel anti-seizure medications.
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Analysis of Mecamylamine Stereoisomers on Human Nicotinic Receptor Subtypes
The Journal of pharmacology and experimental therapeutics, 2001Co-Authors: Roger L. Papke, Paul R. Sanberg, R. Douglas ShytleAbstract:Because Mecamylamine, a nicotinic receptor antagonist, is used so often in nicotine research and because Mecamylamine may have important therapeutic properties clinically, it is important to fully explore and understand its pharmacology. In the present study, the efficacy and potency of Mecamylamine and its stereoisomers were evaluated as inhibitors of human α3β4, α3β2, α7, and α4β2 nicotinic acetylcholine receptors (nAChRs), as well as mouse adult type muscle nAChRs and rat N -methyl-d-aspartate (NMDA) receptors expressed in Xenopus oocytes. The selectivity of Mecamylamine for neuronal nAChR was manifested primarily in terms of slow recovery rates from Mecamylamine-induced inhibition. Neuronal receptors showed a prolonged inhibition after exposure to low micromolar concentrations of Mecamylamine. Muscle-type receptors showed a transient inhibition by similar concentrations of Mecamylamine, and NMDA receptors were only transiently inhibited by higher micromolar concentrations. Mecamylamine inhibition of neuronal nAChR was noncompetitive and voltage dependent. Although there was little difference between S -(+)-Mecamylamine and R -(−)-Mecamylamine in terms of 50% inhibition concentration values for a given receptor subtype, there appeared to be significant differences in the off-rates for the Mecamylamine isomers from the receptors. Specifically, S -(+)-Mecamylamine appeared to dissociate more slowly from α4β2 and α3β4 receptors than did R- (−)-Mecamylamine. In addition, it was found that muscle-type receptors appeared to be somewhat more sensitive to R- (−)-Mecamylamine than to S- (+)-Mecamylamine. Together, these findings suggest that in chronic (i.e., therapeutic) application, S- (+)-Mecamylamine might be preferable to R- (−)-Mecamylamine in terms of equilibrium inactivation of neuronal receptors with decreased side effects associated with muscle-type receptors.
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Mecamylamine effects on haloperidol-induced catalepsy and defecation.
The International journal of neuroscience, 2001Co-Authors: Paul R. Sanberg, Mary B. Newman, John J. Manresa, Sarah E. Potts, Franco Alvarez, David W. Cahill, R. Douglas ShytleAbstract:Recent clinical experience with Tourette syndrome (TS) patients suggests that the nicotinic receptor antagonist, Mecamylamine (Inversine®), may be a useful adjunct to neuroleptic therapy for controlling tic symptom. This is consistent with previous preclinical findings demonstrating that Mecamylamine can potentiate the cataleptic effects of neuroleptics in rats. However, these earlier preclinical studies employed high doses (1–2.5 mg/kg) of Mecamylamine that may not be clinically relevant since human doses of Mecamylamine used to treat TS have been much lower (0.03–0.1 mg/kg). In order to test the potential therapeutic properties of Mecamylamine preclinically, we conducted catalepsy experiments in rats employing both a low and high dose of Mecamylamine in combination with haloperidol. Sixty-four male Sprague Dawley rats were randomized into four treatment groups (n equals; 16/group). Each rat received an injection of either saline or Mecamylamine (0.1 or 3.0 mg/kg sc) followed one hour later with a second...
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Corticosterone-attenuating and anxiolytic properties of Mecamylamine in the rat
Progress in neuro-psychopharmacology & biological psychiatry, 2001Co-Authors: Mary B. Newman, Paul R. Sanberg, Stanley J. Nazian, David M. Diamond, R. Douglas ShytleAbstract: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.
Lance R. Mcmahon - One of the best experts on this subject based on the ideXlab platform.
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Discriminative stimulus effects of Mecamylamine and nicotine in rhesus monkeys: Central and peripheral mechanisms.
Pharmacology Biochemistry and Behavior, 2019Co-Authors: Colin S. Cunningham, Megan J. Moerke, Lance R. McmahonAbstract:Abstract 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).
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The discriminative stimulus effects of Mecamylamine in nicotine-treated and untreated rhesus monkeys.
Behavioural pharmacology, 2014Co-Authors: Colin S. Cunningham, Megan J. Moerke, Lance R. McmahonAbstract:The extent to which chronic nicotine treatment can alter the effects of the nicotinic acetylcholine receptor (nAChR) antagonist Mecamylamine, and whether those effects can be attenuated by nicotine has not been clearly established in the literature. Here, the discriminative stimulus effects of Mecamylamine were compared in one group of rhesus monkeys receiving continuous infusion of nicotine base (5.6 mg/kg/day s.c.) 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 of Mecamylamine in monkeys receiving continuous nicotine and 5.6 mg/kg of 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 across 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 non-competitive interaction at nAChRs and indicates that Mecamylamine-induced withdrawal cannot be readily modified by nicotine.
