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PubMed2005

Evaluation in rats and primates of [11C]-mecamylamine, a potential nicotinic acetylcholine receptor radioligand for positron emission tomography.

Mecamylamine is a well-described non specific antagonist of nicotinic acetylcholine receptors (nAChRs), used in therapy and in psychopharmacological studies. [(11)C]-Mecamylamine was prepared and evaluated as a putative radioligand for positron emission tomography to study nicotinic acetylcholine receptors. The radiosynthesis consisted in the [(11)C]-methylation of the desmethyl precursor within 40 min with 30-40% radiochemical yield decay corrected. Biodistribution studies in rats showed that radioligand crossed the blood-brain barrier (0.39% ID at 30 min) and only unmetabolized tracer was recovered from brain at 45 min. Ex vivo autoradiography studies in rats did not indicate preferential uptake, and pre-treatment mecamylamine or with chlorisondamine, an nicotinic receptor inhibitor, did not demonstrate a significant specific binding. To investigate possible specie differences and effects of anesthesia, in vivo positron emission tomography (PET) studies were carried out on anaesthetized baboons and conscious macaques. The regional brain distribution of [(11)C]-mecamylamine in the two species of primates exhibited similar kinetics as did the rat with steady state reached about 45-50 min after radiotracer administration. Uptake values were two-fold higher in brain of conscious macaque than in anaesthetized baboon (thalamus: 0.258% ID/(kg mL) in conscious macaques and 0.129% ID/(kg mL) in baboons). PET images showed a radioactivity distribution which was quite homogeneous throughout the brain but with somewhat higher uptake in grey matter than in white. Brain distribution was unaltered by saturation or displacement studies. Possible explanation for the failure to establish specific binding in vivo could be long-lived structural modifications of the ionotropic channel by the unlabeled ligand administered before the tracer. In conclusion, [(11)C]-mecamylamine did not satisfy the requirements for a PET tracer of nicotinic acetylcholine receptors.

Anesthesia↗
PubMed2000

Comorbid bipolar disorder in Tourette's syndrome responds to the nicotinic receptor antagonist mecamylamine (Inversine).

BACKGROUND: We have previously proposed that the therapeutic effect of transdermal nicotine in Tourette's syndrome may involve nicotinic receptor inactivation resulting from a prolonged continuous exposure to nicotine. In vitro studies with nicotine and preliminary positive experience with mecamylamine (Inversine), a nicotinic receptor antagonist, in the clinical treatment of Tourette's syndrome patients, further supports the receptor inactivation hypothesis. METHODS: We retrospectively documented an unexpected therapeutic response to mecamylamine (2.5-7.5 mg/day) in two Tourette's syndrome patients who were subsequently found to have comorbid bipolar disorder as defined by DSM-IV criteria. RESULTS: In patient 1, the mood-stabilizing effect of mecamylamine was noticed by the patient during the course of mecamylamine treatment and brought to our attention, whereas for patient 2, manic symptoms were only apparent clinically following cessation of mecamylamine treatment. CONCLUSIONS: The clinical observations presented here suggest that nicotinic antagonists might be potential therapeutic agents for the treatment of bipolar disorder. Double-blind, placebo-controlled studies are now necessary to investigate these observations under more rigorous conditions.

Adolescent↗
PubMed1998

Mecamylamine selectively blocks nicotinic receptors on vasomotor sympathetic C neurons.

Mecamylamine differentially blocked fast nicotinic transmission in two functional subsets of sympathetic neurons within lumbar paravertebral ganglia of the bullfrog. EC50s for inhibition of postsynaptic compound action potentials were 27.3+/-2.5 microM in the secretomotor B system and 5.7+/-0.7 microM in the vasomotor C system. This 5.2:1 selectivity is 2.6 times greater than observed previously with d-tubocurarine, a nonselective blocker of nicotinic receptors, and it indicates that mecamylamine preferentially interacts with nicotinic receptors on sympathetic C neurons. We tested this by analyzing the effect of mecamylamine upon synaptic currents. In both cell types, the drug produced a qualitatively similar picture of open-channel blockade. It reduced EPSC amplitude, speeded EPSC decay, and became more effective with membrane hyperpolarization and repetitive activity. Despite these similarities, 8 microM mecamylamine reduced EPSC amplitude to a greater extent in C neurons, and the rate constant for drug binding to open channels was 4.4 times greater in B cells, irrespective of membrane potential. This implies that the unblocking rate for mecamylamine is much slower in C cells than B cells, and it shows that the drug recognizes a structural difference between nicotinic receptors on these two populations of sympathetic neurons.

Animals↗
PubMed2000

Mecamylamine blockade of both positive and negative effects of IV nicotine in human volunteers.

The ganglionic blocker mecamylamine blocks the positive reinforcing effects of IV nicotine, but has been shown to increase cigarette smoking behavior under some conditions. The effects of mecamylamine on subjective and physiologic responses to IV nicotine were evaluated in seven healthy male volunteer cigarette smokers who provided informed consent and resided on a clinical pharmacology research unit. On four separate days, each subject was given a different oral dose of mecamylamine (placebo, 5, 10, or 20 mg). One hour later subjects received the first of four doses of IV nicotine (placebo, 0.75, 1.5, and 3.0 mg); the remaining injections were given at 1-h intervals. Both the positive effects following 0.75 mg and negative effects following 3.0 mg of nicotine were significantly reversed by mecamylamine. Thus, the mecamylamine-induced increase in smoking may be due both to competitive blockade of nicotinic receptors and nicotine's reversal of aversive effects.

Adult↗
PubMed1997

Effects of mecamylamine on spontaneous EEG and performance in smokers and non-smokers.

In a previous study, mecamylamine, a centrally active nicotine antagonist, exacerbated EEG signs of tobacco abstinence in abstinent smokers. In the present study, the effects of mecamylamine were compared in non-smokers and nondeprived smokers. Mecamylamine (0, 5 and 10 mg, p.o.) was administered to six smokers and six non-smokers; eight of these subjects were also given a 20 mg dose. Before drug administration, resting EEG was similar in both groups. In both groups, mecamylamine caused dose-related decreases in alpha frequency and increases in delta frequency; beta frequency was increased by the 5 and 10 mg doses. The similarity of effects in smokers and non-smokers suggests a direct pharmacological action rather than precipitated nicotine withdrawal. Significant baseline differences existed between smokers and non-smokers in systolic blood pressure, pulse rate, skin temperature and pupil diameter. Response time slowed in both vigilance and distractibility tasks and delayed recall was impaired. Mecamylamine increased ratings of: "relaxed," "nodding," "sleepy" and "coasting." This small-sample study tentatively suggests that nicotinic cholinergic mechanisms modulate brain electrical activity and cognitive function in smokers and non-smokers. Disruption of these neural systems could mediate the symptoms of tobacco withdrawal and be involved in the pathophysiology of Alzheimer's disease.

Adult↗
PubMed2000

Simultaneous determination of mecamylamine, nicotine, and cotinine in plasma by gas chromatography-mass spectrometry.

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.

Cotinine↗
PubMed1999

A nicotine antagonist, mecamylamine, reduces cue-induced cocaine craving in cocaine-dependent subjects.

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.

Adolescent↗
PubMed1991

Synthesis of 2-exo- and 2-endo-mecamylamine analogues. Structure-activity relationships for nicotinic antagonism in the central nervous system.

Nine analogues of mecamylamine (2) which differ in the number and substitution pattern of methyl groups, were prepared. In four of these analogues the amine functionality is in an endo orientation. Enantiomers of 2-endo- and 2-exo-N-methylfenchylamine (25 and 26, respectively) were also prepared. The hydrochloride salts of these compounds were tested for nicotinic antagonism relative to mecamylamine in vivo and none was found to be as potent as mecamylamine, although a broad range of activity was observed. In general, methyl substituents at the C1, C2, and C7 positions of the mecamylamine structure do not appear to be significant for antagonistic activity. Methyl substituents at C3, however, appear to be very important for activity. Three sets of enantiomers of N-methylfenchylamine analogues, 28-30, possessing structural features of mecamylamine and nicotine were also prepared. These compounds were inactive as antagonists. Only a small degree of stereoselectivity was elicited in this series, less than that seen with enantiomers of nicotine. Antagonists with the exo N-methylamine functionality are slightly more active than the endo isomers. The extent to which structural modification might change lipophilicities was estimated through calculated partition coefficients; such changes alone appeared insufficient to explain differences in activities of the analogues. Lastly, a tolerance for a tertiary (dimethyl) amine functionality was demonstrated in addition to the lack of tolerance for bulkier substituents at C3 or on the nitrogen.

Analgesia↗
PubMed2003

Cardiovascular effects of nicotine, chlorisondamine, and mecamylamine in the pigeon.

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.

Animals↗
PubMed1977

Comparative studies on anti-nicotinic action of hexamethonium, mecamylamine and adenosine in the guinea pig isolated ileum.

The mechanism of anti-nicotinic actions of hexamethonium, mecamylamine and adenosine was investigated in guinea pig isolated ileum. Mecamylamine shifted the dose-response curves for nicotine to the right with a gradual depression. On the other hand, hexamethonium shifted the curves to the right without a depression and adenosine made only a gradual depression, suggesting the different modes of their antinicotinic actions. The transmurally-stimulated twitch response was unaffected, partially inhibited and abolis hed by hexamethonium, mecamylamine and adenosine, respectively. These three compounds also had little effect on direct muscle response to acetylcholine and on the acetylcholinesterase activity of the ileum. From these results, it is suggested that the antagonism to the effect of nicotine shown by mecamylamine does not appear to be a simple competitive blockade of ganglionic receptors as is the case with hexamethonium and that adenosine may antagonize the effect of nicotine non-competitively. The mechanism by which mecamylamine and adenosine showed anti-nicotinic action is discussed.

Acetylcholine↗
PubMed1993

Discrimination of agonist-antagonist mixtures: experiments with nicotine plus mecamylamine.

Discrimination of a mixture of an agonist plus an antagonist has been analysed by training rats to discriminate (-)-nicotine (0.32mg/kg s.c.) from saline; in different groups of rats (n = 8), nicotine was administered either alone or in combination with the non-competitive nicotine antagonist mecamylamine (0.1-0.8mg/kg s.c.). Rats were trained in a two-bar operant conditioning procedure with a tandem schedule of food reinforcement. After 50 sessions, rats trained with nicotine alone had acquired the discrimination with an accuracy of about 85%. In combination, mecamylamine blocked accuracy during acquisition in a dose-related manner. In generalization tests, rats trained with nicotine alone yielded a typical dose-response curve for nicotine (ED(50) = 0.082mg/kg), without depression of response rate. In rats trained with nicotine plus 0.2mg/kg of mecamylamine, the ED(50) for the discriminative effect of nicotine was lowered (ED(50) = 0.036mg/kg), again without depression of response rate. In rats trained with nicotine plus 0.4-0.8mg/kg of mecamylamine, nicotine did not acquire stimulus control over behaviour (flat dose-response relationships), but in these animals, nicotine had a pronounced response rate-decreasing effect. These characteristics of discriminations based on nicotine plus mecamylamine differed substantially from those of previously described discriminations of nicotine plus midazolam, supporting the hypothesis that interactions between the latter drugs were based on a behavioural mechanism (overshadowing) rather than on interactions at the level of receptors.

Journal Article↗
PubMed1963

DEPRESSION OF THE VASOMOTOR CENTRE BY MECAMYLAMINE, INDEPENDENT OF ITS GANGLION-BLOCKING ACTIVITY.

Mecamylamine depressed the vasomotor centre independently of its ganglion-blocking action. The central action was elicited by small amounts of the drug when it was confined to the central nervous system of dogs and cats anaesthetized with pentobarbital sodium and of spinal cats. The spinal site of action was shown by the inhibition of vasomotor responses due to spinal compression in cats, when mecamylamine was introduced intrathecally in a dose too small to block autonomic ganglia. The supraspinal site of action was shown by intravertebral arterial injection of mecamylamine into cats, which caused hypotension and selectively blocked the electrically evoked pressor responses from the medulla without affecting the "nicotinic" ganglionic responses to acetylcholine. Injection of mecamylamine into the cerebral ventricles of dogs produced hypotension, and the reflex vasomotor responses to stimulation of afferent fibres in the vagus nerves and to occlusion of the common carotid arteries were inhibited without any change in the response of the nictitating membrane to preganglionic nervous stimulation.

Acetylcholine↗
PubMed1994

Effects of THA and physostigmine on spatial navigation and avoidance performance in mecamylamine and PCPA-treated rats.

The present study compares the effects of two cholinesterase inhibitors, tetrahydroaminoacridine (THA, 1 and 3 mg/kg) and physostigmine (0.12 and 0.36 mg/kg), on spatial navigation (water maze, WM) and avoidance (step through passive avoidance, PA) performance. THA and physostigmine did not facilitate WM or PA performance in control or p-chlorophenylalanine (PCPA)-treated rats. THA at 3 mg/kg, but not at 1 mg/kg, completely restored the defect in WM and PA performance in rats pretreated with 7.5 mg/kg mecamylamine, a centrally active nicotinic antagonist. Physostigmine completely restored behavior in WM and PA tests at 0.12 and 0.36 mg/kg in mecamylamine-treated rats. In rats pretreated with mecamylamine+PCPA, 3 mg/kg THA to some extent restored WM performance but had no effect on PA retention. Likewise, physostigmine partially restored WM performance but did not facilitate PA retention in mecamylamine+PCPA-pretreated rats. The present study suggests that serotonergic dysfunction may decrease the efficacy of cholinesterase inhibitors to reverse the defect in WM and PA behavior occurring as a consequence of a decrease in activity of nicotinic-mediated functions.

Animals↗
PubMed2002

Open field habituation learning is improved by nicotine and attenuated by mecamylamine administered posttrial into the nucleus accumbens.

Using the paradigm of habituation learning in the open field, we tested the effects of unilateral microinjections of the agonist nicotine (8.0, 40.0, and 80.0 microg) and the nicotine receptor antagonist mecamylamine (0.1, 1.0, 10.0 microg) into the core of the nucleus accumbens. When injected posttrial, that is, immediately after the first exposure to the open field, nicotine dose-dependently enhanced behavioral habituation during the test on the following day, indicating a facilitation of memory, whereas mecamylamine impaired habituation at the highest dose, but not at the two lower doses. When injected 5 h after the learning trial, nicotine (40 microg) and mecamylamine (10 microg) impaired habituation on the subsequent day. A control experiment did not provide evidence for possible proactive effects of mecamylamine. These findings are discussed with respect to the possible behavioral functions of cholinergic, and especially nicotinic, mechanisms in the nucleus accumbens. They may also be relevant for understanding cholinergic-linked psychopathologies such as Alzheimer's disease, since the nucleus accumbens is one of the sites where cholinergic neurons are lost in this neurodegenerative disease.

Animals↗
PubMed1994

The nicotinic antagonist mecamylamine precipitates nicotine abstinence syndrome in the rat.

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.

Animals↗
PubMed2002

Effects of nicotine and mecamylamine on choice accuracy in an operant visual signal detection task in female rats.

RATIONALE: During the past decade, central nicotinic systems have been shown in both experimental animals and humans to play an important role in cognitive function. However, the way in which specific aspects of cognitive function are affected by nicotinic systems has remained unclear. In humans, the most pronounced action of nicotine is to improve attention, but in rats, memory improvement is more easily seen. This may be due to differences in methods for assessing attention in rats and humans or to species differences in the roles of nicotinic systems in cognitive function. In the current study, we explored the effects of nicotine and mecamylamine using an operant visual signal detection task designed to model sustained attention processes common to rats and humans. METHODS: Adult female rats ( n=35) were trained to perform the signal detection task to a stable baseline of about 75% accuracy. The rats were then assigned to two subgroups of high and low accuracy based on overall accuracy (hits and correct rejections) at the end of training. All rats were then injected (SC, 10 min before testing) with saline or different doses of nicotine (0.0125, 0.025, 0.05, 0.1, 0.2 and 0.4 mg/kg) or the nicotinic antagonist mecamylamine (1, 2 and 4 mg/kg). RESULTS: A low dose range of nicotine (0.0125, 0.025, and 0.05 mg/kg) caused a dose-related increase in percent correct rejection. This dose range did not affect correct detections of the signal (percent hit). Higher doses of nicotine (0.1, 0.2 and 0.4 mg/kg) did not affect percent correct rejection, but did have a time-dependent effect on percent hit. Early in the session, the higher doses of nicotine reduced percent hit, whereas during the later part of the session higher doses of nicotine increased percent hit. Effects of nicotine did not differ between the high- and low-accuracy rats. Mecamylamine decreased choice accuracy, reducing both percent hit and percent correct rejection. Mecamylamine reduced percent hit in the low-accuracy rats at a lower drug dose than in the high-accuracy rats. CONCLUSIONS: These results support the involvement of nicotinic systems in attention in rats, as has been shown in humans. This rat model of sustained attention may provide a good approach to studying neural mechanisms underlying the effects of nicotinic cholinergic receptors on attention and a means to evaluate the potential of novel nicotinic agonists to counteract attentional dysfunction.

Animals↗
PubMed2003

Castration in rats impairs performance during acquisition of a working memory task and exacerbates deficits in working memory produced by scopolamine and mecamylamine.

RATIONALE: Although much research has focused on the effects of ovarian hormones on learning and memory in females, less information is available regarding the effects of testicular hormones on learning and memory in males. Additionally, despite evidence of an interaction of testicular hormones and the cholinergic system in areas of the brain implicated in learning and memory, no information is available regarding the behavioral consequences of that interaction. OBJECTIVES: We assessed the effect of castration in male rats on working memory during acquisition of a radial maze. We also assessed the interactive effects of castration and scopolamine, a muscarinic receptor antagonist, as well as mecamylamine, a nicotinic receptor antagonist, on behavior. METHODS: Young adult male rats were castrated or underwent sham surgeries. Beginning 10 days after surgeries, performance on a task of working memory was assessed across 24 days of acquisition in an eight-arm radial maze. Following acquisition, scopolamine and mecamylamine dose-effect curves were established. RESULTS: Castration of male rats significantly decreased arm-choice accuracy during acquisition. Castration significantly exacerbated impairments in arm-choice accuracy produced by scopolamine as well as mecamylamine, without altering the disruptive effects of the drugs on the rate at which rats entered the arms of the maze. CONCLUSIONS: These results indicate that castration in male rats impairs working memory during acquisition of a spatial maze task. Additionally, these results suggest that the absence of testicular hormones increases the sensitivity of male rats to the impairing effects of scopolamine as well as mecamylamine on working memory.

Animals↗
PubMed2001

Caffeine, nicotine and mecamylamine share stimulus properties in the preexposure conditioned taste aversion procedure.

RATIONALE: The present study examined whether nicotine and caffeine, two of the most widely used psychoactive drugs, share stimulus properties in the preexposure conditioned taste aversion (CTA) procedure. OBJECTIVES: To determine whether nicotine would attenuate the formation of a caffeine-induced CTA and further assess whether pretreatment with mecamylamine, a nicotinic receptor antagonist, would reverse nicotine's attenuating effect of a caffeine-induced CTA. METHODS: Male Wistar rats were preexposed with one of three doses of nicotine (0.6, 1.2 and 2.0 mg/kg, s.c.) for three consecutive days, then 24 h following the final preexposure injection were conditioned with caffeine (20 mg/kg and 30 mg/kg, i.p.) in a standard two-bottle test. There were four conditioning trials and four drug-free test days. In a follow-up study, rats were pretreated with mecamylamine (2 mg/kg, i.p.) prior to preexposure injections with nicotine (0.6 mg/kg, i.p.), then subsequently conditioned with caffeine (20 mg/kg, i.p.) as described above. RESULTS: The lowest nicotine dose (0.6 mg/kg) attenuated the caffeine induced CTAs (20 mg/kg and 30 mg/kg) but the higher nicotine doses showed no such attenuating effect. In addition, mecamylamine reversed the nicotine-induced attenuation of the caffeine-induced CTA and also directly attenuated it. CONCLUSIONS: These results suggested that caffeine, nicotine and mecamylamine share overlapping stimulus properties and that the nature of this relationship may involve action at the nicotinic-cholinergic receptor.

Animals↗