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PubMed2000

Intraaccumbal mecamylamine infusion does not affect dopamine output in the nucleus accumbens of chronically nicotine-treated rats.

Recently we have shown that the nicotinic receptor (nAChR) antagonist mecamylamine both when administered systemically and locally into the ventral tegmental area (VTA) to chronically nicotine-treated rats reduces dopamine (DA) output in the nucleus accumbens (NAC) and elicits behavioral withdrawal signs. However, the putative contributory role of nAChRs in the NAC in mediating these effects of systemic mecamylamine has not been clarified. Therefore, we here investigated the effect on extracellular levels of DA in the NAC of local intraaccumbal administration of mecamylamine to chronically nicotine-treated rats and its putative behavioral correlates. In these experiments local application of mecamylamine into the NAC, in a concentration that increased NAC DA levels in control rats, did not affect DA output or behavior in the nicotine-treated animals. These results provide further support for the contention that nAChRs in the VTA, but not in the NAC, are of major importance for the mesolimbic DA reduction and associated behavioral signs in nicotine withdrawal.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1993

The mesolimbic dopamine-activating properties of ethanol are antagonized by mecamylamine.

It has been suggested that ethanol may interact with the central nicotinic acetylcholine receptor, thus providing a basis for the often observed high consumption of both ethanol and nicotine. In the present in vivo microdialysis study, ethanol (2.5 g/kg) moderately increased dopamine overflow in the rat nucleus accumbens. The central nicotinic acetylcholine receptor antagonist mecamylamine totally counteracted this effect in a dose (1.0 mg/kg) that did not alter dopamine overflow per se. Ethanol also increased the overflow of dihydroxyphenylacetic acid and homovanillic acid, but this effect was not altered by mecamylamine (1.0 mg/kg). Furthermore, the ethanol-induced enhancement of 3,4-dihydroxyphenylalanine accumulation in the mesolimbic dopamine terminal area after NSD 1015 (an inhibitor of l-aromatic amino acid decarboxylase) was completely antagonized by mecamylamine in doses (3.0 and 6.0 mg/kg) that exerted no effects per se. Neither ethanol nor mecamylamine changed the catecholamine synthesis rate in the striatum or the cerebral cortex. These results provide further evidence that ethanol-induced activation of the mesolimbic dopamine system (increased dopamine synthesis and release) may be mediated via stimulation of central nicotinic acetylcholine receptors. It is suggested that antagonists of central nicotinic acetylcholine receptors may be useful in the treatment of alcoholism.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1994

Effect of nicotine, lobeline, and mecamylamine on sensory gating in the rat.

In normal subjects, if an acoustic startle stimulus is immediately preceded by a small brief change in background noise intensity, the magnitude of the subsequent startle response is decreased. This prepulse inhibition (PPI) of an acoustic startle response has been shown to be associated with sensorimotor gating. PPI is disrupted in schizophrenic patients and has been linked to attentional disorders characteristic of this disease. We tested the effects of (-)-nicotine, (0.19, 0.62, and 1.9 mumol/kg IP) (equivalent to 0.03, 0.1, and 0.3 mg/kg base) and the nicotinic cholinergic receptor (nAChR) channel blocker, mecamylamine (5.0 and 50 mumol/kg IP) (equivalent to 1.0 and 10.0 mg/kg) on PPI of the acoustic startle response in the rat. Nicotine increased the PPI at the lowest prepulse signal levels but not at the stronger levels. Mecamylamine was without effect at 5.0 mumol/kg, but the 50 mumol/kg dose decreased the inhibition at both weak and strong prepulse (PP) levels. Mecamylamine (5.0 mumol/kg) pretreatment did not block the (-)-nicotine-induced increase in PPI. Lobeline (0.19, 0.62, 1.9, and 6.2 mumol/kg IP) (equivalent to 0.071, 0.23, 0.71, and 2.3 mg/kg) was without effect. These results are consistent with a mecamylamine-insensitive effect of nicotine to improve gating in normal rats. The nAChR subtype involved in producing nicotine's increase of PPI needs further investigation.

Acoustic Stimulation↗

PubMed2006

Mecamylamine blocks nicotine-induced enhancement of the P20 auditory event-related potential and evoked gamma.

Cigarette smoking is significantly more prevalent in individuals with schizophrenia than in non-affected populations. Certain neurocognitive deficits and disruptions common in schizophrenia may be altered by smoking, leading to the hypothesis that schizophrenics engage in smoking behavior to alleviate specific neurocognitive symptoms of the disorder. Additionally, research suggests that individuals with schizophrenia have altered auditory event-related potentials (ERPs) and abnormalities in evoked gamma oscillations which are both indices of sensory information processing. This study was conducted to examine the effect of acute administration of nicotine and the non-specific nicotinic antagonist mecamylamine on the P20 and N40 components of the ERP and evoked gamma oscillations in mice. Acute nicotine (1 mg/kg) significantly increased P20 amplitude, an effect that was blocked by pretreatment with mecamylamine (2 mg/kg). Additionally, acute nicotine increased the normal burst of evoked gamma following an auditory stimulus. The increase in evoked gamma was also blocked by mecamylamine pretreatment. Although acute nicotine decreased amplitude of the N40 component, this decrease was not attenuated by mecamylamine. These results replicate findings that nicotine may enhance early sensory information processing through the nicotinic acetylcholinergic receptor system in an established model (ERPs) and extend these findings in an emerging, novel model (evoked gamma oscillations) of sensory information processing. The results also support the hypothesis that nicotine may be beneficial to individuals with deficits in neurocognitive functions, such as those suffering from schizophrenia.

Acetylcholine↗

PubMed2006

Cholinergic modulation of Pavlovian fear conditioning in rats: differential effects of intrahippocampal infusion of mecamylamine and methyllycaconitine.

The cholinergic system has consistently been implicated in Pavlovian fear conditioning. Considerable work has been done to localize specific nicotinic receptor subtypes in the hippocampus and determine their functional importance; however, the specific function of many of these subtypes has yet to be determined. An alpha7 nicotinic antagonist methyllycaconitine (MLA) (35 microg), and a broad spectrum non-alpha7 nicotinic antagonist mecamylamine (35 microg) was injected directly into the dorsal hippocampus or overlying cortex either 15 min pre-, 1 min post-, or 6h post-fear conditioning. One week after conditioning, retention of contextual and cue (tone) conditioning were assessed. A significant impairment in retention of contextual fear was observed when mecamylamine was injected 15 min pre- and 1 min post-conditioning. No significant impairment was observed when mecamylamine was injected 6h post-conditioning. Likewise, a significant impairment in retention of contextual fear was observed when MLA was injected 1 min post-conditioning; however, in contrast, MLA did not show any significant impairments when injected 15 min pre-conditioning, but did show a significant impairment when injected 6h post-conditioning. There were no significant impairments observed when either drug was injected into overlying cortex. No significant impairments were observed in cue conditioning for either drug. In general, specific temporal dynamics involved in nicotinic receptor function were found relative to time of receptor dysfunction. The results indicate that the greatest deficits in long-term retention (1 week) of contextual fear are produced by central infusion of MLA minutes to hours post-conditioning or mecamylamine within minutes of conditioning.

Aconitine↗

PubMed2005

Dynorphin A (2-13) improves mecamylamine-induced learning impairment accompanied by reversal of reductions in acetylcholine release in rats.

Accumulating evidence indicates that the endogenous opioid peptides dynorphin A (1-17) and synthetic dynorphin A (1-13) interact not only with opioid receptors but also with as yet poorly characterized non-opioid binding sites. Dynorphin A (1-13) improved impairments of learning and memory via not only kappa-opioid receptor-mediated, but also 'non-opioid' mechanisms. In the present study, the effects of des-tyrosine(1) dynorphin A (2-13) as a non-opioid metabolite of dynorphin A, and dynorphin A (1-13) on mecamylamine-induced impairment of the acquisition of learning in rats were investigated using a step-through type passive avoidance task. Further, hippocampal acetylcholine release was examined using in vivo microdialysis. Mecamylamine significantly shortened the step-through latency when given 30 min before the acquisition trial. Not only dynorphin A (1-13) but also dynorphin A (2-13) attenuated the mecamylamine-induced impairment of the acquisition of learning. The effect of dynorphin A (2-13) was not blocked by pre-treatment with nor-binaltorphimine (nor-BNI), a selective kappa-opioid receptor antagonist. Dynorphin A (2-13) completely abolished the decrease in the extracellular acetylcholine concentration induced by mecamylamine and this effect was not blocked by nor-BNI. Taken together with our previous findings, the present results may indicate that dynorphin A (2-13) improves impairment of learning and/or memory in 'non-opioid' mechanisms and dynorphin A (1-13) ameliorates impairment of the acquisition of learning via not only kappa-opioid receptor-mediated mechanisms but also 'non-opioid' mechanisms, by regulating the release of extracellular acetylcholine.

Acetylcholine↗

PubMed1997

3-[2,4-Dimethoxybenzylidene]anabaseine (DMXB) selectively activates rat alpha7 receptors and improves memory-related behaviors in a mecamylamine-sensitive manner.

The alpha7 nicotinic receptor agonist 3-[2,4-dimethoxybenzylidene]anabaseine (DMXB; GTS-21) was investigated for its ability to: (1) activate a variety of nicotinic receptor subtypes in Xenopus oocytes; (2) improve passive avoidance and spatial Morris water task performances in mecamylamine-sensitive manners in bilaterally nucleus basalis lesioned rats; and (3) elevate high-affinity [3H]acetylcholine (ACh) and high-affinity alpha-[125I]bungarotoxin binding in rat neocortex following 2 weeks of daily injections. DMXB (100 microM) activated alpha7 homo-oligomeric receptors, without significant activity at alpha2-, alpha3- and alpha4-containing subtypes. Mecamylamine blocked rat alpha7 receptors weakly if co-administered with agonist, but much more potently when pre-applied. Bilateral ibotenic acid lesions of the nucleus basalis interfered with passive avoidance and spatial memory-related behaviors. DMXB (0.5 mg/kg, i.p.) improved passive avoidance behavior in lesioned animals in a mecamylamine-sensitive manner. DMXB (0.5 mg/kg 15 min before each session) also improved performance in the training and probe components of the Morris water task. DMXB-induced improvement in the probe component but not the training phase was mecamylamine-sensitive. [3H]ACh binding was elevated after 14 days of daily i.p. injections with 0.2 mg/kg nicotine but not after 1 mg/kg DMXB. Neither drug elevated high-affinity alpha-[125I]bungarorotoxin binding over this interval.

Animals↗

PubMed1997

Accumbal dopamine overflow after ethanol: localization of the antagonizing effect of mecamylamine.

It has been suggested that ethanol exerts its mesolimbic dopamine activating effects and its reinforcing effects via interaction with central nicotinic acetylcholine receptors, thus providing a basis for the often observed covariation between ethanol and nicotine consumption. We have previously demonstrated that the central nicotinic acetylcholine receptor antagonist mecamylamine totally counteracts the ethanol-induced elevation of extracellular dopamine in the nucleus accumbens, as measured by in vivo microdialysis. A contribution of peripheral nicotinic receptor blockade could, however, not be excluded. In the present study, mecamylamine (1.0 mg/kg, i.p.) again totally counteracted the ethanol-induced dopamine overflow, as measured by in vivo microdialysis, while the quarternary nicotinic receptor antagonist hexamethonium (10 mg/kg, i.p.) did not. Furthermore, the increase in accumbal dopamine overflow after systemic ethanol (2.5 g/kg, i.p.) was counteracted by local perfusion of mecamylamine (50 microM) in the ipsilateral ventral tegmental area, but not by mecamylamine perfusion in the nucleus accumbens. Ethanol-induced accumbal dopamine overflow was also counteracted by perfusion of hexamethonium (250 microM) in the ventral tegmental area. These results provide further evidence that ethanol-induced activation of the mesolimbic dopamine system is mediated via stimulation of central nicotinic acetylcholine receptors, and that the receptor population within the ventral tegmental area may be the most important in this regard. It is suggested that antagonists of central nicotinic acetylcholine receptors may be useful in the treatment of alcoholism.

Animals↗

PubMed1987

Effects of the nicotinic receptor blocker mecamylamine on radial-arm maze performance in rats.

Lesions of cholinergic neurons have been found by many investigators to impair choice accuracy in the radial arm maze. Because muscarinic receptor blockers, such as scopolamine, have also repeatedly been found to impair choice accuracy in the radial-arm maze, it has generally been thought that the critical effect of cholinergic lesions is the deafferentation of muscarinic receptors. The possible involvement of nicotinic receptors in the cholinergic bases of cognitive performance in the radial-arm maze has not been as well investigated. The present study examined the effects of the blockade of nicotinic receptors on performance of female Sprague-Dawley rats in the radial-arm maze. Acute administration of the the nicotinic receptor blocker, mecamylamine (10 mg/kg) was found to significantly impair radial-arm maze choice accuracy. This dose also caused a significant increase in response latency in the maze. The effect on choice behavior but not locomotor speed seemed to be due to the central effects of mecamylamine, because administration of the peripheral nicotine receptor blocker, hexamethonium (20 mg/kg), did not impair choice accuracy, even though it did increase response latency to a similar degree as the 10-mg/kg dose of mecamylamine. Lower doses of mecamylamine (2.5 and 5 mg/kg) did not impair choice accuracy. These results indicate that central nicotinic as well as muscarinic cholinergic receptors are involved with cognitive functioning.

Animals↗

PubMed1996

Mecamylamine-induced impairment of acquisition and retrieval of olfactory conditioning in the honeybee.

Mecamylamine, a nicotinic receptor antagonist, was injected into the honeybee brain haemolymph. The effects of the drug were investigated on Pavlovian conditioning of the proboscis extension reflex. The conditioned response was acquired after a one-trial learning session, consisting of an olfactory-conditioned stimulus combined with a gustatory antennal unconditioned stimulus. The drug was injected at different times before or after the learning session in order to dissociate its effects on acquisition, consolidation and retrieval processes. The performance was evaluated in short-delayed recall tasks. To control potential effects on sensory-motor activity, the effects of the drug were also investigated on sensory processes (through olfactory and gustatory functions) and on motor processes of proboscis extension. The results of conditioning experiments showed that pretrial injection induced a decrease of retention performance 1 h after the learning trial. Mecamylamine injected 20 min after the learning session induced a time-dependent impairment of retention performance, as has been shown by the performance level registered from 10 to 80 min after injection. A 5-min post-trial injection had no effect on retention performance. Control experiments did not reveal any effect of mecamylamine on the response reflex of proboscis extension and on responsiveness to olfactory stimuli (geraniol, lavender and vanillin). The absence of effects on sensory perception combined with the amnestic effect induced by pre- or late post-trial injections lead us to conclude that mecamylamine specially impaired acquisition and retrieval processes. The involvement of nicotinic-like receptors in these processes is discussed.

Animals↗

PubMed2002

Modulation of kappa-opioidergic systems on mecamylamine-precipitated nicotine-withdrawal aversion in rats.

The present study was designed to examine the modulation of the kappa-opioidergic system on mecamylamine-precipitated nicotine-withdrawal aversion. The nicotinic receptor antagonist mecamylamine, which is known to pass the blood-brain barrier, produced a place aversion in rats chronically treated with nicotine using an osmotic mini-pump. This effect was significantly attenuated by pretreatment with -opioid receptor agonists U50,488H (1.0 mg/kg, s.c.) and TRK-820 (0.03 mg/kg, s.c.). The attenuation of mecamylamine-precipitated nicotine-withdrawal aversion by U50,488H was completely reversed by the combination with a selective -opioid receptor antagonist nor-binaltorphimine (10.0 mg/kg, i.p.). These results suggest that the activation of endogenous -opioidergic systems can suppress the mecamylamine-precipitated nicotine-withdrawal aversion.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1999

Behavioral and biochemical manifestations of mecamylamine-precipitated nicotine withdrawal in the rat: role of nicotinic receptors in the ventral tegmental area.

Brain mesolimbic dopamine (DA) neurons are considered critical for the dependence-producing action of nicotine, and its stimulatory effect on behavior and DA neurotransmission appears largely mediated via nicotinic receptors (nAChRs) in the ventral tegmental area (VTA). The nAChR antagonist mecamylamine administered systemically in chronically nicotine-treated rats elicits a behavioral withdrawal syndrome concomitant with a reduced DA output in the nucleus accumbens (NAC). Here, we investigated the behavioral and biochemical consequences of intrategmental administration of mecamylamine in rats chronically infused with nicotine by means of minipumps for 14 days (9 mg/kg/day). Bilateral, intrategmental mecamylamine injections (1, 3 or 9 micrograms/0.5 microliter/side) dose-dependently increased abstinence signs such as gasps, teeth chatter, and reduced locomotor activity in nicotine-treated, but not in control animals. Moreover, a unilateral intrategmental injection of 9 micrograms mecamylamine reduced DA output in the ipsilateral NAC of chronically nicotine-treated rats, but not in control animals. Consequently, nAChRs in the VTA may be involved not only in the stimulatory effects of acute nicotine administration, but also in the withdrawal reaction following cessation of chronic nicotine treatment.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2002

Anxiolytic effects of mecamylamine in two animal models of anxiety.

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.

Animals↗

PubMed2002

Effects of puerarin on scopolamine-, mecamylamine-, p-chloroamphetamine- and dizocilpine-induced inhibitory avoidance performance impairment in rats.

Puerarin at 10-50 mg/kg attenuated the mecamylamine- but not scopolamine-induced acquisition impairment of inhibitory avoidance performance in an inverse U-shape manner. p-Chloroamphetamine- and dizocilpine-induced acquisition impairment were reversed by puerarin at 25-50 mg/kg. Both piracetam, and tacrine attenuated impairment of inhibitory avoidance performance induced by all used drugs. Furthermore, puerarin, piracetam and tacrine alone did not alter step-through latency in the training trail but puerarin at 50 mg/kg and tacrine plus mecamylamine prolonged it in comparison with mecamylamine alone. From these results, we suggest that puerarin attenuated the deficits of inhibitory avoidance performance induced by mecamylamine, p-chloroamphetamine, and dizocilpine, the effects were related to increasing cholinergic activity via nicotinic but not muscarinic receptors, activating NMDA receptors, and decreasing serotonergic neuronal activity.

Amnesia↗

PubMed2005

A placebo controlled, double-blind study of mecamylamine treatment for cocaine dependence in patients enrolled in an opiate replacement program.

A placebo controlled, double-blind trial of mecamylamine treatment of cocaine dependence was performed in methadone or LAAM maintained subjects who met DSM-IV criteria for cocaine dependence. After an eight-week placebo run-in screening period, 35 subjects were randomly assigned to receive either mecamylamine (6 mg/day) or placebo transdermal patches for a 16-week treatment period. Outcome measures included quantitative urine benzoylecognine (BE) levels, self-report of cocaine use, cocaine craving, global impression scores, mood, retention, and safety. Mecamylamine was well tolerated, and study retention did not differ by treatment group. Evidence for cocaine use, based on urine BE levels and cocaine abstinence rates, did not differ by treatment group. Self reported cocaine use, cocaine craving, and global impression scores showed moderate improvement in both groups, with a significantly greater reduction in cocaine craving (p < 0.05) and self-rated severity of cocaine dependence (p < 0.05) in the placebo group. This pilot study does not support the effectiveness of mecamylamine for the treatment of cocaine dependence in methadone or LAAM maintained patients.

Administration, Cutaneous↗

PubMed1975

Absorption of morphine, butylscopolamine, mecamylamine and phenobarbitone from the small intestine of the triparanol-treated rat in situ.

The absorption of three basic drugs (morphine, butylscopolamine and mecamylamine) and an acidic drug (phenobarbitone) from the rat small intestine in situ was investigated by using a single perfusion technique. The effect of intestinal damage on absorption was studied by treating rats with triparanol 25-50 mg/kg every 24 h for three weeks. Treatment with triparanol decreased the cholesterol concentration in the intestinal wall. The absorption of morphine and mecamylamine was increased by treatment with triparanol, whereas the absorption of butylscopolamine was decreased and that of phenobarbitone remained unaltered. Treatment with triparanol decreased the concentration of mecamylamine in the intestinal wall, but the concentrations of other drugs were unchanged. When comparing the present in situ and previous in vitro results the decreased absorption of butylscopolamine after triparanol in situ was opposite to the finding in vitro. The increased absorption of morphine and unaltered absorption of phenobarbitone were in accordance with the finding in vitro. In situ the absorption of mecamylamine was increased, although in vitro it was unchanged. The structural damage, differences in composition of the intestinal wall and intestinal blood flow are supposed to be the reasons for changes in absorption.

Animals↗

PubMed1990

Pharmacological evaluation of the antagonism of nicotine's central effects by mecamylamine and pempidine.

The nature of mecamylamine's and pempidine's antagonism of nicotine in the central nervous system has not been defined clearly. Although these compounds are thought to be noncompetitive antagonists in the brain due to the fact that they do not compete effectively for agonist binding to brain tissue in vitro, pharmacological evidence is lacking. The alteration of nicotine's dose-response curves for depression of spontaneous activity and antinociception was determined in the presence of increasing concentrations of pempidine. Pempidine was found to increase the ED50 of nicotine (0.73 mg/kg) for depression of spontaneous activity in a dose-related manner. At a dose of 3 mg/kg, pempidine increased nicotine's ED50 4.7-fold. The maximum effect of nicotine was achieved in the presence of the highest dose of pempidine, suggesting competitive antagonism. However, pempidine did decrease the maximum effect of nicotine in producing antinociception at doses that increased the ED50 13.7-fold which suggests a noncompetitive action. The structural requirements for mecamylamine's antagonism of these nicotine effects was also determined in order to address the question of whether the antagonists are interacting at a receptor site. The structure-activity relationships of the mecamylamine analogs revealed that the N-, 2- and 3-methyl groups were important for optimal potency. Optical isomerism was found to have little effect on potency. Addition of pyridinyl groups to the nitrogen abolished the activity of these compounds. The structural requirements for the agonists and antagonists therefore appear to be quite different. The alterations produced similar results for antagonism of both effects of nicotine. Mecamylamine and pempidine therefore appear to exhibit both competitive and noncompetitive properties in antagonizing the central effects of nicotine.

Analgesia↗

PubMed1964

ACTIONS OF MECAMYLAMINE, DIMECAMINE, PEMPIDINE AND THEIR TWO QUATERNARY METHO-SALTS AT THE NEUROMUSCULAR JUNCTION.

Mecamylamine, dimecamine and pempidine differed in neuromuscular-blocking activity on the isolated phrenic nerve-diaphragm preparation of the rat from the corresponding methiodides by a factor of less than two. It was concluded that the active component of each amine was the cation acting extracellularly. The finding that the neuromuscular-blocking activity of mecamylamine at pH 6.7 was similar to the activity at pH 7.7 did not refute this conclusion. Mecamylamine, dimecamine methiodide, dimecamine and pempidine, at concentrations insufficient to cause block, could increase the twitch response of the rat diaphragm; the ability to do this increased in the above order. With pempidine (the most active compound) this effect, on the isolated sartorius muscle of the frog, was a direct action. During steady partial block by each of the compounds, the responses to brief tetanic stimulation, to neostigmine and to an increase in calcium concentration were similar to those observed during block by tubocurarine. From indirect evidence, pempidine methiodide appeared both to enhance the release of acetylcholine from motor-nerve terminals and to cause postsynaptic block.

Abdominal Muscles↗