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PubMed1987

Mecamylamine pretreatment increases subsequent nicotine self-administration as indicated by changes in plasma nicotine level.

Acute administration of mecamylamine, a centrally active nicotinic cholinergic agonist, has been shown to increase amount of smoking as indicated by smoking topography (e.g., puff rate, puff duration), expired carbon monoxide changes, and other inferential measures. In the present study, subjects showed significantly greater increases in plasma nicotine following smoking of two high-nicotine research cigarettes when pretreated with mecamylamine than when pretreated with placebo, even though no significant differences in puff volume or puff number were detected. Interestingly, none of our subjects reported nausea, although some achieved plasma nicotine levels at which nausea would typically be expected. We attribute the observed increases in nicotine intake to compensatory behavior designed to overcome mecamylamine's blocking effects.

Adult↗

PubMed2004

Effects of nicotine and mecamylamine on cognition in rhesus monkeys.

RATIONALE: Nicotine and other agonists of nicotinic cholinergic receptors (nAChR) have been shown to improve performance in specific memory domains in rodents and monkeys. Such beneficial effects are observed in preclinical models of age-related cognitive decline, stimulating interest in nAChR ligands as possible therapeutics. Prior work has typically focused on assays of spatial working memory in rodent studies and visual recognition memory in monkey studies. OBJECTIVE: The current study was conducted to determine the role played by nAChRs in multiple types of memory in monkeys. METHODS: Rhesus monkeys (n=6) were trained to perform a battery of six behavioral tasks and then serially challenged with acute doses of nicotine (3.2-56 microg/kg, i.m.) and the nAChR antagonist mecamylamine (0.32-1.78 mg/kg, i.m.). RESULTS: Nicotine improved performance on tests designed to assay visual recognition memory, spatial working memory and visuo-spatial associative memory, while mecamylamine impaired visuo-spatial associative memory. Ballistic and fine motor performance was not significantly improved by nicotine but fine motor performance was impaired by mecamylamine. CONCLUSIONS: Although nicotine may improve performance in multiple domains, effects on visuo-spatial associative memory is the most specifically attributable to nAChR signaling.

Animals↗

PubMed2000

Mecamylamine prevents tolerance but enhances whole brain [3H]epibatidine binding in response to repeated nicotine administration in rats.

RATIONALE: Chronic administration of nicotine in rats results in upregulation of neuronal nicotinic receptors. Upregulation has been proposed to reflect receptor desensitization, which may underlie functional tolerance to nicotine's effects. However, evidence indicates that tolerance and upregulation do not always parallel each other, suggesting that either upregulation does not always reflect desensitization, or mechanisms other than receptor desensitization account for tolerance to nicotine. OBJECTIVES: The present studies examined tolerance to nicotine-induced antinociception and changes in receptor binding after two regimens of intermittent nicotine injections in rats. The role of receptor activation in upregulation and tolerance was also examined by co-administering nicotine with the non-competitive antagonist, mecamylamine. METHODS: Sprague-Dawley rats were administered a short (once-daily, s.c. for 6 days (0.35 mg/kg)) or long (twice-daily for 11 days (0.66 mg/kg)) series of injections and tolerance to nicotine-induced antinociception and [3H]epibatidine binding in whole brain were measured. RESULTS: The short series of injections resulted in tolerance to nicotine-induced antinociception, but failed to increase [3H]epibatidine binding. In contrast, the long series of injections resulted in both tolerance and increased receptor binding. Once-daily pairings of mecamylamine (1 mg/kg, s.c.) with nicotine (0.35 mg/kg) for 6 days blocked the development of tolerance, indicating receptor activation is necessary for tolerance to occur. Pairing mecamylamine with nicotine (0.66 mg/kg) twice daily for 11 days blocked tolerance but produced a greater increase in [3H]epibatidine binding than nicotine alone. CONCLUSIONS: A dissociation of tolerance from receptor upregulation was observed in the present study. The finding that receptor activation may be necessary for tolerance but not upregulation is discussed within the context of possible mechanisms controlling tolerance to nicotine.

Animals↗

PubMed2000

Effects of the competitive nicotinic antagonist erysodine on behavior occasioned or maintained by nicotine: comparison with mecamylamine.

RATIONALE: The cellular effects of nicotine underlying its addictive liability are thought to be mediated by neuronal nicotinic receptors (nACHRs) in the central nervous system. It is believed that densely expressed beta32-containing nACHRs in the central nervous system are responsible for these actions, but few data are available that can directly assess subtype mediation of nicotine's acute subjective and reinforcing effects. OBJECTIVE: The present study compared the effects of the competitive nACHR antagonist erysodine and the noncompetitive antagonist mecamylamine in rats trained to discriminate or self-administer nicotine. METHODS: Adult male rats were trained to discriminate 0.4-mg/kg injections of nicotine from vehicle in a two-lever procedure of food-maintained behavior, or to self-administer 0.03-mg/kg injections of nicotine under fixed-ratio 5 or progressive-ratio schedules of reinforcement. Additional rats were trained under a food-maintained procedure of lever pressing. RESULTS: Erysodine (0.3-10 mg/kg) and mecamylamine (0.1-1.0 mg/kg) blocked nicotine discrimination, although only erysodine produced the rightward shift that would be predicted of a competitive antagonist. Erysodine (0.32-32 mg/kg) and mecamylamine (0.32-3.2 mg/kg) also selectively reduced nicotine self-administration on a fixed-ratio schedule and lowered break points on a progressive-ratio schedule. CONCLUSIONS: Based on the known affinity of erysodine for alpha4beta2 nACHRs and its selectivity relative to alpha7 and alpha1beta1gammadelta receptors, the present data support a critical role of beta2-containing nACHR constructs in the discriminative and reinforcing actions of nicotine.

Animals↗

PubMed1996

An oral self-administration model of nicotine preference in rats: effects of mecamylamine.

A new oral model of nicotine self-administration in rats has been described. The model utilizes a two-lever operant procedure with rats having a choice between nicotine and water reinforcement. Most (16 of 20) rats exhibited reliable preferences for nicotine solutions equal to or less than 32 micrograms/ml; preferences were inversely related to the concentration of nicotine. Mecamylamine (0.25-5.0 mg/kg), a nicotinic antagonist, reduced preferences for a low nicotine concentration (4 micrograms/ml) and enhanced preferences for a high nicotine concentration (32 micrograms/ml). The relationship of nicotine concentration to nicotine preference appeared to be consistent with previous reports of nicotine self-administration using the intravenous route in rats as well as the respiratory route (i.e., smoking) in humans. The mecamylamine-induced changes in nicotine preference were consistent with its nicotinic antagonist action as well as with effects of mecamylamine reported in humans. This model should be useful in the preclinical assessment of new agents as potential therapies in smoking cessation programs.

Animals↗

PubMed1997

Mecamylamine- or scopolamine-induced learning impairment: ameliorated by nefiracetam.

Nefiracetam is undergoing preclinical and clinical tests as a cognition-enhancing drug in Alzheimer's disease (AD). Nicotinic cholinergic receptors are lost in AD, and nicotinic as well as muscarinic cholinergic receptors are involved in the modulation of eyeblink conditioning. Experiments were carried out using young rabbits to examine the effect of nefiracetam on cholinergic antagonists to nicotinic (mecamylamine) and muscarinic (scopolamine) receptors. Rabbits were tested for 15 days in the 750 ms delay eyeblink classical conditioning paradigm in paired and explicitly unpaired conditions. Nefiracetam at a dose of 15 mg/kg significantly ameliorated the effects of 0.5 mg/kg mecamylamine, and nefiracetam at a dose of 10 mg/kg significantly ameliorated the effect of 1.5 mg/kg scopolamine. The vehicle alone and nefiracetam alone groups performed similarly to the groups treated with mecamylamine or scopolamine and nefiracetam. Reversal by nefiracetam of a nicotinic as well as a muscarinic cholinergic antagonist indicates that the drug may affect deficits specific to AD.

Animals↗

PubMed1990

Nicotine effects in mouse hippocampus are blocked by mecamylamine, but not other nicotinic antagonists.

Previous data indicated that bath-application of nicotine to mouse hippocampal slices resulted in a concentration-dependent increase in the amplitude of the orthodromic population spike and the appearance of multiple population spikes in the CA1 pyramidal cell layer. d-Tubocurarine (4-100 microM), alpha-bungarotoxin (10-160 microM), and atropine (40-200 microM) had similar effects, although for alpha-bungarotoxin these excitatory effects were transient. Mecamylamine (1.6-3.2 mM) inhibited the population spike, while hexamethonium (3.2 mM) had no effect. These cholinergic antagonists were tested for their ability to block excitatory effects of nicotine (800 microM) at antagonist concentrations which were at or near threshold for intrinsic effects. Of the 5 antagonists tested, only mecamylamine (400 microM) effectively inhibited the nicotine-induced increase of the population spike amplitude and the appearance of multiple population spikes. These results suggest that nicotine exerts electrophysiological effects via a subclass of nicotinic cholinergic receptors that is neither neuromuscular nor ganglionic in the classical sense; these brain nicotinic receptors are sensitive to mecamylamine, but not to hexamethonium, alpha-bungarotoxin, or D-tubocurarine.

Action Potentials↗

PubMed1990

Effects of acute nicotine and mecamylamine administration on somatostatin concentration and binding in the rat brain.

Since nicotine and somatostatin have regulatory effects on locomotor activity it was of interest to determine whether the receptors for somatostatin are modulated by the cholinergic nicotine-like effects. An i.v. dose of 0.3 mg/kg nicotine induced an increase in the concentrations of somatostatin-like immunoreactivity at 4 min in the parietal cortex and at 15 min in the hippocampus. These changes were associated with a significant increase in the total number of specific somatostatin receptors in the parietal cortex at 15 min and in the hippocampus at 30 min following injection. To determine if the above mentioned changes are related to the nicotine activation of central nicotine-like acetylcholine receptors, a cholinergic nicotinic blocking agent, mecamylamine, was administered before the nicotine injection. Pretreatment with mecamylamine (5.0 mg/kg i.v.) prevented the nicotine-induced changes in somatostatin level and binding in both brain areas. Mecamylamine alone had no observable effect on the somatostatinergic system. These results suggest that the somatostatinergic system can be regulated by nicotine-like acetylcholine receptors and may be involved in some of the behavioral central effects of nicotine.

Animals↗

PubMed1985

Effects of nicotine on schedule-controlled behaviour. Role of fixed-interval length and modification by mecamylamine and chlorpromazine.

The effects of nicotine, alone and in combination with mecamylamine and chlorpromazine, were studied in one group of rats exposed to a fixed-interval 30 sec schedule of food reinforcement, and a second group exposed to a fixed-interval 120 sec schedule. For both groups nicotine increased overall response rates in a dose-related fashion up to a maximum at 0.3 mg/kg. Examination of the within-interval response patterns showed that nicotine tended to increase the low level response rates in the early and middle parts of the interval and decrease, or increase to a proportionally smaller extent, the higher level response rates at the end of the interval. The response rate and pattern of the animal, rather than the schedule to which it was exposed, was found to be the main determinant of the effects of nicotine. Mecamylamine (1.0 mg/kg) blocked most of the changes in rate produced by nicotine, although in the group exposed to the fixed-interval 30 sec schedule, the increases in response rate tended to predominate after combined administration of mecamylamine and nicotine. Chlorpromazine (1.0 mg/kg) failed to block the effects of nicotine in either group. Instead, the effects of combined administration of nicotine and chlorpromazine were similar to the added effects of the two compounds given alone. It appears that the behavioural effects of nicotine are not mediated through catecholaminergic systems.

Animals↗

PubMed1989

Nicotine-induced inhibition of cerebellar Purkinje neurons: specific actions of nicotine and selective blockade by mecamylamine.

The specificity and pharmacological characteristics of the effects of local administration of nicotine on cerebellar Purkinje cells in the rat were examined electrophysiologically. Local application of nicotine, whether by pressure-ejection or by iontophoresis, depressed the spontaneous discharge of Purkinje neurons in a reversible and dose-dependent manner. This action could not be mimicked by local application of vehicle alone. The inhibitory effects of (-)-nicotine were several-fold more potent than that of the (+)-enantiomer. Systemic administration of the ganglion blocker mecamylamine reliably and reproducibly antagonized the nicotine-induced inhibitions of Purkinje cells whereas nicotine-induced excitation of interneurons was not altered. Local pressure-ejection of mecamylamine also antagonized the inhibitory actions of nicotine, administered by iontophoresis. Since the central effects of nicotine on behavior are stereospecific and sensitive to mecamylamine, the data in this study further support the hypothesis that the actions of nicotine on Purkinje neurons are mediated by ganglionic-like receptors. These findings also suggest that the Purkinje cell may serve as a good cellular model for studies on central pharmacology of nicotine.

Animals↗

PubMed1990

Oxiracetam prevents mecamylamine-induced impairment of active, but not passive, avoidance learning in mice.

The nicotinic antagonist mecamylamine (2.5 and 5 mg/kg/IP) depressed both active (shuttle-box) and passive (step-through) avoidance learning in mice of the DBA/2 strain. The nootropic drug oxiracetam (50 and 100 mg/kg/IP) improved acquisition in the multitrial active avoidance test, but had no effect on one-trial passive avoidance learning. When the two drugs were combined, oxiracetam did not counteract mecamylamine-induced impairment of passive avoidance learning, even if it maintained a facilitating action on shuttle-box avoidance acquisition in mice receiving the nicotinic receptor blocker. Prevention of mecamylamine-induced shuttle-box avoidance depression by oxiracetam indicates that central nicotinic mechanisms are probably involved in the improving effects exerted by nootropic drugs on learning.

Animals↗

PubMed1993

Differential effects of scopolamine and mecamylamine on working and reference memory in the rat.

The effects of the muscarinic antagonist scopolamine (0.1-0.6 mg/kg, IP) and the nicotinic antagonist mecamylamine (1-10 mg/kg) were compared in T-maze alternation and discrimination tasks in the rat. Scopolamine dose dependently disrupted performance on the alternation task and potentiated the increase in errors made in controls when the delay between forced and choice runs was increased from 0 to 30 s. Mecamylamine disrupted performance at the 10-mg/kg dose only and dose dependently inhibited the increase in errors made in controls when the delay between forced and choice runs was increased to 30 s. In simple T-maze discrimination, only the 0.6-mg/kg dose of scopolamine disrupted performance of the task, while mecamylamine at both 5 and 10 mg/kg disrupted task performance. These results confirm that working memory tasks are more sensitive to central muscarinic blockade than reference memory tasks. They also demonstrate that in delay conditions working memory performance is enhanced following central nicotinic blockade while reference memory performance is disrupted. This suggests that centrally active muscarinic and nicotinic antagonists have dissociable effects on memory processes in the rat.

Animals↗

PubMed2005

Mecamylamine attenuates ephedrine-induced hyperactivity in rats.

Ephedrine is a central nervous system stimulant that has a pharmacological profile similar to amphetamines. Ephedrine induces hyperactivity after acute administration to rats and locomotor sensitization develops to ephedrine with repeated administration. Recent research suggests that nicotinic receptors (nAChRs) play a role in the development of locomotor sensitization to d-amphetamine and the goal of the present study was to determine if nAChRs similarly mediate the effects of ephedrine after acute and repeated drug injection. On 12 consecutive days, rats were pretreated with the nAChR antagonist mecamylamine (0.3-3.0 mg/kg) or saline followed by (-)-ephedrine (10-30 mg/kg) or saline injection and locomotor activity was measured. Ephedrine produced a dose-dependent increase in locomotor activity, and sensitization to ephedrine developed with repeated injection. Mecamylamine pretreatment attenuated the hyperactivity and sensitization produced by repeated, but not acute, ephedrine (10 mg/kg) injection. The inhibitory effect of mecamylamine was overcome at the higher ephedrine dose (30 mg/kg). The present results indicate that nAChRs play a mediating role in the development of locomotor sensitization to ephedrine.

Animals↗

PubMed2005

Blockade of the expression of mecamylamine-precipitated nicotine withdrawal by calcium channel antagonists.

The present study focused on the evaluation of nicotine abstinence syndrome in mice and on the influence of calcium channel blockers on the expression of the somatic signs of nicotine withdrawal. Our experimental protocol consisted of intermittent administration of nicotine, 2.5 mgkg(-1), subcutaneously (s.c.), four times daily for 7 days. In attempt to precipitate nicotine abstinence, mice were given one injection of mecamylamine (3 mgkg(-1), intraperitoneally (i.p.)), 1h after the last nicotine injection, on the test day (day 8) in the morning. Additionally, body weight changes, locomotor activity and anxiogenic responses in the elevated plus maze test were also evaluated in nicotine withdrawn mice. Our data shown that the L-type calcium channel antagonists, nimodipine, verapamil, flunarizine and diltiazem (5 and 10 mgkg(-1), i.p., each), injected before mecamylamine administration, dose-dependently attenuated the expression of nicotine withdrawal signs. Moreover, 24h after terminating nicotine treatment, we also observed additional nicotine abstinence measures, such as loss of body weight followed by a slight body weight gain, decrease of spontaneous locomotor activity and anxiogenic responses. These findings obtained using our valuable rodent model of nicotine dependence suggest the involvement of calcium-dependent mechanisms in the expression of mecamylamine-precipitated nicotine abstinence syndrome.

Animals↗

PubMed1999

Mecamylamine-precipitated nicotine-withdrawal aversion in Lewis and Fischer 344 inbred rat strains.

Many studies have indicated that Lewis and Fischer 344 inbred rat strains show marked differences in behavioral responses to abused drugs. In the present study, we sought to determine whether these two strains of rats show different responses in mecamylamine-precipitated nicotine-withdrawal aversion using the conditioned place preference paradigm. Rats were treated subcutaneously with 10 mg/kg/day nicotine for 7 days using an osmotic minipump. After chronic nicotine infusion, the nicotinic receptor antagonist mecamylamine produced a significant place aversion in Lewis, but not in Fischer 344 rats. These results suggest that mecamylamine-precipitated nicotine-withdrawal aversion is strongly regulated by genetic factors.

Animals↗

PubMed1999

Induction of pulmonary cytochrome P4501A1: interactive effects of nicotine and mecamylamine.

The effect of the nicotinic receptor antagonist mecamylamine on nicotine-mediated convulsions and induction of pulmonary cytochrome P4501A1 (CYP1A1) was examined in the rat. Mecamylamine blocked the convulsions and inhibited CYP1A1 induction by nicotine at the level of CYP1A1 activity (93%) and protein (97%), but independently induced the enzyme also at the level of activity and protein. The results show that mecamylamine antagonizes both the CYP1A1 induction and convulsions by nicotine but, independently, is an inducer of the enzyme. The results indicate that CYP1A1 induction is not a consequence of the convulsant effects of nicotine.

Animals↗

PubMed2001

Nicotine improvement of Morris water task performance after fimbria-fornix lesion is blocked by mecamylamine.

The focus of this study was to analyze the effects of nicotine on behavioural compensation after fimbria-fornix (FF) lesions in rats tested on the Morris water task (MWT). Nicotine (0.3 mg/kg) was injected subcutaneously for 11 consecutive days before, for 11 consecutive days after, or for 11 consecutive days before and after a FF lesion. Additionally, a lesion group was included that was given mecamylamine (1.0 mg/kg), a nicotine antagonist, 10 min before nicotine administration as well as mecamylamine-only, no treatment lesion, and sham groups. All drug administration ceased 24 h before three consecutive days of behavioural testing on the MWT. Results showed that the sham group and animals receiving both a pre- and post-lesion treatment of nicotine performed significantly better than all other groups, and the pre- and post-lesion nicotine group performed equivalent to sham controls on both acquisition and a probe trial. The compensatory effect of nicotine was blocked by mecamylamine. This study demonstrates that nicotine stimulates recovery from brain damage and the results are discussed in relation to neural mechanisms and potential applications.

Animals↗

PubMed2002

Mecamylamine blocks enhancement of reference memory but not working memory produced by post-training injection of nicotine in rats tested on the radial arm maze.

The focus of this study was to analyze whether the psychostimulant nicotine would enhance reference and working memory consolidation in rats tested on the 8-arm radial arm maze. Mecamylamine, a nicotine antagonist, was used to attempt to block the enhancement of memory consolidation. All rats were given one training trial/day for 12 consecutive days, and 4 arms were baited. Rats were separated into five groups: the saline-nicotine group received an intraperitoneal (i.p.) injection of saline immediately after each trial followed 15 min later by an subcutaneous (s.c.) injection of nicotine (0.6 mg/kg free base); the nicotine-delay group received an s.c. injection of nicotine 2 h after each training trial, two groups received an i. p. injection of one of two different doses of mecamylamine (2.5 and 6.0 mg/kg) immediately after each trial, which was followed 15 min later by an s.c. nicotine injection, and a control group received an i.p. injection of saline immediately and 15 min after each training trial. Results showed that the saline-nicotine group made fewer reference and working memory errors than the saline- or nicotine-delay groups, but only the effect of nicotine on reference memory was blocked by the higher dose of mecamylamine. It appears from these results that nicotine's effects on reference and working memory may be mediated through different mechanisms.

Animals↗