-
Alcoholism, Clinical and Experimental... May 2003Recent studies have implicated central nicotinic cholinergic receptor systems in the reinforcing properties of alcohol. In laboratory animals, mecamylamine, a central... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
BACKGROUND
Recent studies have implicated central nicotinic cholinergic receptor systems in the reinforcing properties of alcohol. In laboratory animals, mecamylamine, a central nicotinic receptor antagonist, reduces the consumption of and preference for alcohol. This study investigated the effect of mecamylamine on the subjective responses to alcohol in humans. It was hypothesized that mecamylamine (7.5 and 15 mg) would attenuate the stimulant-like subjective effects of alcohol (0.8 g/kg) and decrease the self-reported desire to consume additional alcohol beverages.
METHODS
Fourteen male and 13 female nonsmokers participated in 6 laboratory sessions. During each session, subjects received, in randomized order under double-blinded conditions, a capsule containing mecamylamine (7.5 or 15 mg) or placebo followed by a beverage containing alcohol (0.8 g/kg) or placebo. Physiologic and subjective-effect measures were taken at 30-min intervals for 2 hr after beverage consumption.
RESULTS
Mecamylamine attenuated the stimulant and euphoric effects of alcohol and reduced the self-reported desire to consume additional alcohol beverages. This effect was most pronounced in men, even though women exhibited greater physiologic reactions to mecamylamine.
CONCLUSIONS
These findings suggest that nicotinic cholinergic receptors are involved in mediating some of the stimulant-like effects of alcohol.
Topics: Adult; Alcohol Drinking; Blood Pressure; Double-Blind Method; Drug Interactions; Ethanol; Female; Heart Rate; Humans; Male; Mecamylamine; Nicotinic Antagonists; Placebos; Sex Characteristics
PubMed: 12766622
DOI: 10.1097/01.ALC.0000065435.12068.24 -
British Journal of Clinical Pharmacology May 2018Establishing a pharmacological challenge model could yield an important tool to understand the complex role of the nicotinic cholinergic system in cognition and to... (Randomized Controlled Trial)
Randomized Controlled Trial
AIMS
Establishing a pharmacological challenge model could yield an important tool to understand the complex role of the nicotinic cholinergic system in cognition and to develop novel compounds acting on the nicotinic acetylcholine receptor.
METHODS
This randomized, double-blind, double-dummy, placebo-controlled, four-way crossover study examined the effects of the nicotinic antagonist mecamylamine on a battery of cognitive and neurophysiological test with coadministration of a placebo, nicotine or galantamine in order to reverse the cognitive impairment caused by mecamylamine.
RESULTS
Thirty-three healthy subjects received a single oral dose of 30 mg of mecamylamine (or placebo) in combination with either 16 mg of oral galantamine or 21 mg of transdermal nicotine (or its double-dummy). Mecamylamine 30 mg induced significant disturbances of cognitive functions. Attention and execution of visual (fine) motor tasks was decreased, short- and long-term memory was impaired and the reaction velocity during the test was slower when compared to placebo. Mecamylamine 30 mg produced a decrease in posterior α and β power in the surface electroencephalogram, effects that were reversed by nicotine coadministration. Memory and motor coordination tests could be partially reversed by the coadministration of nicotine.
CONCLUSIONS
Mecamylamine administration induced slowing of the electroencephalogram and produced decrease in performance of tests evaluating motor coordination, sustained attention and short- and long-term memory. These effects could be partially reversed by the coadministration of nicotine, and to a lesser extent by galantamine.
Topics: Adolescent; Adult; Cognition; Cross-Over Studies; Double-Blind Method; Drug Interactions; Electroencephalography; Galantamine; Healthy Volunteers; Humans; Male; Mecamylamine; Middle Aged; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Reaction Time; Young Adult
PubMed: 29319910
DOI: 10.1111/bcp.13507 -
Behavioural Brain Research Nov 1996Mecamylamine, a nicotinic receptor antagonist, was injected into the honeybee brain haemolymph. The effects of the drug were investigated on Pavlovian conditioning of...
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.
Topics: Animals; Bees; Behavior, Animal; Brain; Conditioning, Classical; Injections; Lighting; Mecamylamine; Memory; Nicotinic Antagonists; Sense Organs; Smell; Taste
PubMed: 8950019
DOI: 10.1016/s0166-4328(96)89081-4 -
Pharmacology, Biochemistry, and Behavior May 2005Ephedrine is a central nervous system stimulant that has a pharmacological profile similar to amphetamines. Ephedrine induces hyperactivity after acute administration to... (Comparative Study)
Comparative Study
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.
Topics: Animals; Ephedrine; Hyperkinesis; Male; Mecamylamine; Rats; Rats, Sprague-Dawley
PubMed: 15894075
DOI: 10.1016/j.pbb.2005.03.008 -
Molecular Brain Sep 2022Nicotinic acetylcholine receptors are thought to be associated with a wide range of phenomena, such as movement, learning, memory, attention, and addiction. However, the...
Systemic injection of nicotinic acetylcholine receptor antagonist mecamylamine affects licking, eyelid size, and locomotor and autonomic activities but not temporal prediction in male mice.
Nicotinic acetylcholine receptors are thought to be associated with a wide range of phenomena, such as movement, learning, memory, attention, and addiction. However, the causal relationship between nicotinic receptor activity and behavior remains unclear. Contrary to the studies that examined the functions of muscarinic acetylcholine receptors, the role of the nicotinic acetylcholine receptors on behavior has not been examined as extensively. Here, we examined the effects of intraperitoneal injection of mecamylamine, a nicotinic acetylcholine receptor antagonist, on the performance of male mice in a head-fixed temporal conditioning task and a free-moving open-field task. The head-fixed experimental setup allowed us to record and precisely quantify the licking response while the mice performed the behavioral task with no external cues. In addition, by combining the utility of the head-fixed experimental design with computer vision analysis based on deep learning algorithms, we succeeded in quantifying the eyelid size of awake mice. In the temporal conditioning task, we delivered a 10% sucrose solution every 10 s using a blunt-tipped needle placed within the licking distance of the mice. After the training, the mice showed increased anticipatory licking toward the timing of sucrose delivery, suggesting that the mice could predict the timing of the reward. Systemic injection of mecamylamine decreased licking behavior and caused eye closure but had no effect on learned conditioned predictive behavior in the head-fixed temporal conditioning task. In addition, the injection of mecamylamine decreased spontaneous locomotor activity in a dose-dependent manner in the free-moving open-field task. The results in the open-field experiments further revealed that the effect of mecamylamine on fecal output and urination, suggesting the effects on autonomic activities. Our achievement of successful eyelid size recording has potential as a useful approach in initial screening for drug discovery. Our study paves a way forward to understanding the role of nicotinic acetylcholine receptors on learning and behavior.
Topics: Animals; Dose-Response Relationship, Drug; Eyelids; Male; Mecamylamine; Mice; Nicotinic Antagonists; Receptors, Nicotinic; Sucrose
PubMed: 36068635
DOI: 10.1186/s13041-022-00959-y -
Pharmacology, Biochemistry, and Behavior Dec 2009Current smokers express the desire to quit. However, the majority find it difficult to remain abstinent. As such, research efforts continually seek to develop more... (Comparative Study)
Comparative Study
Current smokers express the desire to quit. However, the majority find it difficult to remain abstinent. As such, research efforts continually seek to develop more effective treatment. One such area of research involves the interoceptive stimulus effects of nicotine as either a discriminative stimulus in an operant drug discrimination task, or more recently as a conditional stimulus (CS) in a discriminated goal-tracking task. The present work investigated the potential role nicotinic acetylcholine receptors play in the CS effects of nicotine (0.4mg/kg) using antagonists with differential selectivity for beta2*, alpha7*, alpha6beta2*, and alpha3beta4* receptors. Methyllycaconitine (MLA) had no effect on nicotine-evoked conditioned responding. Mecamylamine and dihydro-beta-erythroidine (DHbetaE) dose-dependently blocked responding evoked by the nicotine CS. In a time-course assessment of mecamylamine and DHbetaE, each blocked conditioned responding when given 5min before testing and still blocked conditioned responding when administered 200min before testing. Two novel bis-picolinium analogs (N, N'-(3, 3'-(dodecan-1,12-diyl)-bis-picolinium dibromide [bPiDDB], and N, N'-(decan-1,10-diyl)-bis-picolinium diiodide [bPiDI]) did not block nicotine-evoked conditioned responding. Finally, pretreatment with low dose combinations of mecamylamine, dextromethorphan, and/or bupropion was used to target alpha3beta4* receptors. No combination blocked conditioned responding evoked by the training dose of nicotine. However, a combination of mecamylamine and dextromethorphan partially blocked nicotine-evoked conditioned responding to a lower dose of nicotine (0.1mg/kg). These results indicate that beta2* and potentially alpha3beta4* nicotinic acetylcholine receptors play a role in the CS effects of nicotine and are potential targets for the development of nicotine cessation aids.
Topics: Animals; Conditioning, Psychological; Dextromethorphan; Dihydro-beta-Erythroidine; Male; Mecamylamine; Nicotine; Rats; Rats, Sprague-Dawley; Receptors, Nicotinic
PubMed: 19778551
DOI: 10.1016/j.pbb.2009.09.012 -
Pharmacology, Biochemistry, and Behavior May 1988Spontaneous EEG was recorded in nine cigarette smokers who had been abstinent from tobacco for 12 hr. Subjects were treated with a capsule containing either centrally... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
Spontaneous EEG was recorded in nine cigarette smokers who had been abstinent from tobacco for 12 hr. Subjects were treated with a capsule containing either centrally acting nicotine blocker, mecamylamine (10 mg), or placebo. At each of three 60-min intervals after the capsule was ingested, the subjects chewed two pieces of gum containing a total of 0, 4 or 8 mg of nicotine. Nicotine and mecamylamine dose combinations were randomized across subjects. Two three-minute periods of spontaneous EEG were recorded before the capsule and before and after gum chewing from bipolar electrode montages at the following positions: Cz-T5, Cz-T6, Cz-F7 and Cz-F8. During one period the subjects relaxed with eyes closed, in the other period they performed a math task with eyes open. When the drugs were given individually, mecamylamine decreased beta power and nicotine gum (4 and 8 mg) increased alpha frequency. Mecamylamine pretreatment prevented the increase in alpha frequency caused by the 4 mg gum dose but not the 8 mg dose. Alpha power was increased by the 8 mg gum dose and that increase was prevented by mecamylamine. Self-reported ratings of the "strength" of the gum were significantly diminished by mecamylamine pretreatment. The data are consistent with the results of earlier studies which indicate that the effects of tobacco administration and withdrawal are mediated by central actions of nicotine.
Topics: Adult; Chewing Gum; Electroencephalography; Humans; Male; Mecamylamine; Middle Aged; Nicotine; Tobacco Use Disorder
PubMed: 3174738
DOI: 10.1016/0091-3057(88)90438-8 -
Psychopharmacology 1986Multiple measures of cigarette smoking, subjective effect and physiological effect were collected during 90-min test sessions in normal volunteers. Before sessions... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
Multiple measures of cigarette smoking, subjective effect and physiological effect were collected during 90-min test sessions in normal volunteers. Before sessions subjects received oral doses of mecamylamine (2.5, 5.0, 10, 20 mg) or placebo. Each dose and placebo was given three times in a randomized block sequence. Mecamylamine increased several measures of cigarette smoking, including number of cigarettes, number of puffs per cigarette, and expired air carbon monoxide level. Mecamylamine also produced modest, dose-related decreases in standing blood pressure and increases in standing heart rate. The subjective effects produced by mecamylamine were not characteristic of those of psychoactive drugs. Mecamylamine appears to have increased cigarette smoking by decreasing the effective dose level of nicotine available from cigarette smoking.
Topics: Adult; Blood Pressure; Female; Heart Rate; Humans; Male; Mecamylamine; Middle Aged; Smoking; Smoking Prevention
PubMed: 3085131
DOI: 10.1007/BF00178502 -
Pharmacology, Biochemistry, and Behavior Jul 2000The ganglionic blocker mecamylamine blocks the positive reinforcing effects of IV nicotine, but has been shown to increase cigarette smoking behavior under some... (Clinical Trial)
Clinical Trial
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.
Topics: Adult; Euphoria; Humans; Male; Mecamylamine; Nicotine; Nicotinic Antagonists; Self Administration; Smoking; Time Factors
PubMed: 10899382
DOI: 10.1016/s0091-3057(00)00252-5 -
Brain Research Mar 1998Mecamylamine differentially blocked fast nicotinic transmission in two functional subsets of sympathetic neurons within lumbar paravertebral ganglia of the bullfrog.... (Comparative Study)
Comparative Study
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.
Topics: Animals; Ganglia, Sympathetic; Mecamylamine; Membrane Potentials; Neurons; Nicotinic Antagonists; Patch-Clamp Techniques; Phenotype; Rana catesbeiana; Synaptic Transmission; Vasomotor System
PubMed: 9554976
DOI: 10.1016/s0006-8993(97)01520-5