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PubMed1994

Age-related effects of the nicotinic antagonist mecamylamine on cognition and behavior.

Studies of the neurochemical pathology of Alzheimer's disease and Parkinson's disease reveal a severe and specific loss of central nicotinic cholinergic receptors. We have investigated the functional significance of this finding for cognitive functioning by studying the effects of the centrally active nicotinic antagonist mecamylamine. Single oral doses of mecamylamine were administered to 12 healthy young males and 15 healthy elderly subjects in doses of 5, 10, and 20 mg in a placebo-controlled, double-blind study. In both groups, the 20-mg dose caused a significant increase in errors in the learning condition of the Repeated Acquisition Task, producing a slower acquisition curve. There was no effect of drug on the performance component (retrieval of previously learned information). However, elderly subjects showed enhanced sensitivity to mecamylamine, with 10-mg dose producing significant impairment of learning not seen in the young normals. On a recognition memory task, there was an age-associated shift in response bias, with the elderly subjects becoming more liberal with increasing dose. Reaction-time measures suggested a dose-related slowing of reaction time on several tasks. Behavioral effects were minimal and physiologic effects were consistent with dose-related ganglionic blockade. These results indicate that acute blockade of nicotinic receptor function can produce measurable and significant cognitive impairment similar to some deficits seen in dementing illnesses, and that there is an age-related increase in sensitivity to nicotinic blockade.

Adult↗
PubMed1971

Effects of mecamylamine on responses of carotid body chemoreceptors in vivo to physiological and pharmacological stimuli.

1. Effects of mecamylamine on the spontaneous discharge rate of afferent fibres of carotid body chemoreceptors in vivo and their responses to ACh, NaCN, HCl and hypoxia were studied in sixteen cats.2. Cats were anaesthetized with sodium pentobarbitone, paralysed with gallamine triethiodide and artificially ventilated. Chemoreceptor excitants were injected into the common carotid artery; mecamylamine was given intravenously.3. Mecamylamine, 230 mug/kg or greater, failed to diminish either the rate of spontaneous discharge of carotid body chemoreceptors at high arterial oxygen tensions (greater than 130 mm Hg), or the responses of these receptors to NaCN (0.5-25 mug), HCl or hypoxic blood.4. Responses of chemoreceptor afferent fibres to ACh (1.0-50 mug) in the same preparations were either completely abolished or considerably reduced by mecamylamine.5. These data do not support the hypothesis of a cholinergic mechanism for the initiation of chemosensory discharges in the carotid body, either at rest or in response to stimuli such as NaCN, acid or hypoxia.

Acetylcholine↗
PubMed1983

Suppression of behavior by intravenous injections of nicotine or by electric shocks in squirrel monkeys: effects of chlordiazepoxide and mecamylamine.

Squirrel monkeys responded under a two-component fixed-ratio schedule of food presentation with both nonpunishment and punishment components. In both components of the multiple schedule, every 30th key-pressing response resulted in food presentation. In the punishment component, the first response in each 30-response fixed ratio also produced either an i.v. injection of nicotine (10-30 micrograms/kg) or an electric shock (1-5 mA). Response-produced nicotine injections or electric shocks functioned similarly to suppress responding by over 70% in the punishment component. Presession treatment with chlordiazepoxide (5.6-10 mg/kg i.m.) markedly increased responding that had been suppressed by either nicotine injection or electric shock. In contrast, presession treatment with the nicotinic antagonist, mecamylamine (0.1-0.3 mg/kg i.m.) increased responding that had been suppressed by nicotine injection but did not increase responding that had been suppressed by electric shock. Thus, chlordiazepoxide appeared to have general rate-increasing effects on suppressed responding, regardless of the nature of the event suppressing responding, whereas mecamylamine appeared to selectively antagonize the suppressant effects of nicotine. Doses of chloridazepoxide and mecamylamine that increased suppressed responding in punishment components either had little effect on or slightly increased responding in nonpunishment components. These results show that under suitable environmental conditions response-produced i.v. injection of nicotine can function effectively as a punisher.

Animals↗
PubMed1981

[Effects of mecamylamine and pempidine, secondary and tertiary amines, on the spinal reflex of cats (author's transl)].

The ganglionic blocking effects of the secondary and tertiary amines, mecamylamine and pempidine, on the spinal reflex of cats of both sexes were investigated. These blocking effects were then compared with findings in the quaternary ammonium compounds such as tetraethylammonium (TEA) and decamethonium (C10). Mecamylamine (5 mg/kg) and pempidine (1 mg/kg) inhibited spinal reflex potentials such as the monosynaptic reflex (MSR), the polysynaptic reflex (PSR) and the dorsal root reflex (DRR). Maximal inhibition occurred 40 min after intravenous administration these drugs. In the case of mecamylamine, the inhibited potentials recovered gradually after reaching the maximum inhibition. However, the inhibitory effect of pempidine was prolonged, and recovery of the potentials did not occur for 6 min or longer. Although 10 mg/kg of C10 and 0.025 mg/kg of nicotine transiently inhibited the MSR and PSR, these compounds had no effect on the DDR. TEA produced prolonged inhibition of the MSR and PSR, and slightly enhanced the DRR. These results demonstrated the differences in DRR responses to secondary and tertiary amines, and quaternary ammoniums.

Animals↗
PubMed1996

Chronic nicotine and mecamylamine treatment increase brain nicotinic receptor binding without changing alpha 4 or beta 2 mRNA levels.

It has recently been shown using regionally dissected tissue that both chronic mecamylamine treatment and chronic nicotine treatment increase the number of [3H]-nicotine binding sites in mouse brain, and that additive increases in the number of binding sites is observed after cotreatment with the two drugs. The studies reported here extend these findings by using quantitative autoradiographic methods to analyze the brains of chronically treated mice at a finer anatomical level of resolution. DBA/2 mice were chronically infused (i.v.) with saline, 4.0 mg/ kg/hr nicotine, 4.0 mg/kg/hr mecamylamine or both drugs for 7 days. The brains of these mice were subsequently analyzed to determine the effects of chronic drug treatment on [3H]-nicotine binding and on the levels of mRNA encoding the nicotinic receptor subunits, alpha 4 and beta 2. [3H]-Nicotine binding was increased in 37 of 46 brain regions after chronic nicotine treatment (average increase = 66.5%), in 41 of 46 regions after chronic mecamylamine treatment (average increase = 56.5%), and in 45 of 46 brain regions after chronic treatment with both drugs (average increase = 107.1%). The changes in [3H]-nicotine binding produced by the two drugs across brain regions were highly (r = 0.98) and significantly correlated. These results are consistent with the proposal that the same receptors are affected by agonist or antagonist treatment. Chronic treatment had no significant effect on the levels of alpha 4 or beta 2 mRNA as measured by in situ hybridization. Therefore, the increases in [3H]-nicotine binding do not arise from changes in the steady-state levels of either alpha 4 or beta 2 mRNA which are believed to encode the subunits of this nicotinic receptor subtype.

Animals↗
PubMed1979

Effects of physostigmine, scopolamine, and mecamylamine on the sleeping time induced by ketamine in the rat.

Male Sprague-Dawley rats weighing 116--241 g were injected i.p. with ketamine hydrochloride, 80 mg per kilo of body weight. Immediately after loss of righting reflex, scopolamine, physostigmine, and mecamylamine were administered i.p. to different groups of rats. Control animals received sterile saline by the same route. The ketamine-induced sleeping time was significantly prolonged by physostigmine and scopolamine, but not by mecamylamine. After the delayed injection of physostigmine, the ketamine sleeping time was longer. These results, although too preliminary for a mechanistic interpretation, suggest that multiple neurotransmitter systems, probably including the cholinergic system, are involved in the mechanism of action of ketamine-induced narcosis.

Animals↗
PubMed2001

Effects of nicotine and mecamylamine-induced withdrawal on extracellular dopamine and acetylcholine in the rat nucleus accumbens.

RATIONALE: Prior research suggests that high levels of acetylcholine (ACh) in the nucleus accumbens (NAc) are associated with aversive states such as morphine withdrawal, but this has not been tested for nicotine withdrawal. OBJECTIVES: The goal was to test the hypothesis that acute nicotine decreases extracellular ACh and increases extracellular dopamine (DA) in the NAc, while withdrawal from nicotine causes an opposite neurochemical imbalance with high extracellular ACh and low DA. METHODS: Rats were prepared with a microdialysis probe in the NAc (primarily the shell region). They received one injection of nicotine (0.5 mg/kg, s.c.) or chronic nicotine (9 mg/kg per day via osmotic minipump). RESULTS: Naive animals receiving acute nicotine showed a mild, significant increase in both ACh (122% of baseline) and DA (124%). After chronic nicotine administration for 7 days, the nicotinic antagonist mecamylamine (1.0 mg/kg, s.c.) precipitated withdrawal with the appearance of somatic signs (teeth chattering and shakes/tremors) and a significant increase in extracellular ACh to 125% of baseline, while extracellular DA decreased to 65%. Control groups receiving saline in place of nicotine or mecamylamine did not show these effects. CONCLUSIONS: Earlier work suggests that the observed release of accumbens ACh and DA in response to acute nicotine administration may be a factor in nicotine-induced suppression of appetite. ACh release during withdrawal, coupled with the decrease in extracellular DA may play a role in the aversive aspects of nicotine withdrawal that contribute to dependency.

Acetylcholine↗
PubMed1987

A cholinergic antagonist, mecamylamine, blocks the phase-shifting effects of light on the circadian rhythm of locomotor activity in the golden hamster.

Despite the well known role of the light-dark cycle in the entrainment of circadian rhythms, very little is known about the neurochemical events that mediate the effects of light on the mammalian circadian clock. Recent anatomical and pharmacological data support the hypothesis that acetylcholine may be involved in relaying light-dark information from the retina to, or within, the circadian clock of rodents. If acetylcholine is required for this response, it should be possible to block the phase-shifting effects of a light pulse by blocking cholinergic neurotransmission. To test this possibility, hamsters free-running in constant darkness received an intraventricular injection of the anticholinergic drug, mecamylamine (450 micrograms), 10 min before being exposed to a 5-min pulse of light known to induce sub-maximal phase shifts in the circadian rhythm of wheel-running behavior. Compared to vehicle-injected control animals, mecamylamine treatment blocked or reduced both the phase-advancing and phase-delaying effects of light. These results support the hypothesis that acetylcholine is involved in mediating the phase-shifting effects of light on the mammalian circadian clock.

Animals↗
PubMed1989

Reversal of a mecamylamine-induced cognitive deficit with the D2 agonist, LY 171555.

Pharmacological blockade of either nicotinic or muscarinic cholinergic receptors has been found to impair choice accuracy in the radial-arm maze. Simultaneous blockade of both of these receptor types causes an additive impairment. However, despite these common effects, nicotinic and muscarinic receptors have been found to have differential involvement with dopamine receptors. The cognitive impairment caused by the muscarinic antagonist scopolamine is reversed by the D1 antagonist SCH 23390 but is unaffected by the D2 antagonist raclopride. In contrast, the cognitive impairment caused by the nicotinic antagonist mecamylamine is unaffected by SCH 23390 but is potentiated by raclopride. In the current study, the D2 agonist LY 171555 was found to be effective in reversing the radial-arm maze choice accuracy impairment caused by mecamylamine. In contrast, the D1 agonist SKF 38393 was not found to be effective. Thus, we have found selective dopaminergic D1 and D2 treatments which counteract the adverse cognitive effects of either nicotinic or muscarinic blockade. A combination of these treatments may be useful in treating the cognitive effects of generalized cholinergic underactivation.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1986

Prophylactic action of hexamethonium, trimethaphan, and mecamylamine against diisopropyl fluorophosphate poisoning in mice.

Prophylactic Action of Hexamethonium, Trimethaphan, and Mecamylamine against Diisopropyl Fluorophosphate Poisoning in Mice. Chiou, G. C. Y., Chang, W. T. S., and Aimoto, T. (1986). Fund. Appl. Toxicol. 6, 35-43. Hexamethonium, trimethaphan, and mecamylamine are ganglionic blockers which can reduce acetylcholine (ACh) release presynaptically. All these agents are capable of protecting mice from diisopropyl fluorophosphate (DFP) intoxication by prolonging the latent period of death or by completely preventing death. Combinations of these agents with 2-pyridine aldoxime methochloride (2-PAM) (50 mg/kg) improved prophylactic action even further. These results indicate that reduction of ACh release presynaptically plus neutralization of organophosphates with 2-PAM could be an effective way to reduce mortality in patients exposed to organophosphorus poisons.

Animals↗
PubMed2005

Receptor protection studies comparing recombinant and native nicotinic receptors: Evidence for a subpopulation of mecamylamine-sensitive native alpha3beta4* nicotinic receptors.

Studies involving receptor protection have been used to define the functional involvement of specific receptor subtypes in tissues expressing multiple receptor subtypes. Previous functional studies from our laboratory demonstrate the feasibility of this approach when applied to neuronal tissues expressing multiple nicotinic acetylcholine receptors (nAChRs). In the current studies, the ability of a variety of nAChR agonists and antagonists to protect native and recombinant alpha3beta4 nAChRs from alkylation were investigated using nAChR binding techniques. Alkylation of native alpha3beta4* nAChRs from membrane preparations of bovine adrenal chromaffin cells resulted in a complete loss of specific [(3)H]epibatidine binding. This loss of binding to native nAChRs was preventable by pretreatment with the agonists, carbachol or nicotine. The partial agonist, cytisine, produced partial protection. Several nAChR antagonists were also tested for their ability to protect. Hexamethonium and decamethonium were without protective activity while mecamylamine and tubocurarine were partially effective. Addition protection studies were performed on recombinant alpha3beta4 nAChRs. As with native alpha3beta4* nAChRs, alkylation produced a complete loss of specific [(3)H]epibatidine binding to recombinant alpha3beta4 nAChRs which was preventable by pretreatment with nicotine. However, unlike native alpha3beta4* nAChRs, cytisine and mecamylamine, provide no protection for alkylation. These results highlight the differences between native alpha3beta4* nAChRs and recombinant alpha3beta4 nAChRs and support the use of protection assays to characterize native nAChR subpopulations.

Alkylation↗
PubMed1998

Reduced dopamine output in the nucleus accumbens but not in the medial prefrontal cortex in rats displaying a mecamylamine-precipitated nicotine withdrawal syndrome.

Mesolimbocortical dopamine (DA) neurotransmission is important in the mediation of the dependence-producing actions of nicotine and other drugs of abuse. Withdrawal from chronic treatment with various types of addictive drugs, including amphetamine, cocaine, ethanol and morphine is associated with a decrease in dopaminergic output in the nucleus accumbens (NAC), whereas the effects of withdrawal from these drugs on dopaminergic output in the medial prefrontal cortex (PFC), as yet, remain largely unknown. This study examined putative changes in the extracellular levels of dopamine and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the NAC and in the PFC of rats displaying behavioral signs of nicotine withdrawal. Rats were infused for 7 days with nicotine via subcutaneously implanted minipumps, whereas control animals carried saline-containing pumps. On the fifth day of infusion a microdialysis probe was implanted in the NAC or the PFC of the rats. Forty-eight hours later the levels of DA and the monoamine metabolites were assessed in the dialysate. The behavioral and biochemical effects of a saline injection and a subsequent challenge with the nicotinic receptor antagonist mecamylamine (1 mg/kg s.c.) were determined. Following mecamylamine challenge in nicotine-treated animals, the levels of DA, DOPAC and HVA in the NAC, but not in the PFC, decreased below pre-injection levels and in relation to control animals. The score of abstinence signs increased in the nicotine-treated rats, as compared both to the score after saline and to that in control animals. The decreased DA output in the NAC in animals displaying nicotine withdrawal signs is similar to that seen after withdrawal of several other drugs of abuse, and may have bearing on motivational deficits associated with the abstinence reactions.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1996

Mecamylamine-precipitated nicotine-withdrawal aversion in rats.

The present study examined a rapid and convenient model for evaluating nicotine dependence using the conditioned place preference paradigm. Rats were chronically infused subcutaneously with 9 mg/kg per day nicotine using an osmotic minipump. After nicotine infusion for 7 days, the nicotinic receptor antagonist mecamylamine produced a place aversion in nicotine-dependent rats, but not in acute nicotine-treated rats or sham-operated rats. These results suggest that the mecamylamine-precipitated withdrawal aversion in rats chronically treated with nicotine may result from physical dependence on nicotine, and may be useful for studying the physical dependence on nicotine.

Analysis of Variance↗
PubMed1998

Effects of nicotine and mecamylamine on rat dorsal raphe neurons.

This study investigates the hypothesis that serotonin mediates certain nicotine effects, such as mood improvement and the suppression of the ponto-geniculo-occipital spikes of rapid eye movement sleep. The influence of nicotine (10-300 microM) on the firing rate of dorsal raphe neurons and on serotonin release was therefore, studied in rat midbrain slices. Nicotine increased the firing rate, 10-90%, in 67.5% recorded neurons and decreased it, 8-100%, in the remaining 32.5%. Serotonin release increased 2-7 times after nicotine administration, regardless of firing frequency, but the absolute value of serotonin release was 3 times higher during the decreases than during the increases in firing rate. Mecamylamine (1-20 microM) transiently stimulated the dorsal raphe neurons and competitively antagonized the nicotine-induced serotonin release. The results support the working hypothesis and additionally show that mecamylamine also stimulates dorsal raphe neurons.

Action Potentials↗
PubMed1997

Attenuation of mecamylamine-precipitated nicotine-withdrawal aversion by the 5-HT3 receptor antagonist ondansetron.

The effect of ondansetron (0.01-0.1 mg/kg, s.c.), a selective 5-HT3 receptor antagonist, on mecamylamine-precipitated nicotine-withdrawal aversion was examined in the conditioned place preference paradigm. Male Sprague-Dawley rats were chronically treated subcutaneously with 9 mg/kg/day (-)-nicotine tartrate using an osmotic minipump. After nicotine treatment for 7 days, mecamylamine (1 mg/kg, s.c.), a nicotinic receptor antagonist, produced place aversion in nicotine-dependent rats. This aversive effect was dose-dependently antagonized by pretreatment with ondansetron 30 min prior to the conditioning. These results suggest that ondansetron may attenuate the place aversion associated with nicotine withdrawal, and may be useful for the treatment of nicotine dependence.

Animals↗
PubMed2002

Mecamylamine decreases accumbal dopamine output in mice treated chronically with nicotine.

The role of nicotinic acetylcholine receptor (nAChR) activation in accumbal dopamine (DA) release during chronic continuous nicotine treatment was studied by in vivo microdialysis in freely-moving mice. Nicotine was administered chronically to NMRI mice in their drinking water. On the 50th day of nicotine administration microdialysis samples were collected at 20 min intervals and their DA, 3,4-dihydroxyphenylacetic acid, homovanillic acid and 5-hydroxyindoleacetic acid contents were measured using a high-performance liquid chromatographic-electrochemical procedure. After collection of four baseline samples the nicotinic antagonist mecamylamine (2 mg/kg, s.c.) was given. The steady-state DA output was larger in the nicotine-treated mice than in the control mice. Mecamylamine reduced the DA output in the nicotine-treated but not in the control mice. Thus, after continuous 50-day administration nicotine still continues to activate nAChRs regulating accumbal DA release.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1957

The effects of mecamylamine in the cat as modified by the administration of carbon dioxide.

A series of cats, anaesthetized with chloralose, was given intravenously a sufficient quantity of mecamylamine to produce hypotension and a 50% neuromuscular block. Inhalation of carbon dioxide then produced a further depression of blood pressure and an increase in the neuromuscular blocking effect. It was shown that, following the administration of carbon dioxide, the plasma mecamylamine levels increased coincident with the increased pharmacological effects.

Animals↗