-
Pharmacology, Biochemistry, and Behavior Feb 1997In a previous study, mecamylamine, a centrally active nicotine antagonist, exacerbated EEG signs of tobacco abstinence in abstinent smokers. In the present study, the...
In a previous study, mecamylamine, a centrally active nicotine antagonist, exacerbated EEG signs of tobacco abstinence in abstinent smokers. In the present study, the effects of mecamylamine were compared in non-smokers and nondeprived smokers. Mecamylamine (0, 5 and 10 mg, p.o.) was administered to six smokers and six non-smokers; eight of these subjects were also given a 20 mg dose. Before drug administration, resting EEG was similar in both groups. In both groups, mecamylamine caused dose-related decreases in alpha frequency and increases in delta frequency; beta frequency was increased by the 5 and 10 mg doses. The similarity of effects in smokers and non-smokers suggests a direct pharmacological action rather than precipitated nicotine withdrawal. Significant baseline differences existed between smokers and non-smokers in systolic blood pressure, pulse rate, skin temperature and pupil diameter. Response time slowed in both vigilance and distractibility tasks and delayed recall was impaired. Mecamylamine increased ratings of: "relaxed," "nodding," "sleepy" and "coasting." This small-sample study tentatively suggests that nicotinic cholinergic mechanisms modulate brain electrical activity and cognitive function in smokers and non-smokers. Disruption of these neural systems could mediate the symptoms of tobacco withdrawal and be involved in the pathophysiology of Alzheimer's disease.
Topics: Adult; Blood Pressure; Cognition; Electroencephalography; Female; Humans; Male; Mecamylamine; Nicotinic Antagonists; Psychomotor Performance; Pulse; Pupil; Skin Temperature; Smoking
PubMed: 9050073
DOI: 10.1016/s0091-3057(96)00183-9 -
Pharmacology 2009Alcohol and nicotine (in the form of tobacco) are 2 commonly used recreational drugs and studies show a high correlation between tobacco use and alcohol consumption. In...
Alcohol and nicotine (in the form of tobacco) are 2 commonly used recreational drugs and studies show a high correlation between tobacco use and alcohol consumption. In the present study, using C57BL/6J mice, we investigated the ability of mecamylamine (a nicotinic antagonist) to reduce alcohol consumption and alcohol preference with free 24-hour access using a 2-bottle choice test drinking procedure. Male C57BL/6J mice were individually housed and acclimatized to 10% alcohol. Immediately following the last day of alcohol acclimatization, the mice (n = 5/group) received subcutaneous injections of mecamylamine (0.5, 1 and 2 mg/kg) or saline consisting of either intermittent (3 injections given every other day) or daily (injections on all 5 days) exposures. Fluid consumption (alcohol and water) was recorded daily. The results showed that mecamylamine significantly reduced alcohol consumption and alcohol preference in both phases of intermittent and daily drug exposures, while the total fluid consumption was unchanged. These results provide further support that mecamylamine is effective in reducing alcohol consumption and preference, and nicotinic-receptor-based drugs could further be explored as potential treatments for alcoholism.
Topics: Alcohol Drinking; Animals; Choice Behavior; Disease Models, Animal; Drinking; Drug Evaluation, Preclinical; Male; Mecamylamine; Mice; Mice, Inbred C57BL; Nicotinic Antagonists
PubMed: 19468256
DOI: 10.1159/000219488 -
The Medical Journal of Australia Jul 1959
Topics: Antihypertensive Agents; Hypertension; Mecamylamine
PubMed: 13797641
DOI: 10.5694/j.1326-5377.1959.tb89276.x -
Journal of the Medical Association of... Sep 1957
Topics: Autonomic Agents; Hypertension; Mecamylamine
PubMed: 13463512
DOI: No ID Found -
European Cytokine Network Dec 2022Endothelial cell activation plays a critical role in leukocyte recruitment during inflammation and infection. We previously found that cholinergic stimulation (via vagus...
BACKGROUND AND OBJECTIVE
Endothelial cell activation plays a critical role in leukocyte recruitment during inflammation and infection. We previously found that cholinergic stimulation (via vagus nerve stimulation) attenuates vascular endothelial impairment and reduces the inflammatory profile in ovariectomized rats. However, the specific molecular mechanism is unclear. This study was designed to explore the effects and molecular mechanisms of cholinergic agonists (acetylcholine [ACh]) on lipopolysaccharide (LPS)-induced endothelial cell activation in vitro.
METHODS
Human umbilical vein endothelial cells (HUVECs) were treated with different concentrations of LPS (10/100/1000 ng/mL) to activate endothelial cells. HUVECs were untreated, treated with ACh (10-5 M) alone, treated with 100 ng/mL LPS alone, or treated with different concentrations of ACh (10-9/10-8/10-7/10-6/10-5 M) before LPS stimulation. HUVECs were also pre-treated with 10-6 M ACh with or without mecamylamine (an nAChR blocker) (10 μΜ) and methyllycaconitine (a specific α7 nAChR blocker) (10 μΜ) and incubated with or without LPS. ELISA, western blotting, cell immunofluorescence, and cell adhesion assays were used to examine inflammatory cytokine production, adhesion molecule expression, monocyte-endothelial cell adhesion and activation of the MAPK/NF-κB pathways.
RESULTS
LPS (at 10 ng/mL, 100 ng/mL and 1,000 ng/mL) increased VCAM-1 expression in HUVECs in a dose-dependent manner (with no significant difference between LPS at 100 ng/mL and 1,000 ng/mL). ACh (10-9 M-10-5 M) blocked adhesion molecule expression (VCAM-1, ICAM-1, and E-selectin) and inflammatory cytokine production (TNF-α, IL-6, MCP-1, IL-8) in response to LPS in a dose-dependent manner (with no significant difference between 10-5 and 10-6 M Ach). LPS was also shown to significantly enhance monocyte-endothelial cell adhesion, which was largely abrogated by treatment with ACh (10-6M). VCAM-1 expression was blocked by mecamylamine rather than methyllycaconitine. Lastly, ACh (10-6 M) significantly reduced LPS-induced phosphorylation of NF-κB/p65, IκBα, ERK, JNK and p38 MAPK in HUVECs, which was blocked by mecamylamine.
CONCLUSIONS
ACh protects against LPS-induced endothelial cell activation by inhibiting the MAPK and NF-κB pathways, which are mediated by nAChR, rather than α7 nAChR. Our results may provide novel insight into the anti-inflammatory effects and mechanisms of ACh.
Topics: Animals; Humans; Rats; Acetylcholine; Human Umbilical Vein Endothelial Cells; Intercellular Adhesion Molecule-1; Lipopolysaccharides; Mecamylamine; NF-kappa B; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1; MAP Kinase Signaling System
PubMed: 37227141
DOI: 10.1684/ecn.2023.0481 -
Psychopharmacology Jul 2009Recent reports describe a restricted access ethanol consumption paradigm where C57Bl/6J mice drink until intoxicated. Termed "drinking in the dark" (DID), this paradigm...
RATIONALE
Recent reports describe a restricted access ethanol consumption paradigm where C57Bl/6J mice drink until intoxicated. Termed "drinking in the dark" (DID), this paradigm has been used as a model of binge drinking. Although neuronal nicotinic acetylcholine receptors (nAChRs) have been implicated in alcohol drinking in rats pre-trained to self-administer ethanol, their role in binge-like ethanol consumption is unknown.
OBJECTIVES
To determine if nAChRs are involved in binge drinking as measured by the DID assay in C57Bl/6J mice.
MATERIALS AND METHODS
Adult male C57Bl/6J mice were injected i.p. with nicotinic receptor antagonists including mecamylamine, hexamethonium, dihydro-beta-erythroidine, and methyllycaconitine. Immediately following injection, mice were presented with 20% ethanol for 2 h in the DID assay to measure ethanol consumption. Nicotinic agonists including cytisine and nicotine were also evaluated. The effects of mecamylamine and nicotine on ethanol-induced dopaminergic neuronal activation in the VTA were evaluated via immunohistochemistry.
RESULTS
Mecamylamine dose dependently reduced ethanol consumption; whereas, the peripheral antagonist hexamethonium had no significant effect. Nicotinic agonists, cytisine and nicotine, reduced ethanol consumption. None of the effective nicotinic receptor drugs reduced sucrose drinking. Mecamylamine blocked ethanol activation of dopaminergic neurons while nicotine alone activated them without additional activation by ethanol.
CONCLUSIONS
Neuronal nAChRs are involved in ethanol consumption in the DID paradigm. The effects of mecamylamine, nicotine, and cytisine on ethanol intake appear to be specific because they do not reduce sucrose drinking. Mecamylamine reduces alcohol consumption by blocking activation of dopaminergic neurons; whereas, nicotinic agonists may activate the same reward pathway as alcohol.
Topics: Alcoholic Intoxication; Animals; Darkness; Dopamine; Dose-Response Relationship, Drug; Ethanol; Immunohistochemistry; Male; Mecamylamine; Mice; Mice, Inbred C57BL; Neurons; Nicotinic Agonists; Nicotinic Antagonists; Receptors, Nicotinic; Reward
PubMed: 19247637
DOI: 10.1007/s00213-009-1488-5 -
The Journal of Laboratory and Clinical... Aug 1957
Topics: Autonomic Agents; Hypertension; Mecamylamine
PubMed: 13449399
DOI: No ID Found -
The International Journal of... Jun 2010The interaction of tricyclic antidepressants with the human (h) alpha4beta2 nicotinic acetylcholine receptor in different conformational states was compared with that... (Comparative Study)
Comparative Study
The interaction of tricyclic antidepressants with the human (h) alpha4beta2 nicotinic acetylcholine receptor in different conformational states was compared with that for the noncompetitive antagonist mecamylamine by using functional and structural approaches. The results established that: (a) [(3)H]imipramine binds to halpha4beta2 receptors with relatively high affinity (K(d)=0.83+/-0.08 microM), but imipramine does not differentiate between the desensitized and resting states, (b) although tricyclic antidepressants inhibit (+/-)-epibatidine-induced Ca(2+) influx in HEK293-halpha4beta2 cells with potencies that are in the same concentration range as that for (+/-)-mecamylamine, tricyclic antidepressants inhibit [(3)H]imipramine binding to halpha4beta2 receptors with affinities >100-fold higher than that for (+/-)-mecamylamine. This can be explained by our docking results where imipramine interacts with the leucine (position 9') and valine (position 13') rings by van der Waals contacts, whereas mecamylamine interacts electrostatically with the outer ring (position 20'), (c) van der Waals interactions are in agreement with the thermodynamic results, indicating that imipramine interacts with the desensitized and resting receptors by a combination of enthalpic and entropic components. However, the entropic component is more important in the desensitized state, suggesting local conformational changes. In conclusion, our data indicate that tricyclic antidepressants and mecamylamine efficiently inhibit the ion channel by interacting at different luminal sites. The high proportion of protonated mecamylamine calculated at physiological pH suggests that this drug can be attracted to the channel mouth before binding deeper within the receptor ion channel finally blocking ion flux.
Topics: Antidepressive Agents, Tricyclic; Binding Sites; Bridged Bicyclo Compounds, Heterocyclic; Calcium Signaling; Cell Line; Humans; Imipramine; Ion Channels; Mecamylamine; Nicotinic Antagonists; Protein Binding; Protein Conformation; Pyridines; Receptors, Nicotinic
PubMed: 20223294
DOI: 10.1016/j.biocel.2010.03.002 -
Pharmacology, Biochemistry, and Behavior Feb 2011This experiment examined the effects of mecamylamine, a nicotinic acetylcholine receptor antagonist, on flash-evoked potentials (FEPs) recorded from the visual cortex...
This experiment examined the effects of mecamylamine, a nicotinic acetylcholine receptor antagonist, on flash-evoked potentials (FEPs) recorded from the visual cortex (VC) and superior colliculus (SC) of chronically implanted male Long-Evans rats, and on body temperature and open field behavior. FEPs were recorded at 20 and 35 min following intraperitoneal injections of saline, and of 0.3, 3.0, and 10.0 mg/kg mecamylamine on separate days. The 0.3 mg/kg dose did not produce significant effects. The amplitude of VC components N₃₀, P₄₈, and P₈₇ increased, N₁₅₀ and P₂₃₁ decreased, and P₂₃, N₄₀, N₅₈, and N₆₈ were unchanged following administration of the 10.0 mg/kg dose. In the SC, component P₂₈ was unaffected, P₃₉ was reduced, and N₄₉ was augmented by the 10.0 mg/kg dose. All component peak latencies were increased by the 3.0 and 10.0 mg/kg doses. Significant hypothermia was also produced by the 3.0 and 10.0 mg/kg doses, suggesting that this was the basis for the increased latencies. The 10.0 mg/kg dose produced a significant decrease in movement during the recording sessions. In subsequent open field observations, both line crossings and rearings were reduced by the 3.0 and 10.0 mg/kg doses. The results suggest that endogenous acetylcholine acting on nicotinic acetylcholine receptors plays at most a modest role in producing FEPs recorded from the VC and SC.
Topics: Animals; Body Temperature; Dose-Response Relationship, Drug; Evoked Potentials, Visual; Male; Mecamylamine; Rats; Rats, Long-Evans
PubMed: 21115032
DOI: 10.1016/j.pbb.2010.11.015 -
Nature Nov 2011
Topics: Antidepressive Agents; Clinical Trials, Phase III as Topic; Depression; Humans; Mecamylamine; Stereoisomerism; Treatment Failure
PubMed: 22094666
DOI: 10.1038/479278a