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Biochemical Pharmacology Nov 1990Mecamylamine, an antagonist to nicotine, does not compete at the nicotinic recognition site, but is believed to block the ion channel of the nicotinic receptor. The... (Comparative Study)
Comparative Study
Mecamylamine, an antagonist to nicotine, does not compete at the nicotinic recognition site, but is believed to block the ion channel of the nicotinic receptor. The present study demonstrates specific, saturable [3H]mecamylamine binding in rat brain membranes. [3H]Mecamylamine binding was destroyed by heating at 100 degrees and trypsin. Scatchard analysis revealed the presence of two sites with Kd values of 9.6 x 10(-8) and 1.1 x 10(-6) M and Bmax values of 7 x 10(-12) and 3 x 10(-11) mol/mg protein respectively. A good correlation was observed between the Ki values for [3H]mecamylamine binding of a number of mecamylamine and related analogues and their ability to block nicotine-induced prostration in rats and seizures in mice. Inorganic cations, particularly divalent, and various ion channel blockers, such as phencyclidine and verapamil, exhibited a high affinity for the [3H]mecamylamine site. Although mecamylamine did not block nicotine binding, nicotine and its analogues exhibited a high affinity for the [3H]mecamylamine site, a finding which suggests that nicotine acts directly on ion channels as well as the nicotinic cholinergic recognition sites. The data are consistent with the notion that mecamylamine interacts with the open ion channel of the nicotinic receptor.
Topics: Animals; Binding Sites; Binding, Competitive; Brain; Cations; Cell Membrane; In Vitro Techniques; Mecamylamine; Nicotine; Rats; Rats, Inbred Strains
PubMed: 2242037
DOI: 10.1016/0006-2952(90)90241-c -
The Journal of Pharmacology and... Jun 2012This study examined mechanisms by which nicotine (1.78 mg/kg base s.c.) produces discriminative stimulus effects in rhesus monkeys. In addition to nicotine, various test...
This study examined mechanisms by which nicotine (1.78 mg/kg base s.c.) produces discriminative stimulus effects in rhesus monkeys. In addition to nicotine, various test compounds were studied including other nicotinic acetylcholine receptor agonists (varenicline and cytisine), antagonists [mecamylamine and the α4β2 receptor-selective antagonist dihydro-β-erythroidine (DHβE)], a nicotinic acetylcholine receptor antagonist/indirect-acting catecholamine agonist (bupropion), and non-nicotinics (cocaine and midazolam). Nicotine, varenicline, and cytisine dose-dependently increased drug-lever responding; the ED(50) values were 0.47, 0.53, and 39 mg/kg, respectively. Bupropion and cocaine produced 100% nicotine-lever responding in a subset of monkeys, whereas mecamylamine, DHβE, and midazolam produced predominantly vehicle-lever responding. The training dose of nicotine resulted in 1128 ng/ml cotinine in saliva. Mecamylamine antagonized the discriminative stimulus effects of nicotine and varenicline, whereas DHβE was much less effective. Nicotine and varenicline had synergistic discriminative stimulus effects. In monkeys responding predominantly on the vehicle lever after a test compound (bupropion, cocaine, and midazolam), that test compound blocked the nicotine-discriminative stimulus, perhaps reflecting a perceptual-masking phenomenon. These results show that nicotine, varenicline, and cytisine produce discriminative stimulus effects through mecamylamine-sensitive receptors (i.e., nicotinic acetylcholine) in primates, whereas the involvement of DHβE-sensitive receptors (i.e., α4β2) is unclear. The current nicotine-discrimination assay did not detect a difference in agonist efficacy between nicotine, varenicline, and cytisine, but did show evidence of involvement of dopamine. The control that nicotine has over choice behavior can be disrupted by non-nicotinic compounds, suggesting that non-nicotinics could be exploited to decrease the control that tobacco has over behavior.
Topics: Alkaloids; Animals; Azocines; Benzazepines; Cocaine; Conditioning, Operant; Discrimination Learning; Dopamine Uptake Inhibitors; Drug Interactions; Female; Hypnotics and Sedatives; Macaca mulatta; Male; Mecamylamine; Midazolam; Nicotine; Nicotinic Agonists; Quinolizines; Quinoxalines; Receptors, Nicotinic; Varenicline
PubMed: 22438471
DOI: 10.1124/jpet.112.193078 -
Brain and Behavior Apr 2020There is a long-standing interest in developing nicotinic acetylcholine receptor (nAChR) antagonists for concomitant use with nAChR agonists (e.g., nicotine replacement)...
OBJECTIVES
There is a long-standing interest in developing nicotinic acetylcholine receptor (nAChR) antagonists for concomitant use with nAChR agonists (e.g., nicotine replacement) as complementary smoking cessation aids. Previous studies demonstrate that daily nicotine treatment confers tolerance to some effects of nicotine, as well as cross-tolerance to other nAChR agonists. The current study assessed the extent to which antagonism of nicotine varies as a function of daily nicotine treatment.
METHODS
Schedule-controlled responding and hypothermia were selected for study because they have been previously used to examine the pharmacology of nicotine, and both are sensitive to the development nicotine tolerance. The rate-decreasing and hypothermic effects of nicotine, as well as antagonism of those effects, were examined in C57BL/6J mice before, during treatment with, and after discontinuation of three daily injections of 1.78 mg/kg nicotine. The nonselective nAChR antagonist mecamylamine and the β2 nAChR antagonist dihydro-β-erythroidine (DHβE) were studied in combination with nicotine.
RESULTS
The ED values of nicotine to produce rate-decreasing and hypothermic effects were, respectively, 0.44 and 0.82 mg/kg prior, 1.6 and 3.2 mg/kg during, and 0.74 and 1.1 mg/kg after discontinuation of daily nicotine treatment. Prior to daily nicotine treatment, mecamylamine decreased response rate and rectal temperature. However, during daily nicotine, mecamylamine (up to 5.6 mg/kg) only decreased rectal temperature. DHβE (up to 5.6 mg/kg) when studied prior to daily nicotine decreased rectal temperature, but that decrease was abolished during chronic nicotine treatment. Mecamylamine and DHβE antagonized the rate-decreasing and hypothermic effects of nicotine before and after daily nicotine; however, during daily nicotine, mecamylamine and DHβE antagonized only the hypothermic effects of nicotine.
CONCLUSIONS
The differential antagonism of rate-decreasing and hypothermic effects implicates differential involvement of nAChR subtypes. The decreased capacity of mecamylamine and DHβE to antagonize nicotine during chronic nicotine treatment may indicate that their effectiveness as smoking cessations might vary as a function of nicotine tolerance and dependence.
Topics: Animals; Dihydro-beta-Erythroidine; Dose-Response Relationship, Drug; Drug Tolerance; Male; Mecamylamine; Mice; Mice, Inbred C57BL; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Smoking Cessation
PubMed: 32092237
DOI: 10.1002/brb3.1581 -
Addiction Biology May 2021Alcohol use disorder is a chronic, relapsing brain disorder causing substantial morbidity and mortality. Cholinergic interneurons (CIN) within the nucleus accumbens...
Alcohol use disorder is a chronic, relapsing brain disorder causing substantial morbidity and mortality. Cholinergic interneurons (CIN) within the nucleus accumbens (nAc) have been suggested to exert a regulatory impact on dopamine (DA) neurotransmission locally, and defects in CIN have been implied in several psychiatric disorders. The aim of this study was to investigate the role of CIN in regulation of basal extracellular levels of DA and in modulation of nAc DA release following ethanol administration locally within the nAc of male Wistar rats. Using reversed in vivo microdialysis, the acetylcholinesterase inhibitor physostigmine was administered locally in the nAc followed by addition of either the muscarinic acetylcholine (ACh) receptor antagonist scopolamine or the nicotinic ACh receptor antagonist mecamylamine. Further, ethanol was locally perfused in the nAc following pretreatment with scopolamine and/or mecamylamine. Lastly, ethanol was administered locally into the nAc of animals with accumbal CIN-ablation induced by anticholine acetyl transferase-saporin. Physostigmine increased accumbal DA levels via activation of muscarinic ACh receptors. Neither scopolamine and/or mecamylamine nor CIN-ablation altered basal DA levels, suggesting that extracellular DA levels are not tonically controlled by ACh in the nAc. In contrast, ethanol-induced DA elevation was prevented following coadministration of scopolamine and mecamylamine and blunted in CIN-ablated animals, suggesting involvement of CIN-ACh in ethanol-mediated DA signaling. The data presented in this study suggest that basal extracellular levels of DA within the nAc are not sustained by ACh, whereas accumbal CIN-ACh is involved in mediating ethanol-induced DA release.
Topics: Acetylcholine; Animals; Cholinergic Antagonists; Dopamine; Ethanol; Male; Mecamylamine; Microdialysis; Nicotinic Antagonists; Nucleus Accumbens; Rats; Rats, Wistar; Scopolamine; Ventral Tegmental Area
PubMed: 32789970
DOI: 10.1111/adb.12959 -
CNS Neuroscience & Therapeutics 2008Both clinical and preclinical data support a potential therapeutic benefit of modulating the activity of CNS neuronal nicotinic receptors (NNRs) to treat depression and... (Review)
Review
Both clinical and preclinical data support a potential therapeutic benefit of modulating the activity of CNS neuronal nicotinic receptors (NNRs) to treat depression and anxiety disorders. Based on the notion that the depressive states involve hypercholinergic tone, we have examined the potential palliative role of NNR antagonism in these disorders, using TC-5214 (S-(+) enantiomer of mecamylamine), a noncompetitive NNR antagonist. TC-5214 demonstrated positive effects in a number of animal models of depression and anxiety. TC-5214 was active in the forced swim test in rats (minimum effective dose (MED)=3 mg/kg i.p.), a classical depression model. It was also active in the behavioral despair test in mice (0.1-3.0 mg/kg i.p.), another model of depression. In the social interaction paradigm in rats, a model of generalized anxiety disorder (GAD), TC-5214 was active at a dose of 0.05 mg/kg s.c. In the light/dark chamber paradigm in rats, a model of GAD and phobia, TC-5214 was also active at a dose of 0.05 mg/kg s.c. Although TC-5214 shows modest selectivity among NNR subtypes, the antidepressant and anxiolytic effects seen in these studies are likely attributable to antagonist effects at the alpha4beta2 NNRs. This is supported by the observation of similar effects with alpha4beta2-selective partial agonists such as cytisine and with alpha4beta2-selective antagonists such as TC-2216. TC-5214 was well tolerated in acute and chronic toxicity studies in mice, rats, and dogs, showed no mutagenicity and displayed safety pharmacology, pharmacokinetic and metabolic profiles appropriate for therapeutic development. Overall, the results support a novel nicotinic cholinergic antagonist mechanism for antidepressant and anxiolytic effects and highlight the potential of NNR antagonists such as TC-5214 as therapeutics for the treatment of anxiety and depression.
Topics: Animals; Antidepressive Agents; Chromosome Aberrations; Dogs; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Female; Gastrointestinal Motility; Humans; Male; Mecamylamine; Mice; Micronucleus Tests; Nicotinic Antagonists; Rats; Rats, Sprague-Dawley; Social Behavior; Stereoisomerism
PubMed: 19040552
DOI: 10.1111/j.1755-5949.2008.00054.x -
Developmental Biology Dec 2022We recently described calcium signaling in the appendicularian tunicate Oikopleura dioica during pre-gastrulation stages, and showed that regularly occurring calcium...
We recently described calcium signaling in the appendicularian tunicate Oikopleura dioica during pre-gastrulation stages, and showed that regularly occurring calcium waves progress throughout the embryo in a characteristic spatiotemporal pattern from an initiation site in muscle lineage blastomeres. Here, we have extended our observations to the period spanning from gastrulation to post-hatching stages. We find that repetitive Ca2+ waves persist throughout this developmental window, albeit with a gradual increase in frequency. The initiation site of the waves shifts from muscle cells at gastrulation and early tailbud stages, to the central nervous system at late tailbud and post-hatching stages, indicating a transition from muscle-driven to neurally driven events as tail movements emerge. At these later stages, both the voltage gated Na+ channel blocker tetrodotoxin (TTX) and the T-type Ca2+ channel blocker and nAChR antagonist mecamylamine eliminate tail movements. At late post-hatching stages, mecamylamine blocks Ca2+ signals in the muscles but not the central nervous system. Post-gastrulation Ca2+ signals also arise in epithelial cells, first in a haphazard pattern in scattered cells during tailbud stages, evolving after hatching into repetitive rostrocaudal waves with a different frequency than the nervous system-to-muscle waves, and insensitive to mecamylamine. The desynchronization of Ca2+ waves arising in different parts of the body indicates a shift from whole-body to tissue/organ-specific Ca2+ signaling dynamics as organogenesis occurs, with neurally driven Ca2+ signaling dominating at the later stages when behavior emerges.
Topics: Animals; Gastrulation; Urochordata; Calcium Signaling; Calcium; Mecamylamine
PubMed: 36162551
DOI: 10.1016/j.ydbio.2022.09.004 -
Neuropsychopharmacology : Official... Jun 2011Nicotine improves cognitive performance and attention in both experimental animals and in human subjects, including patients affected by neuropsychiatric disorders....
Nicotine improves cognitive performance and attention in both experimental animals and in human subjects, including patients affected by neuropsychiatric disorders. However, the specific molecular mechanisms underlying nicotine-induced behavioral changes remain unclear. We have recently shown in mice that repeated injections of nicotine, which achieve plasma concentrations comparable to those reported in high cigarette smokers, result in an epigenetically induced increase of glutamic acid decarboxylase 67 (GAD(67)) expression. Here we explored the impact of synthetic α(4)β(2) and α(7) nAChR agonists on GABAergic epigenetic parameters. Varenicline (VAR), a high-affinity partial agonist at α(4)β(2) and a lower affinity full agonist at α(7) neuronal nAChR, injected in doses of 1-5 mg/kg/s.c. twice daily for 5 days, elicited a 30-40% decrease of cortical DNA methyltransferase (DNMT)1 mRNA and an increased expression of GAD(67) mRNA and protein. This upregulation of GAD(67) was abolished by the nAChR antagonist mecamylamine. Furthermore, the level of MeCP(2) binding to GAD(67) promoters was significantly reduced following VAR administration. This effect was abolished when VAR was administered with mecamylamine. Similar effects on cortical DNMT1 and GAD(67) expression were obtained after administration of A-85380, an agonist that binds to α(4)β(2) but has negligible affinity for α(3)β(4) or α(7) subtypes containing nAChR. In contrast, PNU-282987, an agonist of the homomeric α(7) nAChR, failed to decrease cortical DNMT1 mRNA or to induce GAD(67) expression. The present study suggests that the α(4)β(2) nAChR agonists may be better suited to control the epigenetic alterations of GABAergic neurons in schizophrenia than the α(7) nAChR agonists.
Topics: Analysis of Variance; Animals; Azetidines; Behavior, Animal; Benzazepines; Cerebral Cortex; Conditioning, Classical; Cues; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases; Epigenomics; Exploratory Behavior; Fear; Freezing Reaction, Cataleptic; Gene Expression Regulation; Glutamate Decarboxylase; Male; Mecamylamine; Methyl-CpG-Binding Protein 2; Mice; Neurons; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Promoter Regions, Genetic; Quinoxalines; RNA, Messenger; Receptors, Nicotinic; Varenicline; gamma-Aminobutyric Acid
PubMed: 21368748
DOI: 10.1038/npp.2011.21 -
Drug and Alcohol Dependence Mar 2017Although both men and women use e-cigarettes, most preclinical nicotine research has focused on its effects in male rodents following injection. The goals of the present...
BACKGROUND
Although both men and women use e-cigarettes, most preclinical nicotine research has focused on its effects in male rodents following injection. The goals of the present study were to develop an effective e-cigarette nicotine delivery system, to compare results to those obtained after subcutaneous (s.c.) injection, and to examine sex differences in the model.
METHODS
Hypothermia and locomotor suppression were assessed following aerosol exposure or s.c. injection with nicotine in female and male mice. Subsequently, plasma and brain concentrations of nicotine and cotinine were measured.
RESULTS
Passive exposure to nicotine aerosol produced concentration-dependent and mecamylamine reversible hypothermic and locomotor suppressant effects in female and male mice, as did s.c. nicotine injection. In plasma and brain, nicotine and cotinine concentrations showed dose/concentration-dependent increases in both sexes following each route of administration. Sex differences in nicotine-induced hypothermia were dependent upon route of administration, with females showing greater hypothermia following aerosol exposure and males showing greater hypothermia following injection. In contrast, when they occurred, sex differences in nicotine and cotinine levels in brain and plasma consistently showed greater concentrations in females than males, regardless of route of administration.
DISCUSSION
In summary, the e-cigarette exposure device described herein was used successfully to deliver pharmacologically active doses of nicotine to female and male mice. Further, plasma nicotine concentrations following exposure were similar to those after s.c. injection with nicotine and within the range observed in human smokers. Future research on vaped products can be strengthened by inclusion of translationally relevant routes of administration.
Topics: Aerosols; Animals; Brain; Cotinine; Dose-Response Relationship, Drug; Drug Delivery Systems; Electronic Nicotine Delivery Systems; Female; Injections, Subcutaneous; Male; Mecamylamine; Mice; Mice, Inbred ICR; Motor Activity; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Sex Characteristics
PubMed: 28157590
DOI: 10.1016/j.drugalcdep.2016.12.004 -
Mediators of Inflammation 2020Breast cancer results from a complex interplay of genetics and environment that alters immune and inflammatory systems to promote tumorigenesis. Obesity and cigarette...
Breast cancer results from a complex interplay of genetics and environment that alters immune and inflammatory systems to promote tumorigenesis. Obesity and cigarette smoking are well-known risk factors associated breast cancer development. Nicotine known to decrease inflammatory signals also modulates immune responses that favor breast cancer development. However, the mechanisms by which nicotine and obesity contribute to breast cancer remain poorly understood. In this study, we examined potential mechanisms by which nicotine (NIC) and high-fat diet (HFD) promote growth of HCC70 and HCC1806 xenografts from African American (AA) triple negative (TN) breast cancer cells. Immunodeficient mice fed on HFD and treated with NIC generated larger HCC70 and HCC1806 tumors when compared to NIC or HFD alone. Increased xenograft growth in the presence of NIC and HFD was accompanied by higher levels of tissue-resident macrophage markers and anti-inflammatory cytokines including IL4, IL13, and IL10. We further validated the involvement of these players by and experiments. We found a proinflammatory milieu with increased expression of IL6 and IL12 in xenografts with HFD. In addition, nicotine or nicotine plus HFD increased a subset of mammary cancer stem cells (MCSCs) and key adipose browning markers CD137 and TMEM26. Interestingly, there was upregulation of stress-induced pp38 MAPK and pERK1/2 in xenografts exposed to HFD alone or nicotine plus HFD. Scratch-wound assay showed marked reduction in proliferation/migration of nicotine and palmitate-treated breast cancer cells with mecamylamine (MEC), a nicotine acetylcholine receptor (nAchR) antagonist. Furthermore, xenograft development in immune-deficient mice, fed HFD plus nicotine, was reduced upon cotreatment with MEC and SB 203580, a pp38MAPK inhibitor. Our study demonstrates the presence of nicotine and HFD in facilitating an anti-inflammatory tumor microenvironment that influences breast tumor growth. This study also shows potential efficacy of combination therapy in obese breast cancer patients who smoke.
Topics: Animal Feed; Animals; Anti-Inflammatory Agents; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Diet, High-Fat; Female; Humans; Imidazoles; Inflammasomes; Inflammation; Mammary Neoplasms, Animal; Mecamylamine; Mice; Neoplasm Transplantation; Neoplastic Stem Cells; Nicotine; Oxidative Stress; Pyridines; Up-Regulation; p38 Mitogen-Activated Protein Kinases
PubMed: 33414685
DOI: 10.1155/2020/5239419 -
Investigative Ophthalmology & Visual... Apr 2008Nicotinic acetylcholine receptors (nAChR) are best known for their role in neurotransmission, but they have recently been demonstrated on vascular endothelial cells....
PURPOSE
Nicotinic acetylcholine receptors (nAChR) are best known for their role in neurotransmission, but they have recently been demonstrated on vascular endothelial cells. Acetylcholine is their endogenous ligand, but they are also stimulated by nicotine. By stimulating nAChR, nicotine promotes tumor angiogenesis as well as atherosclerotic plaque neovascularization. In this study, the authors investigated the role of nAChR in the pathogenesis of choroidal neovascularization (CNV).
METHODS
The effect of the nonselective nAChR antagonist mecamylamine was tested on human retinal and choroidal endothelial cells in vitro and in a murine model of CNV.
RESULTS
Several nAChR isoforms were identified in retinal and choroidal microvascular endothelial cells, and the ability of these cells to form tubules when grown in growth factor-reduced basement membrane matrix and supplemented with VEGF was suppressed by the nAChR antagonist mecamylamine. Supplementation of the drinking water of mice with nicotine increased the size of CNV lesions at Bruch membrane rupture sites, an effect that was blocked by subcutaneous administration of mecamylamine (50 mg/kg/d) by an osmotic pump. In the absence of nicotine, CNV formation was suppressed by the infusion of 50 mg/kg/d mecamylamine or by topical application 0.1 or 1% mecamylamine to the cornea.
CONCLUSIONS
These data suggest that endogenous activation of nAChR promotes CNV and that activation of nAChR by nicotine may contribute to the increased incidence of CNV seen in smokers with age-related macular degeneration (AMD). Topically administered mecamylamine could provide an appealing new treatment approach for CNV.
Topics: Animals; Cells, Cultured; Choroid; Choroidal Neovascularization; Disease Models, Animal; Endothelium, Vascular; Female; Humans; Immunoblotting; Mecamylamine; Mice; Mice, Inbred C57BL; Nicotine; Nicotinic Antagonists; Protein Isoforms; RNA, Messenger; Receptors, Nicotinic; Retinal Vessels
PubMed: 18385094
DOI: 10.1167/iovs.07-0089