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Proceedings of the National Academy of... Feb 2009The orosensory responses elicited by nicotine are relevant for the development and maintenance of addiction to tobacco products. However, although nicotine is described...
The orosensory responses elicited by nicotine are relevant for the development and maintenance of addiction to tobacco products. However, although nicotine is described as bitter tasting, the molecular and neural substrates encoding the taste of nicotine are unclear. Here, rats and mice were used to determine whether nicotine activates peripheral and central taste pathways via TRPM5-dependent mechanisms, which are essential for responses to other bitter tastants such as quinine, and/or via nicotinic acetylcholine receptors (nAChRs). When compared with wild-type mice, Trpm5(-/-) mice had reduced, but not abolished, chorda tympani (CT) responses to nicotine. In both genotypes, lingual application of mecamylamine, a nAChR-antagonist, inhibited CT nerve responses to nicotine and reduced behavioral responses of aversion to this stimulus. In accordance with these findings, rats were shown to discriminate between nicotine and quinine presented at intensity-paired concentrations. Moreover, rat gustatory cortex (GC) neural ensemble activity could also discriminate between these two bitter tastants. Mecamylamine reduced both behavioral and GC neural discrimination between nicotine and quinine. In summary, nicotine elicits taste responses through peripheral TRPM5-dependent pathways, common to other bitter tastants, and nAChR-dependent and TRPM5-independent pathways, thus creating a unique sensory representation that contributes to the sensory experience of tobacco products.
Topics: Animals; Electrodes; Mecamylamine; Mice; Mice, Knockout; Nicotine; Nicotinic Antagonists; Quinine; Rats; Reverse Transcriptase Polymerase Chain Reaction; TRPM Cation Channels; Taste
PubMed: 19164511
DOI: 10.1073/pnas.0810184106 -
International Journal of Molecular... Mar 2021Myoclonus-dystonia (DYT-SGCE, formerly DYT11) is characterized by alcohol-sensitive, myoclonic-like appearance of fast dystonic movements. It is caused by mutations in...
Myoclonus-dystonia (DYT-SGCE, formerly DYT11) is characterized by alcohol-sensitive, myoclonic-like appearance of fast dystonic movements. It is caused by mutations in the gene encoding ε-sarcoglycan leading to a dysfunction of this transmembrane protein, alterations in the cerebello-thalamic pathway and impaired striatal plasticity. To elucidate underlying pathogenic mechanisms, we investigated induced pluripotent stem cell (iPSC)-derived striatal medium spiny neurons (MSNs) from two myoclonus-dystonia patients carrying a heterozygous mutation in the gene (c.298T>G and c.304C>T with protein changes W100G and R102X) in comparison to two matched healthy control lines. Calcium imaging showed significantly elevated basal intracellular Ca content and lower frequency of spontaneous Ca signals in SGCE MSNs. Blocking of voltage-gated Ca channels by verapamil was less efficient in suppressing KCl-induced Ca peaks of SGCE MSNs. Ca amplitudes upon glycine and acetylcholine applications were increased in SGCE MSNs, but not after GABA or glutamate applications. Expression of voltage-gated Ca channels and most ionotropic receptor subunits was not altered. SGCE MSNs showed significantly reduced GABAergic synaptic density. Whole-cell patch-clamp recordings displayed elevated amplitudes of miniature postsynaptic currents and action potentials in SGCE MSNs. Our data contribute to a better understanding of the pathophysiology and the development of novel therapeutic strategies for myoclonus-dystonia.
Topics: Acetylcholine; Action Potentials; Adult; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Signaling; Cell Differentiation; Cells, Cultured; Corpus Striatum; Dendritic Spines; Dystonic Disorders; Female; Gene Expression; Glycine; Humans; Induced Pluripotent Stem Cells; Male; Mecamylamine; Middle Aged; Patch-Clamp Techniques
PubMed: 33808167
DOI: 10.3390/ijms22073565 -
Genes, Brain, and Behavior Mar 2019Common genetic factors may contribute to the high comorbidity between tobacco smoking and alcohol use disorder. Here, we assessed behavioral and biological effects of...
Common genetic factors may contribute to the high comorbidity between tobacco smoking and alcohol use disorder. Here, we assessed behavioral and biological effects of nicotine in replicate mouse lines selectively bred for high (HAP2/3) or low alcohol preference (LAP2/3). In Experiment 1, free-choice (FC) oral nicotine and quinine intake were assessed in HAP2/3 and LAP2/3 mice. Effects of nicotinic acetylcholine receptor blockade by mecamylamine on nicotine intake in HAP2 mice were also examined. In Experiment 2, HAP2/3 and LAP2/3 mice were tested for differences in sensitivity to nicotine-induced taste conditioning. In Experiment 3, the effects of a single nicotine injection on nucleus accumbens (NAc) and dorsal striatum monoamine levels in HAP2/3 and LAP2/3 mice were tested. In Experiment 1, HAP2/3 mice showed greater nicotine intake and intake ratio than LAP2/3 mice. There were no line differences in quinine intake. Mecamylamine reduced nicotine intake and intake ratio in HAP2 mice. In Experiment 2, HAP2/3 mice showed weaker nicotine-induced conditioned taste aversion (CTA) compared with LAP2/3 mice. In Experiment 3, nicotine treatment increased NAc dopamine turnover across both HAP2/3 and LAP2/3 mouse lines. These results show that there is a positive genetic correlation between oral alcohol intake (high alcohol intake/preference selection phenotype) and oral nicotine intake and a negative genetic correlation between oral alcohol intake and sensitivity to nicotine-induced CTA.
Topics: Alcoholism; Animals; Biogenic Monoamines; Female; Genotype; Male; Mecamylamine; Mice; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Nucleus Accumbens; Reinforcement, Psychology; Tobacco Smoking
PubMed: 30129253
DOI: 10.1111/gbb.12515 -
Journal of Substance Abuse Treatment Nov 2018Mecamylamine is a nicotinic acetylcholine receptor (nAChR) antagonist that was recently used in a clinical trial to treat alcohol use disorder (AUD) in both smokers and... (Randomized Controlled Trial)
Randomized Controlled Trial
Mecamylamine is a nicotinic acetylcholine receptor (nAChR) antagonist that was recently used in a clinical trial to treat alcohol use disorder (AUD) in both smokers and non-smokers. The current manuscript reports a reanalysis of data from this clinical trial in which we examine changes in smoking that occurred over the course of the trial. We focused on examining the effects of mecamylamine on smoking and the association between reductions in alcohol use and smoking. Participants were the subgroup of smokers who participated in the clinical trial of mecamylamine (10 mg/day) to treat their AUD (n = 76). Smoking was assessed prior to randomization and tracked throughout the course of the 12-week medication treatment phase. Participants were categorized as treatment responders or non-responders based on their changes in drinking over the course of the clinical trial. Participants showed a reduction in smoking over the course of the clinical trial, but there were no significant differences in smoking outcomes between the mecamylamine and placebo groups. Among moderate/high dependence smokers, those who successfully reduced drinking showed a significant reduction in cigarettes smoked per day over the clinical trial. Mecamylamine had no detectable effect on smoking outcomes. Reductions in alcohol use predicted more favorable smoking outcomes among moderate/high tobacco dependence smokers irrespective of medication condition. The reduction in smoking among patients who decreased their alcohol use responders highlights an opportunity for patients being treated for AUD to reduce their smoking.
Topics: Adult; Alcohol Drinking; Alcoholism; Double-Blind Method; Female; Humans; Male; Mecamylamine; Middle Aged; Nicotinic Antagonists; Tobacco Smoking; Treatment Outcome
PubMed: 30243424
DOI: 10.1016/j.jsat.2018.08.015 -
Biomedicine & Pharmacotherapy =... Aug 2021There is substantial evidence that GABA agonist, baclofen, prevents somatic and motivational responses induced by nicotine withdrawal and may target drug cue...
There is substantial evidence that GABA agonist, baclofen, prevents somatic and motivational responses induced by nicotine withdrawal and may target drug cue vulnerabilities in humans. In this context, we explored different aspects associated with the possible mechanisms whereby the GABA receptors might influence nicotine withdrawal. Male mice received nicotine (2.5 mg/kg, s.c.) 4 times daily, for 7 consecutive days. Nicotine-treated mice received the nicotinic acetylcholine receptor antagonist, mecamylamine (MEC, 2 or 3.5 mg/kg, s.c.), to precipitate the withdrawal state. A second group of dependent mice received 2-hydroxysaclofen (GABA receptor antagonist, 1 mg/kg, s.c.) before MEC-precipitated abstinence. Somatic signs of nicotine withdrawal were measured for 30 min. Anxiogenic-like response associated to nicotine withdrawal was assessed by the elevated plus maze test. The dysphoric/aversive effect induced by nicotine withdrawal was evaluated using conditioned place aversion paradigm. Dopamine, serotonin and its metabolites concentrations were determined by HPLC in the striatum, cortex and hippocampus. Finally, α4β2 nicotinic acetylcholine receptor density was determined in several brain regions using autoradiography assays. The results showed that MEC-precipitated nicotine withdrawal induced somatic manifestations, anxiogenic-like response and dysphoric/aversive effect, and 2-hydroxysaclofen potentiated these behavioral responses. Additionally, 2-hydroxysaclofen was able to change striatal dopamine levels and α4β2 nicotinic acetylcholine receptor density, both altered by MEC-precipitated nicotine withdrawal. These findings provide important contributions to elucidate neurobiological mechanisms implicated in nicotine withdrawal. We suggest that GABA receptor activity is necessary to control alterations induced by nicotine withdrawal, which supports the idea of targeting GABA receptors to treat tobacco addiction in humans.
Topics: Animals; Baclofen; Behavior, Animal; Brain; Dopamine; GABA-B Receptor Antagonists; Male; Mecamylamine; Mice; Nicotine; Nicotinic Antagonists; Receptors, GABA-B; Receptors, Nicotinic; Substance Withdrawal Syndrome
PubMed: 34144406
DOI: 10.1016/j.biopha.2021.111786 -
Neuropharmacology Apr 2019Cigarette smokers with brain damage involving the insular cortex display cessation of tobacco smoking, suggesting that this region may contribute to nicotine addiction....
Cigarette smokers with brain damage involving the insular cortex display cessation of tobacco smoking, suggesting that this region may contribute to nicotine addiction. In the present study, we speculated that molecules in the insular cortex that are sensitive to experimental traumatic brain injury (TBI) in mice might provide leads to ameliorate nicotine addiction. Using targeted lipidomics, we found that TBI elicited substantial increases of a largely uncharacterized lipid, N-acyl-glycine, N-oleoyl-glycine (OlGly), in the insular cortex of mice. We then evaluated whether intraperitoneal administration of OlGly would alter withdrawal responses in nicotine-dependent mice as well as the rewarding effects of nicotine, as assessed in the conditioned place preference paradigm (CPP). Systemic administration of OlGly reduced mecamylamine-precipitated withdrawal responses in nicotine-dependent mice and prevented nicotine CPP. However, OlGly did not affect morphine CPP, demonstrating a degree of selectivity. Our respective in vitro and in vivo observations that OlGly activated peroxisome proliferator-activated receptor alpha (PPAR-α) and the PPAR-α antagonist GW6471 prevented the OlGly-induced reduction of nicotine CPP in mice suggests that this lipid acts as a functional PPAR-α agonist to attenuate nicotine reward. These findings raise the possibility that the long chain fatty acid amide OlGly may possess efficacy in treating nicotine addiction.
Topics: Animals; Brain Injuries, Traumatic; Cerebral Cortex; Conditioning, Classical; Glycine; Male; Mecamylamine; Mice; Nicotine; Oleic Acids; Oxazoles; PPAR alpha; Reward; Substance Withdrawal Syndrome; Tobacco Use Disorder; Tyrosine
PubMed: 29567093
DOI: 10.1016/j.neuropharm.2018.03.020 -
American Journal of Physiology. Cell... Apr 2009We have investigated here whether a preconditioned stimulation of nicotinic and muscarinic receptors augmented the catecholamine release responses elicited by...
We have investigated here whether a preconditioned stimulation of nicotinic and muscarinic receptors augmented the catecholamine release responses elicited by supramaximal 3-s pulses of 100 muM acetylcholine (100ACh) or 100 mM K(+) (100K(+)) applied to fast-perifused bovine adrenal chromaffin cells. Threshold concentrations of nicotine (1-3 muM) that caused only a tiny secretion did, however, augment the responses elicited by 100ACh or 100K(+) by 2- to 3.5-fold. This effect was suppressed by mecamylamine and by Ca(2+) deprivation, was developed with a half-time (t(1/2)) of 1 min, and was reversible. The nicotine effect was mimicked by threshold concentrations of ACh, choline, epibatidine, and oxotremorine-M but not by methacholine. Threshold concentrations of K(+) caused lesser potentiation of secretion compared with that of threshold nicotine. The data are compatible with an hypothesis implying 1) that continuous low-frequency sympathetic discharge places chromaffin cells at the adrenal gland in a permanent "hypersensitive" state; and 2) this allows an explosive secretion of catecholamines by high-frequency sympathetic discharge during stress.
Topics: Acetylcholine; Adrenal Glands; Animals; Bridged Bicyclo Compounds, Heterocyclic; Calcium; Catecholamines; Cattle; Cells, Cultured; Choline; Chromaffin Cells; Dose-Response Relationship, Drug; Mecamylamine; Methacholine Chloride; Muscarinic Agonists; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Oxotremorine; Potassium; Pyridines; Receptors, Muscarinic; Receptors, Nicotinic; Sympathetic Nervous System; Time Factors
PubMed: 19211912
DOI: 10.1152/ajpcell.00600.2008 -
American Journal of Physiology.... Jul 2015Acetylcholine (Ach) has vasodilatory actions. However, data are conflicting about the role of Ach in regulating blood flow in subcutaneous adipose tissue (ATBF). This... (Clinical Trial)
Clinical Trial
Acetylcholine (Ach) has vasodilatory actions. However, data are conflicting about the role of Ach in regulating blood flow in subcutaneous adipose tissue (ATBF). This may be related to inaccurate ATBF recording or to the responder/nonresponder (R/NR) phenomenon. We showed previously that healthy individuals are R (ATBF increases postprandially by >50% of baseline BF) or NR (ATBF increases ≤50% postprandially). Our objective was to assess the role of the cholinergic system on ATBF in R and NR subjects. ATBF was manipulated by in situ microinfusion of vasoactive agents (VA) in AT and monitored by the (133)Xenon washout technique (both recognized methods) at the VA site and at the control site. We tested incrementally increasing doses of Ach (10(-5), 10(-3), and 10(-1) mol/l; n = 15) and Ach receptor antagonists (Ra) before and after oral administration of 75-g glucose using atropine (muscarinic Ra; 10(-4) mol/l, n = 13; 10(-5) mol/l, n = 22) and mecamylamine (nicotinic Ra; 10(-3) mol/l, n = 15; 10(-4) mol/l, n = 10). Compared with baseline [2.41 (1.36-2.83) ml·100 g(-1)·min(-1)], Ach increased ATBF dose dependently [3.32 (2.80-5.09), 6.46 (4.36-9.51), and 10.31 (7.98-11.52), P < 0.0001], with no difference between R and NR. Compared with control side, atropine (both concentrations) had no effect on fasting ATBF; only atropine 10(-4) mol/l decreased post-glucose ATBF [iAUC: 1.25 (0.32-2.91) vs. 1.98 (0.64-2.94); P = 0.04]. This effect was further apparent in R. Mecamylamine had no impact on fasting and postglucose ATBF in R and NR. Our results suggest that the cholinergic system is implicated in ATBF regulation, although it has no role in the blunting of ATBF response in NR.
Topics: Acetylcholine; Adult; Atropine; Blood Pressure; Cholinergic Agents; Female; Heart Rate; Humans; Male; Mecamylamine; Receptors, Cholinergic; Regional Blood Flow; Subcutaneous Fat; Xenon Radioisotopes; Young Adult
PubMed: 25968573
DOI: 10.1152/ajpendo.00016.2015 -
Pharmacology, Biochemistry, and Behavior Dec 2019Cigarette smoking and resultant nicotine dependence remain major public health problems. Most smokers begin before the age of 18, yet preclinical models have...
Cigarette smoking and resultant nicotine dependence remain major public health problems. Most smokers begin before the age of 18, yet preclinical models have insufficiently characterized the development of nicotine dependence in adolescence. To categorize the short-term effects of chronic nicotine administration throughout adolescence and adulthood, we exposed male Sprague Dawley rats to 14 days of continuously delivered nicotine (0, 1.2 or 4.8 mg/kg/d) using a subcutaneous osmotic minipump, starting between postnatal day 33 (p33) and p96. Next, to explore the effects of extended exposure to chronic nicotine, we exposed male Sprague Dawley rats to 42 days of continuous nicotine starting in adolescence (p33) or early adulthood (p68). Somatic and affective signs of precipitated withdrawal (PW) were observed after a mecamylamine (1.5 mg/kg, i.p.) challenge as compared to a saline injection. Short term nicotine exposure starting at p96, well within the adult period, elicited a significant increase in somatic PW as measured by a composite behavioral score. In contrast, adolescent exposure to nicotine elicited a unique behavioral profile, dependent on the starting age of exposure. Late adolescence exposure was characterized by scratching while adult exposure was characterized by facial tremors and yawns. Extended exposure to nicotine resulted in age specific characteristic nicotine withdrawal behaviors, including scratches, ptosis and locomotion, distinct from the short-term exposure. Thus, nicotine dependence severity, based on the expression of total somatic PW behaviors, is not observed until the adult period, and differences between adolescents and adults are observed using a more nuanced behavioral scoring approach. We conclude that age of nicotine initiation affects somatic withdrawal signs and their magnitude. These data serve as a foundation for understanding the underlying brain mechanisms of nicotine dependence and their development over adolescence and early adulthood.
Topics: Age Factors; Animals; Behavior, Animal; Dose-Response Relationship, Drug; Infusions, Subcutaneous; Locomotion; Male; Mecamylamine; Nicotine; Nicotinic Antagonists; Rats; Rats, Sprague-Dawley; Severity of Illness Index; Substance Withdrawal Syndrome; Tobacco Use Disorder
PubMed: 31669000
DOI: 10.1016/j.pbb.2019.172802 -
Frontiers in Immunology 2019Type I diabetes (T1D) is a T cell-driven autoimmune disease that results in the killing of pancreatic β-cells and, consequently, loss of insulin production. Using the...
Type I diabetes (T1D) is a T cell-driven autoimmune disease that results in the killing of pancreatic β-cells and, consequently, loss of insulin production. Using the multiple low-dose streptozotocin (MLD-STZ) model of experimental autoimmune diabetes, we previously reported that pretreatment with a specific acetylcholinesterase inhibitor (AChEI), paraoxon, prevented the development of hyperglycemia in C57BL/6 mice. This correlated with an inhibition of T cell infiltration into the pancreatic islets and a reduction in pro-inflammatory cytokines. The cholinergic anti-inflammatory pathway utilizes nicotinic and muscarinic acetylcholine receptors (nAChRs and mAChRs, respectively) expressed on a variety of cell types. In this study, we carried out a comparative analysis of the effect of specific antagonists of nAChRs or mAChRs on the development of autoimmune diabetes. Co-administration of mecamylamine, a non-selective antagonist of nAChRs maintained the protective effect of AChEI on the development of hyperglycemia. In contrast, co-administration of atropine, a non-selective antagonist of mAChRs, mitigated AChEI-mediated protection. Mice pretreated with mecamylamine had an improved response in glucose tolerance test (GTT) than mice pretreated with atropine. These differential effects of nAChR and mAChR antagonists correlated with the extent of islet cell infiltration and with the structure and functionality of the β-cells. Taken together, our data suggest that mAChRs are essential for the protective effect of cholinergic stimulation in autoimmune diabetes.
Topics: Acetylcholinesterase; Animals; Atropine; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Disease Models, Animal; Female; GPI-Linked Proteins; Hyperglycemia; Insulin-Secreting Cells; Male; Mecamylamine; Mice; Mice, Inbred C57BL; Muscarinic Antagonists; Nicotinic Antagonists; Paraoxon; Receptors, Muscarinic; Receptors, Nicotinic; Streptozocin
PubMed: 31156627
DOI: 10.3389/fimmu.2019.01038