SciCombinator

Discover the most talked about and latest scientific content & concepts.

Concept: Mecamylamine

29

Intestinal epithelial intercellular tight junctions (TJs) provide a rate-limiting barrier restricting passive transepithelial movement of solutes. TJs are highly dynamic areas, and their permeability is changed in response to various stimuli. Defects in the intestinal epithelial TJ barrier may contribute to intestinal inflammation or leaky gut. The gastrointestinal tract may be the largest extrapineal source of endogenous melatonin. Melatonin released from the duodenal mucosa is a potent stimulant of duodenal mucosal bicarbonate secretion (DBS). The aim of this study was to elucidate the role of melatonin in regulating duodenal mucosal barrier functions, including mucosal permeability, DBS, net fluid flux, and duodenal motor activity, in the living animal. Rats were anesthetized with thiobarbiturate, and a ~30-mm segment of the proximal duodenum with an intact blood supply was perfused in situ. Melatonin and the selective melatonin receptor antagonist luzindole were perfused luminally or given intravenously. Effects on permeability (blood-to-lumen clearance of Cr-EDTA), DBS, mucosal net fluid flux, and duodenal motility were monitored. Luminal melatonin caused a rapid decrease in paracellular permeability and an increase in DBS, but had no effect on duodenal motor activity or net fluid flux. Luzindole did not influence any of the basal parameters studied, but significantly inhibited the effects of melatonin. The nonselective and noncompetitive nicotinic acetylcholine receptor antagonist mecamylamine abolished the effect of melatonin on duodenal permeability and reduced that on DBS. In conclusion, these findings provide evidence that melatonin significantly decreases duodenal mucosal paracellular permeability and increases DBS. The data support the important role of melatonin in the neurohumoral regulation of duodenal mucosal barrier.

Concepts: Nicotine, Acetylcholine, Myasthenia gravis, Muscarinic acetylcholine receptor, Nicotinic acetylcholine receptor, Acetylcholine receptor, Duodenum, Mecamylamine

27

Oseltamivir, an anti-influenza virus drug, has strong antipyretic effects in mice (Ono et al., 2008) and influenza patients. In addition, hypothermia has been reported as an adverse event. The prodrug oseltamivir is converted to oseltamivir carboxylate (OC), an active metabolite of influenza virus neuraminidase. In this study, core body temperature was measured in mice, and oseltamivir and OC were administered intracerebroventricularly (i.c.v.) or intraperitoneally (i.p). Low i.c.v. doses of oseltamivir and OC dose-dependently produced hypothermia. Zanamivir (i.c.v.), another neuraminidase inhibitor, did not produce hypothermia. These results suggested that the hypothermic effects of oseltamivir (i.p. and i.c.v.) and OC (i.c.v.) are not due to neuraminidase inhibition. OC (i.p.) did not lower body temperature. Although mecamylamine (i.c.v.) blocked the hypothermic effect of nicotine administered i.c.v., the hypothermic effects of oseltamivir and OC (i.c.v.) were not blocked by mecamylamine (i.c.v.). The effect of oseltamivir (i.p.) was markedly increased by s.c.-preadministered mecamylamine and also hexamethonium, a peripherally acting ganglionic blocker, suggesting their potentiating interaction at peripheral sites. The hypothermic effect of nicotine (i.c.v.) was decreased by lower doses of oseltamivir (i.c.v.), suggesting the anti-nicotinic action of oseltamivir. These results suggest that oseltamivir (i.p.) causes hypothermia through depression of sympathetic temperature regulatory mechanisms via inhibition of nicotinic receptor function and through unknown central mechanisms.

Concepts: Hypothermia, Influenza, Acetylcholine, Nicotinic acetylcholine receptor, Oseltamivir, Neuraminidase, Viral neuraminidase, Mecamylamine

2

Electrophysiology and microdialysis studies have provided compelling evidence that moderate-to-high ethanol concentrations enhance dopamine (DA) neurotransmission in the nucleus accumbens (NAc) through the mesolimbic DA system. However, with fast scan cyclic voltammetry (FSCV), acute exposure to moderate-high doses of ethanol decreases evoked DA release at terminals in the NAc. The aim of this study was to evaluate the involvement of nicotinic acetylcholine receptors (nAChRs) in modulating the effects of ethanol on DA release in the NAc of C57BL/6 mice ex vivo and in vivo. Local stimulation evoked robust, frequency-dependent DA release in the NAc slice preparation, with maximal release at 40 Hz in the shell and 20 Hz in the core. Nicotine decreased DA release in a concentration-dependent (0.01 - 10 μM) manner in the shell and core with an IC50 of 0.1 μM ex vivo and 0.5 mg/kg in vivo. Nicotine and ethanol inhibition of DA release was blocked by the α6*-nAChR antagonist α-conotoxins CtxMII or α-CtxMII [H9A; L15A] ex vivo (100 nM) in the core, but not the shell. Furthermore, the non-specific nAChR antagonist mecamylamine (2 mg/kg) blocked the effects of ethanol in the core in vivo. These findings suggest that DA release is inhibited by ethanol via nAChRs in the NAc, and that DA modulation by nAChRs differ in the core vs. the shell, with α6*-nAChRs affecting DA release in the core, but not in the shell.

Concepts: Nicotine, Acetylcholine, Myasthenia gravis, Muscarinic acetylcholine receptor, Nicotinic acetylcholine receptor, Acetylcholine receptor, Dopamine, Mecamylamine

0

Nicotinic acetylcholine receptors (nAChRs), particularly the α7 nAChR, are implicated in the pathophysiology of both autism spectrum disorder (ASD) and aggressive behavior. We explored the feasibility, tolerability, and preliminary efficacy of targeting nAChRs using transdermal nicotine to reduce aggressive symptoms in adults with ASD. Eight subjects were randomized in a double-blind crossover trial of 7 mg transdermal nicotine or placebo, each for 1 week. All participants tolerated nicotine treatment well. Five subjects contributed data to the primary outcome, Aberrant Behavior Checklist-Irritability (ABC-I) subscale change from baseline, which was improved by nicotine compared to placebo. Sleep ratings were also improved by nicotine and correlated with ABC-I improvement. These findings support further investigation of nAChR agonists for aggression and sleep in ASD.

Concepts: Nicotine, Acetylcholine, Myasthenia gravis, Muscarinic acetylcholine receptor, Nicotinic acetylcholine receptor, Acetylcholine receptor, Neuromuscular junction, Mecamylamine

0

Inhaled cigarette smoke stimulated vagal bronchopulmonary C-fibers via an action of nicotine on neuronal nicotinic acetylcholine receptor (nAChR). Recent studies have reported that nicotine at high concentrations can also activate the transient receptor potential ankyrin 1 receptor (TRPA1) expressed in these sensory nerves. This study was carried out to characterize the airway response to inhaled nicotine aerosol and to investigate the relative roles of nAChR and TRPA1 in this response. Guinea pigs were anesthetized and mechanically ventilated; one tidal volume of nicotine aerosol (2% solution) was diluted by equal volume of air and delivered directly into the lung via a tracheal cannula in a single breath. Our results showed: 1) Inhalation of nicotine aerosol triggered an immediate and pronounced bronchoconstriction; the increase in total pulmonary resistance (RL) reached a peak of 588 {plus minus} 205% in 10-40 sec, which gradually returned to baseline after 1-5 min. 2) Pretreatment with either atropine (i.v.) or mecamylamine (aerosol) almost completely abolished the nicotine-induced bronchoconstriction; the mecamylamine pretreatment did not block the bronchoconstriction and bradycardia evoked by electrical stimulation of the distal end of one sectioned vagus nerve, indicating its minimal systemic effects. 3) Pretreatment with HC-030031, a selective TRPA1 antagonist, abolished the bronchoconstriction induced by allyl isothiocyanate, a selective TRPA1 agonist, but did not attenuate the nicotine-evoked bronchoconstriction. In conclusion, inhalation of a single breath of nicotine aerosol evoked acute bronchoconstriction mediated through the cholinergic reflex pathway. This reflex response was triggered by activation of nAChR, but not TRPA1, located in airway sensory nerves.

Concepts: Nicotine, Acetylcholine, Myasthenia gravis, Muscarinic acetylcholine receptor, Nicotinic acetylcholine receptor, Acetylcholine receptor, Atropine, Mecamylamine

0

Nicotine evokes chorda tympani (CT) taste nerve responses and an aversive behavior in Trpm5 knockout (KO) mice. The agonists and antagonists of nicotinic acetylcholine receptors (nAChRs) modulate neural and behavioral responses to nicotine in wildtype (WT) mice, Trpm5 KO mice and rats. This indicates that nicotine evokes bitter taste by activating a Trpm5-dependent pathway and a Trpm5-independent but nAChR-dependent pathway. Rat CT responses to ethanol are also partially inhibited by nAChR blockers, mecamylamine and dihydro-β-erythroidine. This indicates that a component of the bitter taste of ethanol is also nAChR-dependent. However, at present the expression and localization of nAChR subunits has not been investigated in detail in taste receptor cells (TRCs). To this end, in situ hybridization, immunohistochemistry and q-RT-PCR techniques were utilized to localize nAChR subunits in fungiform and circumvallate TRCs in WT mice, Trpm5-GFP transgenic mice, nAChR KO mice, and rats. The expression of mRNAs for α7, β2 and β4 nAChR subunits was observed in a subset of rat and WT mouse circumvallate and fungiform TRCs. Specific α3, α4, α7, β2, and β4 antibodies localized to a subset of WT mouse circumvallate and fungiform TRCs. In Trpm5-GFP mice α3, α4, α7, and β4 antibody binding was observed in a subset of Trpm5-positive circumvallate TRCs. Giving nicotine (100 μg/ml) in drinking water to WT mice for 3 weeks differentially increased the expression of α3, α4, α5, α6, α7, β2 and β4 mRNAs in circumvallate TRCs to varying degrees. Giving ethanol (5%) in drinking water to WT mice induced an increase in the expression of α5 and β4 mRNAs in circumvallate TRCs with a significant decrease in the expression of α3, α6 and β2 mRNAs. We conclude that nAChR subunits are expressed in Trpm5-positive TRCs and their expression levels are differentially altered by chronic oral exposure to nicotine and ethanol.

Concepts: Nicotine, Acetylcholine, Myasthenia gravis, Muscarinic acetylcholine receptor, Nicotinic acetylcholine receptor, Acetylcholine receptor, Ligand-gated ion channel, Mecamylamine

0

Nicotine acts as an agonist for nicotinic acetylcholine receptors (nAChRs), and mecamylamine, a nonselective nAChR antagonist, attenuates effects of nicotine on delay discounting in some rat strains; whether nicotine’s attenuation is specific to nAChR antagonism is unknown.

Concepts: Nicotine, Acetylcholine, Myasthenia gravis, Muscarinic acetylcholine receptor, Nicotinic acetylcholine receptor, Acetylcholine receptor, Neuromuscular junction, Mecamylamine

0

Determining neurobiological factors that contribute to individual variance in drug addiction vulnerability allows for identification of at-risk populations, use of preventative measures and personalized medicine in the treatment of substance use disorders. Rodents that exhibit high locomotor activity when exploring an inescapable novel environment (high-responder; HR) are more susceptible to the reinforcing effects of many abused compounds, including nicotine, as compared to animals that exhibit low locomotor activity (low-responder; LR). Given that nicotinic acetylcholine receptor (nAChR) modulation of reward-related dopamine signaling at accumbal dopamine terminals is critical for the acquisition of drug self-administration, we hypothesized that nAChR modulation of dopamine release would be predicted by an animal’s novelty response. Using voltammetry in the nucleus accumbens core of rats, we found that nicotine produced opposite effects in HR and LR animals on stimulation frequencies that model phasic dopamine release, whereby release magnitude was either augmented or attenuated, respectively. Further, nicotine suppressed stimulation frequencies that model tonic release in LR animals, but had no effect in HR animals. The differential effects of nicotine were likely due to desensitization of nAChRs, since the nAChR antagonists mecamylamine (non-selective, 2 μM), dihydro-beta-erythroidine (β2-selective, 500 nM), and α-conotoxin MII (α6-selective, 100 nM) produced effects similar to nicotine. Moreover, dihydro-beta-erythroidine failed to show differential effects in HR and LR rats when applied after α-conotoxin MII, suggesting a critical role of α6β2 compared non α6-containing nAChRs in the differential effects observed in these phenotypes. These results delineate a potential mechanism for individual variability in behavioral sensitivity to nicotine.

Concepts: Nicotine, Acetylcholine, Myasthenia gravis, Muscarinic acetylcholine receptor, Nicotinic acetylcholine receptor, Acetylcholine receptor, Dopamine, Mecamylamine

0

The strong reinforcing effects of nicotine and the negative symptoms such as anxiety experienced during a quit attempt often lead to relapse and low success rates for smoking cessation. Treatments that not only block the reinforcing effects of nicotine but also attenuate the motivation to relapse are needed to improve cessation rates. Recent genetic and preclinical studies have highlighted the involvement of the α3, β4, and α5 nicotinic acetylcholine receptor (nAChR) subunits and the α3β4 nAChR subtype in nicotine dependence and withdrawal. However, the involvement of these nAChR in relapse is not fully understood. We previously reported that the α3β4 nAChR partial agonist AT-1001 selectively decreases nicotine self-administration in rats without affecting food responding. In the present experiments, we examined the efficacy of AT-1001 in attenuating reinstatement of nicotine-seeking behavior in a model of stress-induced relapse. Rats extinguished from nicotine self-administration were treated with the pharmacological stressor yohimbine prior to AT-1001 treatment and reinstatement testing. We also examined whether AT-1001 produced any withdrawal-related effects when administered to nicotine-dependent rats. We found that AT-1001 dose-dependently reduced yohimbine stress-induced reinstatement of nicotine seeking. When administered to nicotine-dependent rats at the dose that significantly blocked nicotine reinstatement, AT-1001 elicited minimal somatic withdrawal signs in comparison to the nicotinic antagonist mecamylamine, which is known to produce robust withdrawal. Our data suggest that α3β4 nAChR-targeted compounds may be a promising approach for nicotine addiction treatment because they can not only block nicotine’s reinforcing effects, but also decrease motivation to relapse without producing significant withdrawal effects.

Concepts: Nicotine, Addiction, Acetylcholine, Muscarinic acetylcholine receptor, Nicotinic acetylcholine receptor, Acetylcholine receptor, Alpha-4 beta-2 nicotinic receptor, Mecamylamine

0

The nicotinic acetylcholine receptor antagonist, mecamylamine, is a potential novel pharmacotherapy for alcohol use disorder. The aims were to compare alcohol consumption between mecamylamine and placebo and test if smoking status modified treatment effects.

Concepts: Nicotine, Acetylcholine, Myasthenia gravis, Muscarinic acetylcholine receptor, Nicotinic acetylcholine receptor, Acetylcholine receptor, Ligand-gated ion channel, Mecamylamine