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1.
Elin Löf Peter Olausson Rosita Stomberg Jane R. Taylor Bo Söderpalm 《Psychopharmacology》2010,212(3):321-328
Rationale
We recently demonstrated that blocking specific nicotinic acetylcholine receptors (nAChRs) abolishes the conditioned reinforcing properties of ethanol-associated cues in rat, suggesting nAChRs as promising pharmacological targets for prevention of cue-induced relapse. 相似文献2.
Rationale
Alcohol and nicotine are commonly co-abused. Genetic correlations between responses to these drugs have been reported, providing evidence that common genes underlie the response to alcohol and nicotine. Nicotinic acetylcholine receptors (nAChRs) in the mesolimbic dopamine system are important in mediating nicotine response, and several studies suggest that alcohol may also interact with these nAChRs.Objective
The aim of this study was to examine the role of nAChRs containing α7 or β2 subunits in ethanol consumption.Methods
A two-bottle choice paradigm was used to determine ethanol consumption in wild-type and nAChR subunit knockout mice. Challenge studies were performed using the α4β2 nAChR partial agonist varenicline.Results
Mice lacking the β2 subunit consumed a similar amount of ethanol compared to their wild-type siblings in an ethanol-drinking paradigm. In contrast, mice lacking the α7 nAChR receptor subunit consumed significantly less ethanol than wild-type mice but consumed comparable amounts of water, saccharin, and quinine. In C57BL/6J mice, varenicline dose-dependently decreased ethanol consumption with a significant effect of 2 mg/kg, without affecting water or saccharin consumption. This effect of varenicline was not reversed in mice lacking either the α7 or β2 subunit, providing evidence that nAChRs containing one of these subunits are not required for this effect of varenicline.Conclusions
This study provides evidence that α7 nAChRs are involved in ethanol consumption and supports the idea that pharmacological manipulation of nAChRs reduces ethanol intake. Additional nAChRs may also be involved in ethanol intake, and there may be functional redundancy in the nicotinic control of alcohol drinking. 相似文献3.
Iku Tsutsui-Kimura Yu Ohmura Takeshi Izumi Taku Yamaguchi Takayuki Yoshida Mitsuhiro Yoshioka 《Psychopharmacology》2010,209(4):351-359
Rationale
Nicotine, a major addictive component of tobacco, has been suggested to provoke impulsivity by activating central α4β2 nicotinic acetylcholine receptors (nAChRs). Although lesion studies have demonstrated the involvement of the medial prefrontal cortex (mPFC) in impulsive action, the precise brain sites responsible for nicotine-induced impulsive action have not been identified. 相似文献4.
Caldarone BJ Wang D Paterson NE Manzano M Fedolak A Cavino K Kwan M Hanania T Chellappan SK Kozikowski AP Olivier B Picciotto MR Ghavami A 《Psychopharmacology》2011,217(2):199-210
Rationale
Nicotinic acetylcholine receptor (nAChR) agonists, partial agonists, and antagonists have antidepressant-like effects in rodents and reduce symptoms of depression in humans.Objectives
The study determined whether the antidepressant-like effect of the nAChR ??2* partial agonist sazetidine-A (sazetidine) in the forced swim test was due to activation or desensitization of ??2* nAChRs. The study also determined if sazetidine??s behavioral responses in the forced swim test corresponded to ??2* nAChRs receptor occupancy and drug bioavailability.Results
Acute antidepressant-like effects in the forced swim test were seen with sazetidine and the full ??2* agonist 5-I-A8350 (BALB/cJ mice) and the less selective ??2* partial agonist varenicline in C57BL/6J but not BALB/cJ mice. The role of ??2* nAChRs was confirmed by results showing: (1) reversal of sazetidine??s antidepressant-like effects in the forced swim test by nAChR antagonists mecamylamine and dihydro-??-erythroidine; (2) absence of sazetidine??s effect in mice lacking the ??2 subunit of the nAChR; and (3) a high correspondence between behaviorally active doses of sazetidine and ??2* receptor occupancy. ??2* receptor occupancy following acute sazetidine, varenicline, and 5-I-A8350 lasted beyond the duration of action in the forced swim test. Sazetidine??s long lasting receptor occupancy did not diminish behavioral efficacy in the forced swim test following repeated dosing.Conclusions
Results demonstrate that activation of a small population of ??2* nAChRs (10?C40%) is sufficient to elicit sazetidine??s antidepressant-like actions without producing tolerance and suggest that ligands that activate ??2* nAChRs would be promising targets for the development of a new class of antidepressant. 相似文献5.
HR Arias H Xing K MacDougall MP Blanton F Soti WR Kem 《British journal of pharmacology》2009,157(2):320-330
Background and purpose
Benzylidene-anabaseines (BAs) are partial agonists of the α7 nicotinic acetylcholine receptor (nAChR) but their mechanism(s) of action are unknown. Our study explores several possibilities, including direct interactions of BAs with the nAChR channel.Experimental approach
Functional and radioligand-binding assays were used to examine the interaction of two BA analogues, 3-(2,4-dimethoxybenzylidene)-anabaseine (DMXBA) and its primary metabolite 3-(4-hydroxy-2-methoxybenzylidene)-anabaseine (4OH-DMXBA) with both agonist and non-competitive antagonist (NCA)-binding sites on muscle-type nAChRs.Key results
Both BAs non-competitively inhibited ACh activation of human fetal muscle nAChRs and sterically inhibited the specific binding of the NCAs [piperidyl-3,4-3H(N)]-(N-(1-(2-thienyl)cyclohexyl)-3,4-piperidine ([3H]TCP) and [3H]dizocilpine to Torpedo nAChRs in the desensitized state. These compounds modulated [3H]tetracaine, [14C]amobarbital and [3H]TCP binding to resting nAChRs by allosteric mechanisms. Both BAs enhanced [3H]TCP binding when the nAChR was initially in the resting but activatable state, suggesting that both compounds desensitized the Torpedo nAChR. Although DMXBA failed to activate human fetal muscle nAChRs, 4OH-DMXBA was found to be a partial agonist. [3H]Nicotine competition-binding experiments confirmed that 4OH-DMXBA has higher affinity than DMXBA for the agonist sites, and that DMXBA is also a competitive antagonist.Conclusions and implications
3-(4-hydroxy-2-methoxybenzylidene)-anabaseine is a partial agonist for human fetal muscle nAChRs, whereas DMXBA only has competitive and NCA activities. The NCA-binding site for BAs overlaps both the phencyclidine-and dizocilpine-binding sites in the desensitized Torpedo nAChR ion channel. The desensitizing property of BAs suggests another possible mode of non-competitive inhibition in addition to direct channel-blocking mechanisms. 相似文献6.
Rationale
The prefrontal cortex (PFC) mediates executive functions, a set of control processes that optimize performance on cognitive tasks. It enables appropriate decision-making and mediates adapted behaviors, all processes impaired in psychiatric or degenerative disorders. Key players of normal functioning of the PFC are neurotransmitter (NT) systems arising from subcortical nuclei and targeting PFC subareas and, also, neuronal nicotinic acetylcholine receptors (nAChRs). These ion channels, located on multiple cell compartments in all brain areas, mediate direct cholinergic transmission and modulate the release of NTs that cross onto PFC neurons or interneurons. 相似文献7.
A Freysoldt J Fleckenstein PM Lang D Irnich P Grafe RW Carr 《British journal of pharmacology》2009,158(3):797-805
Background and purpose:
Amitriptyline is often prescribed as a first-line treatment for neuropathic pain but its precise mode of analgesic action remains uncertain. Amitriptyline is known to inhibit voltage-dependent ion channels and also to act as an antagonist at ligand-gated ion channels, such as nicotinic acetylcholine receptors (nAChRs). In the present study, we tested the effect of amitriptyline on nicotinic responses of unmyelinated axons in isolated segments of human peripheral nerve. In particular, a comparison was made between the concentrations of amitriptyline necessary for inhibition of nAChRs and those required for inhibition of the compound C-fibre action potential.Experimental approach:
Isolated axon fascicles were prepared from short segments of human sural nerve, and multiple measures of axonal excitability were recorded using computer-controlled threshold tracking software.Key results:
Amitriptyline (EC50 2.6 µM) reduced the nicotine-induced increase in C-fibre excitability but only slightly altered the amplitude and latency to onset of the compound action potential. In contrast, tetrodotoxin produced a clear reduction in the amplitude and a prolongation of action potential onset latency but was without effect on the nicotine-induced increase in axonal excitability.Conclusions and implications:
These data demonstrate that low concentrations of amitriptyline suppress the response of human peripheral C-type axons to nicotine by directly inhibiting nAChRs. Blockade of tetrodotoxin-sensitive, voltage-dependent sodium channels does not contribute to this effect. An inhibitory action of amitriptyline on nAChRs in unmyelinated nociceptive axons may be an important component of amitriptyline''s therapeutic effect in the treatment of neuropathic pain. 相似文献8.
A A Feduccia J A Simms D Mill H Y Yi S E Bartlett 《British journal of pharmacology》2014,171(14):3420-3431
BACKGROUND AND PURPOSE
Varenicline, a neuronal nicotinic acetylcholine receptor (nAChR) modulator, decreases ethanol consumption in rodents and humans. The proposed mechanism of action for varenicline to reduce ethanol consumption has been through modulation of dopamine (DA) release in the nucleus accumbens (NAc) via α4*-containing nAChRs in the ventral tegmental area (VTA). However, presynaptic nAChRs on dopaminergic terminals in the NAc have been shown to directly modulate dopaminergic signalling independently of neuronal activity from the VTA. In this study, we determined whether nAChRs in the NAc play a role in varenicline''s effects on ethanol consumption.EXPERIMENTAL APPROACH
Rats were trained to consume ethanol using the intermittent-access two-bottle choice protocol for 10 weeks. Ethanol intake was measured after varenicline or vehicle was microinfused into the NAc (core, shell or core-shell border) or the VTA (anterior or posterior). The effect of varenicline treatment on DA release in the NAc was measured using both in vivo microdialysis and in vitro fast-scan cyclic voltammetry (FSCV).KEY RESULTS
Microinfusion of varenicline into the NAc core and core-shell border, but not into the NAc shell or VTA, reduced ethanol intake following long-term ethanol consumption. During microdialysis, a significant enhancement in accumbal DA release occurred following systemic administration of varenicline and FSCV showed that varenicline also altered the evoked release of DA in the NAc.CONCLUSION AND IMPLICATIONS
Following long-term ethanol consumption, varenicline in the NAc reduces ethanol intake, suggesting that presynaptic nAChRs in the NAc are important for mediating varenicline''s effects on ethanol consumption. 相似文献9.
Rationale
Much evidence indicates that individuals use tobacco primarily to experience the psychopharmacological properties of nicotine. Varenicline, a partial ??4??2 nicotinic acetylcholine receptor (nAChR) agonist, is effective in reducing nicotine craving and relapse in smokers, suggesting that ??4??2 nAChRs may play a key role in nicotine dependence. In rats, the effect of varenicline on nicotine intake has only been studied with limited access to the drug, a model of the positive reinforcing effect of nicotine. Varenicline has not been tested on the increase in motivation to take nicotine in nicotine-dependent rats.Objectives
The present study evaluated the effects of varenicline on nicotine intake in rats with extended access to nicotine self-administration (23?h/day), a condition leading to the development of nicotine dependence. We hypothesized that varenicline??s effects on nicotine self-administration would be greater in rats with extended than limited access to the drug and after forced abstinence rather than during baseline self-administration.Results
Varenicline dose-dependently decreased nicotine self-administration in rats with limited (1?h/day) and extended (23?h/day) access. Despite an increased sensitivity to the motivational effects of abstinence on nicotine intake compared with limited-access rats, varenicline was equally effective in decreasing nicotine intake in dependent rats with extended access to nicotine.Conclusion
These results suggest that ??4??2 nAChRs are critical in mediating the positive reinforcing effects of nicotine but may not be a key element underlying the negative reinforcement process responsible for the increased nicotine intake after abstinence in dependent subjects. 相似文献10.
Robert Wickham Wojciech Solecki Liza Rathbun J. Michael McIntosh Nii A. Addy 《Psychopharmacology》2013,229(1):73-82
Rationale
Phasic dopamine (DA) signaling underlies reward learning. Cholinergic and glutamatergic inputs into the ventral tegmental area (VTA) are crucial for modulating burst firing activity and subsequent phasic DA release in the nucleus accumbens (NAc), but the specific VTA nicotinic receptor subtypes that regulate phasic DA release have not been identified.Objective
The goal was to determine the role of VTA N-methyl-d-aspartate receptors (NMDARs) and specific subtypes of nicotinic acetylcholine receptors (nAChRs) in regulating phasic DA release in the NAc core.Methods
Fast-scan cyclic voltammetry in anesthetized rats was combined with intra-VTA micro-infusion to evaluate the ability of glutamatergic and cholinergic drugs to modulate stimulated phasic DA release in the NAc core.Results
VTA NMDAR blockade with AP-5 decreased, while VTA NMDAR activation with NMDA increased NAc peak phasic DA release. Intra-VTA administration of the nonspecific nAChR antagonist mecamylamine produced a persistent decrease in phasic DA release. Infusion of the α6-selective antagonist α-conotoxin MII (α-ctx MII) produced a robust, but transient decrease in phasic DA, whereas infusion of selective doses of either the α4β2-selective antagonist, dihydro-beta-erythroidine, or the α7 antagonist, methyllycaconitine, had no effect. Co-infusion of AP-5 and α-ctx MII produced a similar phasic DA decrease as either drug alone, with no additive effect.Conclusions
The results suggest that VTA α6β2 nAChRs, but not α4β2 or α7 nAChRs, regulate phasic DA release in the NAc core and that VTA α6β2 nAChRs and NMDA receptors act at a common site or target to regulate NAc phasic DA signaling. 相似文献11.
Ellis JR Nathan PJ Villemagne VL Mulligan RS Saunder T Young K Smith CL Welch J Woodward M Wesnes KA Savage G Rowe CC 《Psychopharmacology》2009,202(1-3):79-91
Introduction
The nicotinic acetylcholine receptor (nAChR) system plays a regulatory role in a number of cognitive processes. Cholinesterase inhibitors (i.e., galantamine) that potentiate cholinergic neurotransmission improve cognitive function in Alzheimer’s disease (AD); however, the relationship between these effects and associated changes in nAChRs are yet to be established in vivo.Materials and methods
2-[18F]Fluoro-A-85380 (2-FA) binds to nAChRs and with positron emission tomography (PET) imaging provides a composite measure of receptor density and ligand affinity. This study aimed to: (1) quantify nAChRs in vivo in 15 drug-naïve patients with mild AD before and after chronic treatment with galantamine, using 2-FA and PET, and (2) examine the relationship between treatment-induced changes in nAChRs and improvements in cognitive function. Participants were nonsmokers and underwent extensive cognitive testing and a PET scan after injection of ~200 MBq of 2-FA on two occasions (before and after 12 weeks, galantamine treatment). A 3-day washout period preceded the second scan. Brain regional 2-FA binding was assessed through a simplified estimation of distribution volume (DVS).Results
Performance on global measures of cognition significantly improved following galantamine treatment (p?0.05). This improvement extended to specific cognitive measures of language and verbal learning. No significant differences in nAChR DVS before and after galantamine treatment were found. The treatment-induced improvement in cognition was not correlated with regional or global nAChR DVS, suggesting that changes in nAChRs may not be responsible for the improvements in cognition following galantamine in patients with mild AD. 相似文献12.
Luisa Ponzoni Daniela Braida Luca Pucci Donzelli Andrea Francesca Fasoli Irene Manfredi Roger L. Papke Clare Stokes Giuseppe Cannazza Francesco Clementi Cecilia Gotti Mariaelvina Sala 《Psychopharmacology》2014,231(24):4681-4693
Rationale
Cigarette smoking is one of the most serious health problems worldwide and people trying to stop smoking have high rates of relapse. Zebrafish (Danio rerio), by combining pharmacological and behavioral assays, is a promising animal model for rapidly screening new compounds to induce smoking cessation.Objectives
This study aims to identify possible acetylcholine nicotinic receptors (nAChRs) involved in mediating nicotine (NIC)-induced conditioned place preference (CPP) in zebrafish and investigate the effect of the CC4 and CC26 cytisine derivatives in reducing NIC-induced CPP.Methods
CPP was evaluated using a two-compartment chamber, and the zebrafish were given CC4 (0.001–5 mg/kg), CC26 (0.001–1 mg/kg), cytisine (0.1–2.5 mg/kg), and varenicline (1–10 mg/kg) alone or with NIC (0.001 mg/kg). Swimming activity was evaluated using a square observational chamber. The affinity of the nicotinic ligands for native zebrafish brain nAChRs was evaluated by binding studies using [3H]-Epibatidine (Epi) and [125I]-αBungarotoxin (αBgtx) radioligands, and their subtype specificity was determined by means of electrophysiological assay of oocyte-expressed α4β2 and α7 subtypes.Results
CC4 and CC26 induced CPP with an inverted U-shaped dose–response curve similar to that of NIC. However, when co-administered with NIC, they blocked its reinforcing or slightly aversive effect. Binding and electrophysiological studies showed that this effect was due to binding to high-affinity heteromeric but not α7-containing receptors.Conclusions
We have further characterized CC4 and identified a new compound (CC26) that may be active in inducing smoking cessation. Zebrafish is a very useful model for screening new compounds that can affect the rewarding properties of NIC. 相似文献13.
Ramón Sotomayor-Zárate Katia Gysling Usoa E. Busto Bruce K. Cassels Lutske Tampier María Elena Quintanilla 《Psychopharmacology》2013,227(2):287-298
Rationale
Neuronal nicotinic acetylcholine receptors (nAChRs) are pharmacological targets that have recently been implicated in the reinforcing effects of many drugs of abuse, including ethanol. Varenicline and cytisine are nAChR partial agonists in clinical use as smoking cessation aids. However, their efficacies to reduce alcohol consumption have not been fully studied.Objectives
This study aims to compare the effects of varenicline and cytisine on ethanol consumption by rats bred for many generations as high ethanol drinkers (UChB).Results
Repeated dosing (0.5 or 1.0 mg/kg/day?i.p.) of varenicline or cytisine, for three consecutive days, to male UChB rats pre-exposed to 10 % (v/v) ethanol and water 24 h/day for 4 weeks, significantly reduced alcohol intake and preference of ethanol over water during 1- and 24-h ethanol access periods. This effect was specific for ethanol intake and was not observed for 0.2 % saccharin or water consumption. Varenicline appears to be more effective than cytisine, probably due to its more favorable pharmacokinetic and pharmacodynamic properties. Long-term use of both nAChRs ligands for more than 8–10 days induced tolerance to their effects on ethanol consumption.Conclusions
This preclinical study in UChB rats demonstrated that both varenicline and cytisine reduce alcohol intake, with varenicline producing a greater and longer-lasting reduction than cytisine. However, dose adjustment will have to be considered as a possible way to counter tolerance arising after continued use. 相似文献14.
Tobey KM Walentiny DM Wiley JL Carroll FI Damaj MI Azar MR Koob GF George O Harris LS Vann RE 《Psychopharmacology》2012,223(2):159-168
Rationale
Alleviating addiction to tobacco products could prevent millions of deaths. Investigating novel compounds selectively targeting α4β2 nAChRs hypothesized to have a key role in the rewarding effects of nicotine may be a useful approach for future treatment.Objectives
The present study was designed to evaluate 2-fluoro-3-(4-nitrophenyl) deschloroepibatidine (4-nitro-PFEB), a potent competitive antagonist of neuronal α4β2 nAChRs, in several animal models related to nicotine reward: drug discrimination, intracranial self-stimulation (ICSS), conditioned place preference, and limited access to self-administration.Methods
Long Evans rats were trained in a two-lever discrimination procedure to discriminate 0.4 mg/kg nicotine (s.c.) from saline. Male Sprague–Dawley rats were stereotaxically implanted with electrodes and trained to respond for direct electrical stimulation of the medial forebrain bundle. ICR mice were evaluated using an unbiased place preference paradigm, and finally, male Wistar rats were implanted with intrajugular catheters and tested for nicotine self-administration under limited access (1 h/day).Results
4-Nitro-PFEB attenuated the discriminative stimulus effects of nicotine, but alone did not produce nicotine-like discriminative stimulus effects. Nicotine-induced facilitation of ICSS reward thresholds was reversed by 4-nitro-PFEB, which alone had no effect on thresholds. 4-Nitro-PFEB also blocked the conditioned place preference produced by nicotine, but alone had no effect on conditioned place preference. Finally, 4-nitro-PFEB dose-dependently decreased nicotine self-administration.Conclusions
These results support the hypothesis that neuronal α4β2 nAChRs play a key role in mediating the rewarding effects of nicotine and further suggest that targeting α4β2 nAChRs may yield a potential candidate for the treatment of nicotine dependence. 相似文献15.
Andrea Cippitelli Jinhua Wu Kelly A Gaiolini Daniela Mercatelli Jennifer Schoch Michelle Gorman Alejandra Ramirez Roberto Ciccocioppo Taline V Khroyan Dennis Yasuda Nurulain T Zaveri Conrado Pascual Xinmin Xie Lawrence Toll 《British journal of pharmacology》2015,172(7):1834-1845
Background and Purpose
The α3β4 subtype of nicotinic acetylcholine receptors (nAChRs) has been implicated in mediating nicotine reinforcement processes. AT-1001 has been recently described as a high-affinity and selective α3β4 nAChR antagonist that blocks nicotine self-administration in rats. The aim of this study was to investigate the mechanism of action underlying the nicotine-suppressive effects of AT-1001.Experimental Approach
Effects of AT-1001 were determined using in vitro assays and rat models of nicotine addiction, and compared with varenicline.Key Results
AT-1001 and its analogue AT-1012 were functionally selective as antagonists for α3β4 over α4β2 nAChRs, but not to the same extent as the binding selectivity, and had partial agonist activity at α3β4 nAChRs. In contrast, varenicline was a partial agonist at α4β2, a weak agonist at α3β4 and inhibited α4β2 at a much lower concentration than it inhibited α3β4 nAChRs. AT-1001 and varenicline also had very different in vivo properties. Firstly, AT-1001 did not exhibit reinforcing properties per se while varenicline was self-administered. Secondly, systemic treatment with AT-1001 did not induce reinstatement of nicotine seeking but rather attenuated reinstatement induced by varenicline, as well as nicotine. Finally, unlike varenicline, AT-1001 selectively blocked nicotine self-administration without altering alcohol lever pressing as assessed in an operant co-administration paradigm.Conclusions and Implications
These findings describe a more complex AT-1001 in vitro profile than previously appreciated and provide further support for the potential of AT-1001 and congeners as clinically useful compounds for smoking cessation, with a mechanism of action distinct from currently available medications. 相似文献16.
Suarez SV Amadon A Giacomini E Wiklund A Changeux JP Le Bihan D Granon S 《Psychopharmacology》2009,202(4):599-610
Rationale
The behavioral effects of nicotine and the role of the beta2-containing nicotinic receptors in these behaviors are well documented. However, the behaviors altered by nicotine rely on the functioning on multiple brain circuits where the high-affinity beta2-containing nicotinic receptors (β2*nAChRs) are located.Objectives
We intend to see which brain circuits are activated when nicotine is given in animals naïve for nicotine and whether the β2*nAChRs are needed for its activation of the blood oxygen level dependent (BOLD) signal in all brain areas.Materials and methods
We used functional magnetic resonance imaging (fMRI) to measure the brain activation evoked by nicotine (1 mg/kg delivered at a slow rate for 45 min) in anesthetized C57BL/6J mice and beta2 knockout (KO) mice.Results
Acute nicotine injection results in a significant increased activation in anterior frontal, motor, and somatosensory cortices and in the ventral tegmental area and the substantia nigra. Anesthetized mice receiving no nicotine injection exhibited a major decreased activation in all cortical and subcortical structures, likely due to prolonged anesthesia. At a global level, beta2 KO mice were not rescued from the globally declining BOLD signal. However, nicotine still activated regions of a meso-cortico-limbic circuit likely via alpha7 nicotinic receptors.Conclusions
Acute nicotine exposure compensates for the drop in brain activation due to anesthesia through the meso-cortico-limbic network via the action of nicotine on β2*nAChRs. The developed fMRI method is suitable for comparing responses in wild-type and mutant mice.17.
The analog of epibatidine having a fluoro substituent at the 3′ position of the pyridine ring has been recently developed and shown to possess binding affinity in the pM range to α4β2 nAChRs and in the nM range to α7 nAChRs and to exhibit potent agonist activity in nicotine-induced analgesia tests. Here we used patch-clamp technique in a whole-cell configuration to compare functional activity of 3′-fluoroepibatidine to that of epibatidine by itself on recombinant α4β2, α7 and α3β4 neuronal nAChRs. The agonist effect of (±)-epibatidine was partial and yielded comparable EC50s of 0.012 μM (72% efficacy) and 0.027 μM (81% efficacy) at α4β2 and α3β4 nAChRs, respectively, but was full at α7 nAChRs with an EC50 of 4.8 μM. Testing of the analog at different concentrations revealed that it acts as a full agonist with an EC50 of 0.36 μM at α4β2 nAChRs and induces partial agonist effect (66% efficacy) at α7 nAChRs with an EC50 of 9.8 μM and an IC50 corresponding to 225 μM. In contrast, the analog caused only 24% maximal activation at the range of concentrations from 0.1 to 100 μM and, in addition, induced an inhibition of α3β4 nAChR function with an IC50 of 8.3 μM. Our functional data, which are in agreement with previous binding and behavioral findings, demonstrate that 3′-fluoro substitution in the pyridine ring of epibatidine results in an improved pharmacological profile as observed by an increased efficacy and selectivity for α4β2 versus α3β4 nAChRs. 相似文献
18.
Frank G. Boess Jean de Vry Christina Erb Timo Flessner Martin Hendrix Joachim Luithle Christoph Methfessel Katrin Schnizler F. Josef van der Staay Marja van Kampen Welf-Burkhard Wiese Gerhard König 《Psychopharmacology》2013,227(1):1-17
Rationale and objective
Agonists of α7 nicotinic acetylcholine receptors (nAChRs) may have therapeutic potential for the treatment of cognitive deficits. This study describes the in vitro pharmacology of the novel α7 nAChR agonist/serotonin 5-HT3 receptor (5-HT3R) antagonist N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-chinolincarboxamide (EVP-5141) and its behavioral effects.Results
EVP-5141 bound to α7 nAChRs in rat brain membranes (K i ?=?270 nM) and to recombinant human serotonin 5-HT3Rs (K i ?=?880 nM) but had low affinity for α4β2 nAChRs (K i ?>?100 μM). EVP-5141 was a potent agonist at recombinant rat and human α7 nAChRs expressed in Xenopus oocytes. EVP-5141 acted as 5-HT3R antagonist but did not block α3β4, α4β2, and muscle nAChRs. Rats trained to discriminate nicotine from vehicle did not generalize to EVP-5141 (0.3–30 mg kg?1, p.o.), suggesting that the nicotine cue is not mediated by the α7 nAChR and that EVP-5141 may not share the abuse liability of nicotine. EVP-5141 (0.3–3 mg kg?1) improved performance in the rat social recognition test. EVP-5141 (0.3 mg kg?1, p.o.) ameliorated scopolamine-induced retention deficits in the passive avoidance task in rats. EVP-5141 (1 mg kg?1, i.p.) improved spatial working memory of aged (26- to 32-month-old) rats in a water maze repeated acquisition task. In addition, EVP-5141 improved both object and social recognition memory in mice (0.3 mg kg?1, p.o.).Conclusions
EVP-5141 improved performance in several learning and memory tests in both rats and mice, supporting the hypothesis that α7 nAChR agonists may provide a novel therapeutic strategy for the treatment of cognitive deficits in Alzheimer's disease or schizophrenia. 相似文献19.
Methadone is a Non‐Competitive Antagonist at the α4β2 and α3* Nicotinic Acetylcholine Receptors and an Agonist at the α7 Nicotinic Acetylcholine Receptor
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Reeta Talka Outi Salminen Raimo K. Tuominen 《Basic & clinical pharmacology & toxicology》2015,116(4):321-328
Nicotine–methadone interactions have been studied in human beings and in various experimental settings regarding addiction, reward and pain. Most methadone maintenance treatment patients are smokers, and methadone administration has been shown to increase cigarette smoking. Previous in vitro studies have shown that methadone is a non‐competitive antagonist at rat α3β4 nicotinic acetylcholine receptors (nAChR) and an agonist at human α7 nAChRs. In this study, we used cell lines expressing human α4β2, α7 and α3* nAChRs to compare the interactions of methadone at the various human nAChRs under the same experimental conditions. A [3H]epibatidine displacement assay was used to determine whether methadone binds to the nicotinic receptors, and 86Rb+ efflux and changes in intracellular calcium [Ca2+]i were used to assess changes in the functional activity of the receptors. Methadone displaced [3H]epibatidine from nicotinic agonist‐binding sites in SH‐EP1‐hα7 and SH‐SY5Y cells, but not in SH‐EP1‐hα4β2 cells. The Ki values for methadone were 6.3 μM in SH‐EP1‐hα7 cells and 19.4 μM and 1008 μM in SH‐SY5Y cells. Methadone increased [Ca2+]i in all cell lines in a concentration‐dependent manner, and in SH‐EP1‐hα7 cells, the effect was more pronounced than the effect of nicotine treatment. In SH‐EP1‐hα4β2 cells, the effect of methadone was negligible compared to that of nicotine. Methadone pre‐treatment abolished the nicotine‐induced response in [Ca2+]i in all cell lines expressing nAChRs. In SH‐EP1‐hα4β2 and SH‐SY5Y cells, methadone had no effect on the 86Rb+ efflux, but it antagonized the nicotine‐induced 86Rb+ ion efflux in a non‐competitive manner. These results suggest that methadone is an agonist at human α7 nAChRs and a non‐competitive antagonist at human α4β2 and α3* nAChRs. This study adds further support to the previous findings that opioids interact with nAChRs, which may underlie their frequent co‐administration in human beings and might be of interest to the field of drug discovery. 相似文献
20.
H Rollema A Shrikhande KM Ward FD Tingley III JW Coe BT O'Neill E Tseng EQ Wang RJ Mather RS Hurst KE Williams M de Vries T Cremers S Bertrand D Bertrand 《British journal of pharmacology》2010,160(2):334-345