-
British Journal of Pharmacology Jun 2018This themed section of the British Journal of Pharmacology is the product of a conference that focussed on nicotinic ACh receptors (nAChRs) that was held on the Greek...
UNLABELLED
This themed section of the British Journal of Pharmacology is the product of a conference that focussed on nicotinic ACh receptors (nAChRs) that was held on the Greek island of Crete from 7 to 11 May 2017. 'Nicotinic acetylcholine receptors 2017' was the fourth in a series of triennial international meetings that have provided a regular forum for scientists working on all aspects of nAChRs to meet and to discuss new developments. In addition to many of the regular participants, each meeting has also attracted a new group of scientists working in a fast-moving area of research. This themed section comprises both review articles and original research papers on nAChRs.
LINKED ARTICLES
This article is part of a themed section on Nicotinic Acetylcholine Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.11/issuetoc/.
Topics: Animals; Binding Sites; Humans; Models, Molecular; Nicotinic Antagonists; Receptors, Nicotinic
PubMed: 29878346
DOI: 10.1111/bph.14209 -
Neuroscience Aug 2021Although ionotropic glutamate receptors and nicotinic receptors for acetylcholine (ACh) have usually been studied separately, they are often co-localized and... (Review)
Review
Although ionotropic glutamate receptors and nicotinic receptors for acetylcholine (ACh) have usually been studied separately, they are often co-localized and functionally inter-dependent. The objective of this review is to survey the evidence for interactions between the two receptor families and the mechanisms underlying them. These include the mutual regulation of subunit expression, which change the NMDA:AMPA response balance, and the existence of multi-functional receptor complexes which make it difficult to distinguish between individual receptor sites, especially in vivo. This is followed by analysis of the functional relationships between the receptors from work on transmitter release, cellular electrophysiology and aspects of behavior where these can contribute to understanding receptor interactions. It is clear that nicotinic receptors (nAChRs) on axonal terminals directly regulate the release of glutamate and other neurotransmitters, α7-nAChRs generally promoting release. Hence, α7-nAChR responses will be prevented not only by a nicotinic antagonist, but also by compounds blocking the indirectly activated glutamate receptors. This accounts for the apparent anticholinergic activity of some glutamate antagonists, including the endogenous antagonist kynurenic acid. The activation of presynaptic nAChRs is by the ambient levels of ACh released from pre-terminal synapses, varicosities and glial cells, acting as a 'volume neurotransmitter' on synaptic and extrasynaptic sites. In addition, ACh and glutamate are released as CNS co-transmitters, including 'cholinergic' synapses onto spinal Renshaw cells. It is concluded that ACh should be viewed primarily as a modulator of glutamatergic neurotransmission by regulating the release of glutamate presynaptically, and the location, subunit composition, subtype balance and sensitivity of glutamate receptors, and not primarily as a classical fast neurotransmitter. These conclusions and caveats should aid clarification of the sites of action of glutamate and nicotinic receptor ligands in the search for new centrally-acting drugs.
Topics: Glutamic Acid; Nicotinic Antagonists; Receptors, Ionotropic Glutamate; Receptors, Nicotinic; alpha7 Nicotinic Acetylcholine Receptor
PubMed: 34111447
DOI: 10.1016/j.neuroscience.2021.06.007 -
British Journal of Pharmacology Jun 2018Over the past four decades, the patch clamp technique and nicotinic ACh (nACh) receptors have established an enduring partnership. Like all good partnerships, each... (Review)
Review
UNLABELLED
Over the past four decades, the patch clamp technique and nicotinic ACh (nACh) receptors have established an enduring partnership. Like all good partnerships, each partner has proven significant in its own right, while their union has spurred innumerable advances in life science research. A member and prototype of the superfamily of pentameric ligand-gated ion channels, the nACh receptor is a chemo-electric transducer, binding ACh released from nerves and rapidly opening its channel to cation flow to elicit cellular excitation. A subject of a Nobel Prize in Physiology or Medicine, the patch clamp technique provides unprecedented resolution of currents through single ion channels in their native cellular environments. Here, focusing on muscle and α7 nACh receptors, we describe the extraordinary contribution of the patch clamp technique towards understanding how they activate in response to neurotransmitter, how subtle structural and mechanistic differences among nACh receptor subtypes translate into significant physiological differences, and how nACh receptors are being exploited as therapeutic drug targets.
LINKED ARTICLES
This article is part of a themed section on Nicotinic Acetylcholine Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.11/issuetoc/.
Topics: Animals; Binding Sites; Humans; Models, Molecular; Nicotinic Antagonists; Patch-Clamp Techniques; Receptors, Nicotinic
PubMed: 28261794
DOI: 10.1111/bph.13770 -
Neuropharmacology May 2020Postsynaptic nAChRs in the peripheral nervous system are critical for neuromuscular and autonomic neurotransmission. Pre- and peri-synaptic nAChRs in the brain modulate... (Review)
Review
Postsynaptic nAChRs in the peripheral nervous system are critical for neuromuscular and autonomic neurotransmission. Pre- and peri-synaptic nAChRs in the brain modulate neurotransmission and are responsible for the addictive effects of nicotine. Subtypes of nAChRs in lymphocytes and non-synaptic locations may modulate inflammation and other cellular functions. All AChRs that function as ligand-gated ion channels are formed from five homologous subunits organized to form a central cation channel whose opening is regulated by ACh bound at extracellular subunit interfaces. nAChR subtype subunit composition can range from α7 homomers to α4β2α6β2β3 heteromers. Subtypes differ in affinities for ACh and other agonists like nicotine and in efficiencies with which their channels are opened and desensitized. Subtypes also differ in affinities for antagonists and for positive and negative allosteric modulators. Some agonists are "silent" with respect to channel opening, and AChRs may be able to signal metabotropic pathways by releasing G-proteins independent of channel opening. Electrophysiological studies that can resolve single-channel openings and molecular genetic approaches have allowed characterization of the structures of ligand binding sites, the cation channel, and the linkages between them, as well as the organization of AChR subunits and their contributions to function. Crystallography and cryo-electron-microscopy are providing increasing insights into the structures and functions of AChRs. However, much remains to be learned about both AChR structure and function, the in vivo functional roles of some AChR subtypes, and the development of better pharmacological tools directed at AChRs to treat addiction, pain, inflammation, and other medically important issues. This article is part of the special issue on 'Contemporary Advances in Nicotine Neuropharmacology'.
Topics: Animals; Binding Sites; Brain; Humans; Inflammation; Ligands; Nicotinic Agonists; Nicotinic Antagonists; Pain; Protein Structure, Secondary; Receptors, Nicotinic; Signal Transduction
PubMed: 32146229
DOI: 10.1016/j.neuropharm.2020.108021 -
Therapeutic Advances in Cardiovascular... Aug 2009Cigarette smoking remains an important risk factor for premature cardiovascular disease and its many complications. There are clear benefits from treating tobacco... (Review)
Review
Cigarette smoking remains an important risk factor for premature cardiovascular disease and its many complications. There are clear benefits from treating tobacco dependence on the rate of clinical outcomes. In addition to behavioral therapies, various pharmacologic strategies have been developed to help achieve this goal. First-line therapies include nicotine replacement, bupropion and varenicline, a partial nicotine antagonist. Second-line treatments include clonidine and nortriptyline. Additional treatment strategies with less proven efficacy include monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, opioid receptor antagonists, bromocriptine, anti-anxiety drugs, nicotinic receptor antagonists (e.g. mecamylamine) and glucose tablets. Various approaches under investigation include inhibitors of the hepatic P450 enzyme (e.g. methoxsalen), cannabinoid-1 receptor antagonists (e.g. rimonabant), and nicotine vaccines.
Topics: Cardiovascular Diseases; Drugs, Investigational; Humans; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Risk Factors; Smoking; Smoking Cessation; Smoking Prevention; Tobacco Use Disorder; Treatment Outcome
PubMed: 19491139
DOI: 10.1177/1753944709335754 -
Biochemical Pharmacology Oct 2019Identifying novel therapeutics for the treatment of substance use disorder (SUD) is an area of intensive investigation. Prior strategies that have attempted to modify... (Review)
Review
Identifying novel therapeutics for the treatment of substance use disorder (SUD) is an area of intensive investigation. Prior strategies that have attempted to modify one or a few neurotransmitter receptors have had limited success, and currently there are no FDA-approved medications for the treatment of cocaine, methamphetamine, and marijuana use disorders. Because drugs of abuse are known to alter the expression of numerous genes in reward-related brain regions, epigenetic-based therapies have emerged as intriguing targets for therapeutic innovation. Here, I evaluate potential therapeutic approaches and challenges in targeting epigenetic factors for the treatment of SUD and highlight examples of promising strategies and future directions.
Topics: Animals; Behavior, Addictive; Brain; Epigenesis, Genetic; Histone Deacetylase Inhibitors; Humans; Narcotic Antagonists; Nicotinic Antagonists; Substance-Related Disorders
PubMed: 31306644
DOI: 10.1016/j.bcp.2019.07.012 -
British Journal of Pharmacology Jan 2006Descriptions of the South American arrow poisons known as curares were reported by explorers in the 16th century, and their site of action in producing neuromuscular... (Review)
Review
Descriptions of the South American arrow poisons known as curares were reported by explorers in the 16th century, and their site of action in producing neuromuscular block was determined by Claude Bernard in the mid-19th century. Tubocurarine, the most important curare alkaloid, played a large part in experiments to determine the role of acetylcholine in neuromuscular transmission, but it was not until after 1943 that neuromuscular blocking drugs became established as muscle relaxants for use during surgical anaesthesia. Tubocurarine causes a number of unwanted effects, and there have been many attempts to replace it. The available drugs fall into two main categories: the depolarising blocking drugs and the nondepolarising blocking drugs. The former act by complex mixed actions and are now obsolete with the exception of suxamethonium, the rapid onset and brief duration of action of which remain useful for intubation at the start of surgical anaesthesia. The nondepolarising blocking drugs are reversible acetylcholine receptor antagonists. The main ones are the atracurium group, which possess a built-in self-destruct mechanism that makes them specially useful in kidney or liver failure, and the vecuronium group, which are specially free from unwanted side effects. Of this latter group, the compound rocuronium is of special interest because its rapid onset of action allows it to be used for intubation, and there is promise that its duration of action may be rapidly terminated by a novel antagonist, a particular cyclodextrin, that chelates the drug, thereby removing it from the acetylcholine receptors.
Topics: Animals; Atracurium; History, 16th Century; History, 19th Century; History, 20th Century; History, 21st Century; Humans; Muscle, Skeletal; Nerve Block; Neuromuscular Blocking Agents; Neuromuscular Depolarizing Agents; Neuromuscular Junction; Neuromuscular Nondepolarizing Agents; Nicotinic Antagonists; Receptors, Nicotinic; Synaptic Transmission; Tubocurarine; Vecuronium Bromide
PubMed: 16402115
DOI: 10.1038/sj.bjp.0706404 -
Molecular Brain Sep 2022Nicotinic acetylcholine receptors are thought to be associated with a wide range of phenomena, such as movement, learning, memory, attention, and addiction. However, the...
Systemic injection of nicotinic acetylcholine receptor antagonist mecamylamine affects licking, eyelid size, and locomotor and autonomic activities but not temporal prediction in male mice.
Nicotinic acetylcholine receptors are thought to be associated with a wide range of phenomena, such as movement, learning, memory, attention, and addiction. However, the causal relationship between nicotinic receptor activity and behavior remains unclear. Contrary to the studies that examined the functions of muscarinic acetylcholine receptors, the role of the nicotinic acetylcholine receptors on behavior has not been examined as extensively. Here, we examined the effects of intraperitoneal injection of mecamylamine, a nicotinic acetylcholine receptor antagonist, on the performance of male mice in a head-fixed temporal conditioning task and a free-moving open-field task. The head-fixed experimental setup allowed us to record and precisely quantify the licking response while the mice performed the behavioral task with no external cues. In addition, by combining the utility of the head-fixed experimental design with computer vision analysis based on deep learning algorithms, we succeeded in quantifying the eyelid size of awake mice. In the temporal conditioning task, we delivered a 10% sucrose solution every 10 s using a blunt-tipped needle placed within the licking distance of the mice. After the training, the mice showed increased anticipatory licking toward the timing of sucrose delivery, suggesting that the mice could predict the timing of the reward. Systemic injection of mecamylamine decreased licking behavior and caused eye closure but had no effect on learned conditioned predictive behavior in the head-fixed temporal conditioning task. In addition, the injection of mecamylamine decreased spontaneous locomotor activity in a dose-dependent manner in the free-moving open-field task. The results in the open-field experiments further revealed that the effect of mecamylamine on fecal output and urination, suggesting the effects on autonomic activities. Our achievement of successful eyelid size recording has potential as a useful approach in initial screening for drug discovery. Our study paves a way forward to understanding the role of nicotinic acetylcholine receptors on learning and behavior.
Topics: Animals; Dose-Response Relationship, Drug; Eyelids; Male; Mecamylamine; Mice; Nicotinic Antagonists; Receptors, Nicotinic; Sucrose
PubMed: 36068635
DOI: 10.1186/s13041-022-00959-y -
Marine Drugs Jun 2018Marine cone snails are a large family of gastropods that have evolved highly potent venoms for predation and defense. The cone snail venom has exceptional molecular... (Review)
Review
Marine cone snails are a large family of gastropods that have evolved highly potent venoms for predation and defense. The cone snail venom has exceptional molecular diversity in neuropharmacologically active compounds, targeting a range of receptors, ion channels, and transporters. These conotoxins have helped to dissect the structure and function of many of these therapeutically significant targets in the central and peripheral nervous systems, as well as unravelling the complex cellular mechanisms modulated by these receptors and ion channels. This review provides an overview of α-conotoxins targeting neuronal nicotinic acetylcholine receptors. The structure and activity of both classical and non-classical α-conotoxins are discussed, along with their contributions towards understanding nicotinic acetylcholine receptor (nAChR) structure and function.
Topics: Animals; Cell Membrane; Conotoxins; Conus Snail; Drug Delivery Systems; Molecular Conformation; Mollusk Venoms; Neurons; Nicotinic Agonists; Nicotinic Antagonists; Receptors, Nicotinic; Structure-Activity Relationship
PubMed: 29899286
DOI: 10.3390/md16060208 -
Molecules (Basel, Switzerland) Jun 2020Zebrafish is becoming a popular animal model in neuropharmacology and drug discovery, mainly due to its ease of handling and low costs involved in maintenance and...
Zebrafish is becoming a popular animal model in neuropharmacology and drug discovery, mainly due to its ease of handling and low costs involved in maintenance and experimental work. This animal displays a series of complex behaviours that makes it useful for assessing the effects of psychoactive drugs. Here, adult zebrafish were used for assessment of the anxiolytic and anti-addictive properties of UFR2709, a nicotinic receptor (nAChR) antagonist, using two behavioural paradigms to test for addiction, the novel tank diving test to assess anxiety and the conditioned place preference (CPP). Furthermore, the expression of nAChR subunits α4 and α7 was measured in the zebrafish brain. The results show that UFR2709 exhibits an anxiolytic effect on zebrafish and blocks the effect evoked by nicotine on CPP. Moreover, UFR2709 significantly decreased the expression of α4 nicotinic receptor subunit. This indicates that UFR2709 might be a useful drug for the treatment of nicotine addiction.
Topics: Animals; Anti-Anxiety Agents; Anxiety; Behavior, Animal; Benzoates; Disease Models, Animal; Nicotine; Nicotinic Antagonists; Pyrrolidines; Receptors, Nicotinic; Reward; Swimming; Zebrafish
PubMed: 32630020
DOI: 10.3390/molecules25132998