-
Scientific Reports Sep 2022Successful cholinergic-noradrenergic pharmacotherapy for obstructive sleep apnea (OSA) is thought to be due to effects at the hypoglossal motor nucleus (HMN). Clinical...
Successful cholinergic-noradrenergic pharmacotherapy for obstructive sleep apnea (OSA) is thought to be due to effects at the hypoglossal motor nucleus (HMN). Clinical efficacy varies with muscarinic-receptor (MR) subtype affinities. We hypothesized that oxybutynin (cholinergic agent in successful OSA pharmacotherapy) is an effective MR antagonist at the HMN and characterized its efficacy with other antagonists. We recorded tongue muscle activity of isoflurane anesthetized rats (121 males and 60 females, 7-13 per group across 13 protocols) in response to HMN microperfusion with MR antagonists with and without: (i) eserine-induced increased endogenous acetylcholine at the HMN and (ii) muscarine. Eserine-induced increased acetylcholine decreased tongue motor activity (p < 0.001) with lesser cholinergic suppression in females versus males (p = 0.017). Motor suppression was significantly attenuated by the MR antagonists atropine, oxybutynin, and omadacycline (MR2 antagonist), each p < 0.001, with similar residual activity between agents (p ≥ 0.089) suggesting similar efficacy at the HMN. Sex differences remained with atropine and oxybutynin (p < 0.001 to 0.05) but not omadacycline (p = 0.722). Muscarine at the HMN also decreased motor activity (p < 0.001) but this was not sex-specific (p = 0.849). These findings have translational relevance to antimuscarinic agents in OSA pharmacotherapy and understanding potential sex differences in HMN suppression with increased endogenous acetylcholine related to sparing nicotinic excitation.
Topics: Acetylcholine; Animals; Atropine; Female; Hypoglossal Nerve; Male; Muscarine; Muscarinic Antagonists; Physostigmine; Rats; Rats, Wistar; Sleep Apnea, Obstructive
PubMed: 36050440
DOI: 10.1038/s41598-022-19233-1 -
Science (New York, N.Y.) Jan 1988Immunocytochemical and electrophysiological evidence suggests that somatostatin may be a transmitter in the hippocampus. To characterize the ionic mechanisms underlying...
Immunocytochemical and electrophysiological evidence suggests that somatostatin may be a transmitter in the hippocampus. To characterize the ionic mechanisms underlying somatostatin effects, voltage-clamp and current-clamp studies on single CA1 pyramidal neurons in the hippocampal slice preparation were performed. Both somatostatin-28 and somatostatin-14 elicited a steady outward current and selectively augmented the noninactivating, voltage-dependent outward potassium current known as the M-current. Since the muscarinic cholinergic agonists carbachol and muscarine antagonized this current, these results suggest a reciprocal regulation of the M-current by somatostatin and acetylcholine.
Topics: Acetylcholine; Action Potentials; Animals; Carbachol; Cesium; Electric Conductivity; Hippocampus; Membrane Potentials; Muscarine; Neurons; Potassium; Rats; Somatostatin; Somatostatin-28
PubMed: 2892268
DOI: 10.1126/science.2892268 -
Helvetica Chimica Acta 1977
Topics: Basidiomycota; Glutamates; Muscarine
PubMed: 893124
DOI: 10.1002/hlca.19770600529 -
The Journal of the Royal College of... Mar 2018The mushroom Amanita muscaria (fly agaric) is widely distributed throughout continental Europe and the UK. Its common name suggests that it had been used to kill flies,...
The mushroom Amanita muscaria (fly agaric) is widely distributed throughout continental Europe and the UK. Its common name suggests that it had been used to kill flies, until superseded by arsenic. The bioactive compounds occurring in the mushroom remained a mystery for long periods of time, but eventually four hallucinogens were isolated from the fungus: muscarine, muscimol, muscazone and ibotenic acid. The shamans of Eastern Siberia used the mushroom as an inebriant and a hallucinogen. In 1912, Henry Dale suggested that muscarine (or a closely related substance) was the transmitter at the parasympathetic nerve endings, where it would produce lacrimation, salivation, sweating, bronchoconstriction and increased intestinal motility. He and Otto Loewi eventually isolated the transmitter and showed that it was not muscarine but acetylcholine. The receptor is now known variously as cholinergic or muscarinic. From this basic knowledge, drugs such as pilocarpine (cholinergic) and ipratropium (anticholinergic) have been shown to be of value in glaucoma and diseases of the lungs, respectively.
Topics: Acetylcholine; Amanita; Asthma; Cholinergic Antagonists; History, 16th Century; History, 17th Century; History, 19th Century; History, 20th Century; History, Ancient; Muscarine; Pilocarpine; Pilocarpus; Pulmonary Disease, Chronic Obstructive; Receptors, Cholinergic; Shamanism
PubMed: 29741535
DOI: 10.4997/JRCPE.2018.119 -
Pharmacological and functional characterization of muscarinic receptors in the frog pars intermedia.Endocrinology Aug 1998The secretion of alphaMSH from the intermediate lobe of the frog pituitary is regulated by multiple factors, including classical neurotransmitters and neuropeptides. In...
The secretion of alphaMSH from the intermediate lobe of the frog pituitary is regulated by multiple factors, including classical neurotransmitters and neuropeptides. In particular, acetylcholine (ACh), acting via muscarinic receptors, stimulates alphaMSH release from frog neurointermediate lobes (NILs) in vitro. The aim of the present study was to characterize the type of receptor and the transduction pathways involved in the mechanism of action of ACh on frog melanotrope cells. The nonselective muscarinic receptor agonists muscarine and carbachol both stimulated alphaMSH release from perifused frog NILs, whereas the M1-selective muscarinic agonist McN-A-343 was virtually devoid of effect. Both the M1>M3 antagonist pirenzepine and the M3>M1 antagonist 4-diphenylacetoxy-N-methylpiperidine methiodide inhibited muscarine-induced alphaMSH release. Administration of a brief pulse of muscarine in the vicinity of cultured melanotrope cells provoked a 4-fold increase in the cytosolic calcium concentration ([Ca2+]i). Suppression of Ca2+ in the culture medium or addition of 3 mM Ni2+ abrogated the stimulatory effect of muscarine on [Ca2+]i and alphaMSH release. In contrast, omega-conotoxin GVIA and nifedipine did not significantly reduce the stimulatory effect of muscarine on [Ca2+]i and alphaMSH secretion. Exposure of NILs to muscarine provoked an increase in inositol phosphate formation, and this effect was dependent on extracellular Ca2+. The inhibitor of polyphosphoinositide turnover neomycin significantly attenuated the muscarine-evoked alphaMSH release. Similarly, pretreatment of frog NILs with phorbol ester markedly reduced the secretory response to muscarine. In contrast, the stimulatory effect of muscarine on alphaMSH release was not affected by the phospholipase A2 inhibitor dimethyl eicosadienoic acid or by the tyrosine kinase inhibitors lavendustin A, genistein, and tyrphostin 25. Muscarine at a high concentration (10(-4) M) only produced a 40% increase in cAMP formation. Preincubation of frog NILs with pertussis toxin did not significantly affect the muscarine-induced stimulation of alphaMSH release. These results indicate that frog melanotrope cells express a muscarinic receptor subtype pharmacologically related to the mammalian M3 receptor. Activation of this receptor causes calcium influx through Ni2+-sensitive Ca2+ channels and subsequent activation of the phopholipase C/protein kinase C transduction pathway.
Topics: Acetylcholine; Animals; Calcium; Carbachol; Cyclic AMP; Enzyme Inhibitors; Inositol Phosphates; Male; Muscarine; Muscarinic Agonists; Muscarinic Antagonists; Pertussis Toxin; Piperidines; Pituitary Gland; Protein-Tyrosine Kinases; Rana ridibunda; Receptors, Muscarinic; Signal Transduction; Virulence Factors, Bordetella; alpha-MSH
PubMed: 9681504
DOI: 10.1210/endo.139.8.6164 -
Journal of Medicinal Chemistry Jul 1978Proton magnetic spectra have been recorded for muscarine and two biologically active cyclopentane analogues. In order to observe homonuclear intramolecular nuclear...
Proton magnetic spectra have been recorded for muscarine and two biologically active cyclopentane analogues. In order to observe homonuclear intramolecular nuclear Overhauser effects, the -N+(CH3)3 signal was irradiated and increases in integrated intensities for other key signals in the molecule were observed. The results indicate that the quaternary side chain in these compounds is in an extended conformation in aqueous solution.
Topics: Magnetic Resonance Spectroscopy; Molecular Conformation; Muscarine
PubMed: 671470
DOI: 10.1021/jm00205a028 -
Journal of the Autonomic Nervous System Dec 1997The concentration-dependence of the effect of muscarine on M-current (IM) and the underlying M-conductance (gM) in B-cells of bullfrog sympathetic ganglion was examined...
The concentration-dependence of the effect of muscarine on M-current (IM) and the underlying M-conductance (gM) in B-cells of bullfrog sympathetic ganglion was examined using whole-cell recording techniques. High concentrations of muscarine (> or = 200 nM) produced the classical suppression and over-recovery of steady-state IM at -30 mV. By contrast, low concentrations of muscarine (< or = 30 nM) shifted the gM activation curve to more negative potentials, increased the activation time constant (tau a) and increased steady-state IM. This effect may reflect muscarine-induced changes in submembrane Ca2+ concentration.
Topics: Adrenergic Fibers; Animals; Calcium Channels; Cell Membrane; Female; In Vitro Techniques; Male; Membrane Potentials; Muscarine; Muscarinic Agonists; Patch-Clamp Techniques; Rana catesbeiana; Receptors, Muscarinic
PubMed: 9470148
DOI: 10.1016/s0165-1838(97)00103-3 -
Neuroscience Letters May 1990Intracellular recordings were made from an isolated rat brain slice preparation containing the dorsolateral septal nucleus (DLSN). Calcium-dependent slow...
Intracellular recordings were made from an isolated rat brain slice preparation containing the dorsolateral septal nucleus (DLSN). Calcium-dependent slow afterdepolarizations (slow-ADPs) were observed in a population of neurons, which exhibited bursts of action potentials. Bath application of muscarine (10-20 microM) augmented the slow-ADP and triggered burst firing on top of the slow-ADP. This effect of muscarine was blocked by atropine (1 microM). Muscarine augmented the slowly decaying inward current (slow-ADC) recorded by voltage clamping the afterpotential of cathodally-evoked spikes. Our data suggest that some of the burst-like activity induced by muscarine in a select population of rat DLSN neurons is mediated partly by augmentation of the current which underlies the slow-ADP.
Topics: Animals; In Vitro Techniques; Male; Membrane Potentials; Muscarine; Rats; Rats, Inbred Strains; Septal Nuclei
PubMed: 2359521
DOI: 10.1016/0304-3940(90)90209-r -
Chemico-biological Interactions Mar 2013Although acetylcholinesterase (AChE) is primarily a hydrolytic enzyme, metabolising the neurotransmitter acetylcholine in cholinergic synapses, it also has some...
Although acetylcholinesterase (AChE) is primarily a hydrolytic enzyme, metabolising the neurotransmitter acetylcholine in cholinergic synapses, it also has some non-catalytic functions in the brain which are far less well characterised. AChE was shown to be secreted or shed from the neuronal cell surface like several other membrane proteins, such as the amyloid precursor protein (APP). Since AChE does not possess a transmembrane domain, its anchorage in the membrane is established via the Proline Rich Membrane Anchor (PRiMA), a transmembrane protein. Both the subunit oligomerisation and membrane anchor of AChE are shared by a related enzyme, butyrylcholinesterase (BChE), the physiological function of which in the brain is unclear. In this work, we have assayed the relative activities of AChE and BChE in membrane fractions and culture medium of three different neuronal cell lines, namely the neuroblastoma cell lines SH-SY5Y and NB7 and the mouse basal forebrain cell line SN56. In an effort to understand the shedding process of AChE, we have used several pharmacological treatments, which showed that it is likely to be mediated in part by an EDTA- and batimastat-sensitive, but GM6001-insensitive metalloprotease, with the possible additional involvement of a thiol isomerase. Cellular release of AChE by SH-SY5Y is significantly enhanced by the muscarinic acetylcholine receptor (mAChR) agonists carbachol or muscarine, with the effect of carbachol blocked by the mAChR antagonist atropine. AChE has been implicated in the pathogenesis of Alzheimer's disease and it has been shown that it accelerates formation and increases toxicity of amyloid fibrils, which have been closely linked to the pathology of AD. In light of this, greater understanding of AChE and BChE physiology may also benefit AD research.
Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Atropine; Butyrylcholinesterase; Carbachol; Cell Line; Cell Membrane; GPI-Linked Proteins; Humans; Metalloproteases; Mice; Muscarine; Muscarinic Agonists; Nerve Tissue Proteins; Neurons
PubMed: 23047022
DOI: 10.1016/j.cbi.2012.09.019 -
Experimental Brain Research Oct 2000Behavioral experiments were conducted to examine the role of the cholinergic receptor-agonist muscarine or its antagonist homatropine on the mating behavior of sexually...
Behavioral experiments were conducted to examine the role of the cholinergic receptor-agonist muscarine or its antagonist homatropine on the mating behavior of sexually experienced male rats. Male copulatory behavior was recorded after intrathecally administered saline, muscarine (7.5 microg), or homatropine (25 microg). Changes in copulatory behavior were assessed by the following parameters: intromission latency, intromission frequency, intercopulatory interval, ejaculation latency, and postejaculatory interval. Intromission frequency, intercopulatory interval, and ejaculation latency were decreased significantly by muscarine. Intrathecal homatropine decreased the number of copulating animals (five out of 13). In the five animals that were able to ejaculate after homatropine, intromission latency, intercopulatory interval, and ejaculation latency increased significantly. The effects of both drugs on locomotion were also tested. Muscarine induced no significant changes in locomotion compared with saline. A significant increase in locomotion was found after homatropine treatment. These results suggest that acetylcholine, acting at spinal-cord muscarinic receptors, may be involved in ejaculation.
Topics: Animals; Copulation; Ejaculation; Injections, Spinal; Male; Motor Activity; Muscarine; Parasympatholytics; Rats; Rats, Wistar; Reaction Time; Spinal Cord; Tropanes
PubMed: 11081831
DOI: 10.1007/s002210000488