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Neurochemical Research Oct 2014Muscimol, a psychoactive isoxazole from Amanita muscaria and related mushrooms, has proved to be a remarkably selective agonist at ionotropic receptors for the... (Review)
Review
Muscimol, a psychoactive isoxazole from Amanita muscaria and related mushrooms, has proved to be a remarkably selective agonist at ionotropic receptors for the inhibitory neurotransmitter GABA. This historic overview highlights the discovery and development of muscimol and related compounds as a GABA agonist by Danish and Australian neurochemists. Muscimol is widely used as a ligand to probe GABA receptors and was the lead compound in the development of a range of GABAergic agents including nipecotic acid, tiagabine, 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol, (Gaboxadol(®)) and 4-PIOL.
Topics: GABA Agonists; Muscimol
PubMed: 24473816
DOI: 10.1007/s11064-014-1245-y -
International Journal of Medicinal... 2023Herbal products found in nature can serve as great systems of study for drug design. The Amanita muscaria mushroom is native to many parts of the Northern Hemisphere and... (Review)
Review
Psychoactive Isoxazoles, Muscimol, and Isoxazole Derivatives from the Amanita (Agaricomycetes) Species: Review of New Trends in Synthesis, Dosage, and Biological Properties.
Herbal products found in nature can serve as great systems of study for drug design. The Amanita muscaria mushroom is native to many parts of the Northern Hemisphere and has a very distinctive appearance with its red cap and white spotted warts. The mushroom comprises several pharmacologically active alkaloids, including muscazone, muscarine, ibotenic acid, and muscimol, the latter two compounds being potent GABA agonists. Muscimol has served as a backbone in the design of GABA agonists devoid of effects on the GABA-metabolizing enzyme, GABA transaminase, and GABA uptake systems. In this sense, several analogs of muscimol have been synthesized and studied including THIP, THPO, iso-THIP, iso-THAZ and 4-PIOL which all interact with the GABA receptors much differently. The growing pharmacological and toxicological interest based on many conflicting opinions on the use of the neuroprotective role of muscimol analogs against some neurodegenerative diseases, its potent role in the treatment of cerebral ischemia and other socially significant health conditions provided the basis for this review.
Topics: Muscimol; Amanita; Isoxazoles; GABA Agonists; gamma-Aminobutyric Acid
PubMed: 37824402
DOI: 10.1615/IntJMedMushrooms.2023049458 -
Reviews in Pure & Applied... 1982
Review
Topics: Animals; Brain; Chemical Phenomena; Chemistry; Cyclic AMP; Cyclic GMP; Extrapyramidal Tracts; Feeding Behavior; Glutamates; Glutamic Acid; Humans; Muscimol; Oxazoles; Receptors, Cell Surface; Receptors, GABA-A; Seizures; Subcellular Fractions; gamma-Aminobutyric Acid
PubMed: 6130573
DOI: No ID Found -
Neurochemical Research Oct 1980Muscimol has been used to increase our knowledge of central GABAergic systems, CNS physiology, and behavior. Some studies concerning the neurophysiological and... (Review)
Review
Muscimol has been used to increase our knowledge of central GABAergic systems, CNS physiology, and behavior. Some studies concerning the neurophysiological and behavioral effects of muscimol and its analogs have been reviewed and analyzed. In vivo iontophoretic studies have greatly increased our knowledge of the active conformation(s) adopted by GABA during its interaction with neuronal synaptic (or extrasynaptic) receptors, and behavioral studies have supported the notion that central GABAergic systems might be involved in convulsions, extrapyramidal functions, and other behaviors. However, behavioral studies with muscimol remain difficult to interpret in terms of central GABAergic systems, especially since muscimol is extensively metabolized and since it appears to interact with membrane sites other than GABA receptors. Muscimol does not appear to be useful for reversing human neurologic-psychiatric disorders.
Topics: Animals; Behavior; Behavior, Animal; Blood-Brain Barrier; Dopamine; Feeding Behavior; Humans; Learning; Memory; Muscimol; Oxazoles; Receptors, Cell Surface; Receptors, GABA-A; Seizures; gamma-Aminobutyric Acid
PubMed: 6258091
DOI: 10.1007/BF00966163 -
Therapeutic Drug Monitoring Aug 2013Psychoactive drugs of fungal origin, psilocin, ibotenic acid, and muscimol among them have been proposed for recreational use and popularized since the 1960s, XX... (Review)
Review
Psychoactive drugs of fungal origin, psilocin, ibotenic acid, and muscimol among them have been proposed for recreational use and popularized since the 1960s, XX century. Despite their well-documented neurotoxicity, they reached reputation of being safe and nonaddictive. Scientific efforts to find any medical application for these hallucinogens in psychiatry, psychotherapy, and even for religious rituals support are highly controversial. Even if they show any healing potential, their usage in psychotherapy is in some cases inadequate and may additionally harm seriously suffering patients. Hallucinogens are thought to reduce cognitive functions. However, in case of indolealkylamines, such as psilocin, some recent findings suggest their ability to improve perception and mental skills, what would motivate the consumption of "magic mushrooms." The present article offers an opportunity to find out what are the main symptoms of intoxication with mushrooms containing psilocybin/psilocin, muscimol, and ibotenic acid. The progress in analytical methods for detection of them in fungal material, food, and body fluids is reviewed. Findings on the mechanisms of their biologic activity are summarized. Additionally, therapeutic potential of these fungal psychoactive compounds and health risk associated with their abuse are discussed.
Topics: Agaricales; Animals; Body Fluids; Hallucinogens; Humans; Ibotenic Acid; Muscimol; Psilocybin
PubMed: 23851905
DOI: 10.1097/FTD.0b013e31828741a5 -
Journal of Neurochemistry Apr 2019Muscimol, the major psychoactive ingredient in the mushroom Amanita muscaria, has been regarded as a universal non-selective GABA-site agonist. Deletion of the GABA...
Muscimol, the major psychoactive ingredient in the mushroom Amanita muscaria, has been regarded as a universal non-selective GABA-site agonist. Deletion of the GABA receptor (GABA R) δ subunit in mice (δKO) leads to a drastic reduction in high-affinity muscimol binding in brain sections and to a lower behavioral sensitivity to muscimol than their wild type counterparts. Here, we use forebrain and cerebellar brain homogenates from WT and δKO mice to show that deletion of the δ subunit leads to a > 50% loss of high-affinity 5 nM [ H]muscimol-binding sites despite the relatively low abundance of δ-containing GABA Rs (δ-GABA R) in the brain. By subtracting residual high-affinity binding in δKO mice and measuring the slow association and dissociation rates we show that native δ-GABA Rs in WT mice exhibit high-affinity [ H]muscimol-binding sites (K ~1.6 nM on α4βδ receptors in the forebrain and ~1 nM on α6βδ receptors in the cerebellum at 22°C). Co-expression of the δ subunit with α6 and β2 or β3 in recombinant (HEK 293) expression leads to the appearance of a slowly dissociating [ H]muscimol component. In addition, we compared muscimol currents in recombinant α4β3δ and α4β3 receptors and show that δ subunit co-expression leads to highly muscimol-sensitive currents with an estimated EC of around 1-2 nM and slow deactivation kinetics. These data indicate that δ subunit incorporation leads to a dramatic increase in GABA R muscimol sensitivity. We conclude that biochemical and behavioral low-dose muscimol selectivity for δ-subunit-containing receptors is a result of low nanomolar-binding affinity on δ-GABA Rs.
Topics: Animals; Brain; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscimol; Protein Binding; Receptors, GABA-A
PubMed: 30565258
DOI: 10.1111/jnc.14646 -
Journal of Psychopharmacology (Oxford,... Dec 2020Previous studies suggest that trace conditioning depends on the anterior cingulate cortex (ACC). To examine the role of ACC in trace fear conditioning further, 48 rats...
Previous studies suggest that trace conditioning depends on the anterior cingulate cortex (ACC). To examine the role of ACC in trace fear conditioning further, 48 rats were surgically prepared for infusion with saline or 62.5 or 125 µg/side muscimol to inactivate ACC reversibly prior to conditioning. A noise stimulus was followed by a 1 mA footshock, with or without a 10-second trace interval between these events in a conditioned suppression procedure. The trace-conditioned groups (10 seconds) showed less test suppression than the control-conditioned groups (0 seconds). Counter to prediction, there was no effect of muscimol infusion on suppression to the noise stimulus in the 10-second trace groups.
Topics: Animals; Association Learning; Behavior, Animal; Conditioning, Classical; Fear; GABA Agonists; Gyrus Cinguli; Male; Muscimol; Rats; Rats, Wistar
PubMed: 33161817
DOI: 10.1177/0269881120965914 -
Science Progress 2022Numbers are one of the three basic concepts of human abstract thinking. When human beings count, they often point to things, one by one, and read numbers in a positive...
Numbers are one of the three basic concepts of human abstract thinking. When human beings count, they often point to things, one by one, and read numbers in a positive integer column. The prefrontal cortex plays a wide range of roles in executive functions, including active maintenance and achievement of goals, adaptive coding and exertion of general intelligence, and completion of time complexity events. Nonhuman animals do not use number names, such as "one, two, three," or numerals, such as "1, 2, 3" to "count" in the same way as humans do. Our previous study established an animal model of counting in monkeys. Here, we used this model to determine whether the prefrontal cortex participates in counting in monkeys. Two 5-year-old female rhesus monkeys (macaques), weighing 5.0 kg and 5.5 kg, were selected to train in a counting task, counting from 1 to 5. When their counting task performance stabilized, we performed surgery on the prefrontal cortex to implant drug delivery tubes. After allowing the monkeys' physical condition and counting performance to recover, we injected either muscimol or normal saline into their dorsal and ventral prefrontal cortex. Thereafter, we observed their counting task performance and analyzed the error types and reaction time during the counting task. The monkeys' performance in the counting task decreased significantly after muscimol injection into the ventral prefrontal cortex; however, it was not affected after saline injection into the ventral prefrontal cortex, or after muscimol or saline injection into the dorsal prefrontal cortex. The ventral prefrontal cortex of the monkey is necessary for counting performance.
Topics: Animals; Female; Humans; Adult; Macaca mulatta; Muscimol; Prefrontal Cortex; Executive Function; Disease Models, Animal
PubMed: 36443989
DOI: 10.1177/00368504221141660 -
Neurosurgery Jul 2019Minimally invasive therapies for drug-resistant epilepsy (DRE) have been advocated. A study of convection-enhanced delivery (CED) of muscimol, a GABAA receptor agonist,...
BACKGROUND
Minimally invasive therapies for drug-resistant epilepsy (DRE) have been advocated. A study of convection-enhanced delivery (CED) of muscimol, a GABAA receptor agonist, was previously completed in non-human primates.
OBJECTIVE
To investigate the safety and anti-epileptic effects of intracerebral muscimol infusion into the epileptic focus of patients with DRE.
METHODS
In this phase 1 clinical trial, 3 adult patients with DRE underwent CED into the seizure focus of artificial CSF vehicle followed by muscimol for 12 to 24 h each using a crossover design. Basic pathophysiology of the epileptic focus was examined by assessing the infusions' effects on seizure frequency, electroencephalogram (EEG) spike-wave activity, and power-spectral EEG frequency.
RESULTS
Inter-ictal neurological function remained normal in all patients. Pathological examination of resected specimens showed no infusion-related brain injuries. Seizure frequency decreased in 1 of 3 patients during muscimol infusion but was unchanged in all patients during vehicle infusion. Mean beta frequencies did not differ significantly before, during, or after infusion periods. Infused fluid provided insufficient MRI-signal to track infusate distribution. In the 2 yr after standard epilepsy surgery, 1 patient had temporary reduction in seizure frequency and 2 patients were seizure-free.
CONCLUSION
CED of muscimol into the epileptic focus of patients with DRE did not damage adjacent brain parenchyma or adversely affect seizure surgery outcome. This study did not confirm that intracerebral muscimol infusion effectively suppressed seizures. A surrogate tracer is recommended to track infusion distribution to the epileptic focus and surrounding structures in future studies using CED to suppress the seizure focus.
Topics: Adult; Anticonvulsants; Brain; Convection; Drug Resistant Epilepsy; Female; Humans; Infusions, Intraventricular; Magnetic Resonance Imaging; Male; Muscimol
PubMed: 30407567
DOI: 10.1093/neuros/nyy480 -
Neural Plasticity 2000Reversible inactivation of brain areas is a useful method for inferring brain-behavior relationships. Infusion of GABA or of the GABA receptor agonist muscimol is... (Review)
Review
Reversible inactivation of brain areas is a useful method for inferring brain-behavior relationships. Infusion of GABA or of the GABA receptor agonist muscimol is considered one interesting reversible inactivation method because it may not affect fibers of passage and may therefore be compared to axon-sparing types of lesions. This article reviews the data obtained with this method in learning and memory experiments. A critical analysis of data, collected in collaboration with Simon Brailowsky, with chronic GABA infusion is presented, together with an illustration of data obtained with muscimol-induced inactivation.
Topics: Animals; Brain; GABA Agonists; Learning; Memory; Muscimol; gamma-Aminobutyric Acid
PubMed: 10709211
DOI: 10.1155/NP.2000.19