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Canadian Journal of Physiology and... Jul 2022Systemic inflammatory response syndrome plays an important role in the development of sepsis. GABAergic and cholinergic pathways activation are considered important for...
Systemic inflammatory response syndrome plays an important role in the development of sepsis. GABAergic and cholinergic pathways activation are considered important for inflammatory response regulation. Tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-12, IL-10, as well as inducible nitric oxide synthase (iNOS)-derived nitric oxide (NO) are important inflammatory mediators involved in the pathogenesis of sepsis. Muscimol, an active compound from the mushroom (L.) Lam., is a potent GABA agonist, inhibits inflammatory response via activating GABA receptor and vagus nerve. However, the effect of muscimol on lipopolysaccharide (LPS)-induced systemic inflammatory response is still unclear. Therefore, we studied the effects of muscimol on systemic inflammatory response and survival rate in endotoxemic mice. Mice endotoxemia was induced by LPS. Muscimol was given to mice or RAW264.7 cells 30 min before LPS (10 mg/kg, i.p., or 10 ng/mL, respectively). Mice received GABAergic and cholinergic receptor antagonists 30 min before muscimol and LPS. Muscimol decreased TNF-α, IL-1β, IL-12, iNOS-derived NO, and increased IL-10 levels and survival rate after LPS treatment. Muscimol significantly decreased nuclear factor kappa B (NF-κB) activity, increased IκB expression, and decreased IKK expression in LPS-treated RAW264.7 cells. GABAergic and cholinergic antagonists failed to reverse muscimol's protection in LPS-treated mice. In conclusion, muscimol protected against systemic inflammatory response in endotoxemic mice may be partially independent of GABAergic and cholinergic receptors.
Topics: Animals; Endotoxemia; Interleukin-10; Interleukin-12; Lipopolysaccharides; Mice; Muscimol; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II; Receptors, Cholinergic; Sepsis; Tumor Necrosis Factor-alpha
PubMed: 35856422
DOI: 10.1139/cjpp-2021-0682 -
Neuroscience 1980
Review
Topics: Animals; Astacoidea; Autoradiography; Blood Vessels; Brain; Cattle; Cerebellum; Culture Techniques; Freezing; Kinetics; Muscimol; Muscles; Oxazoles; Pia Mater; Polyethylene Glycols; Rats; Receptors, Neurotransmitter; Sodium; Subcellular Fractions; Substrate Specificity; gamma-Aminobutyric Acid
PubMed: 6248815
DOI: 10.1016/0306-4522(80)90165-7 -
Epilepsy Research Feb 2023Intracerebral drug delivery is an emerging treatment strategy aiming to manage seizures in patients with systemic drug-resistant epilepsies. In rat seizure and epilepsy...
Intracerebral drug delivery is an emerging treatment strategy aiming to manage seizures in patients with systemic drug-resistant epilepsies. In rat seizure and epilepsy models, the GABA receptor agonist muscimol has shown powerful antiseizure potential when injected acutely into the subthalamic nucleus (STN), known for its capacity to provide remote control of different seizure types. However, chronic intrasubthalamic muscimol delivery required for long-term seizure suppression has not yet been investigated. We tested the hypothesis that chronic convection-enhanced delivery (CED) of muscimol into the STN produces long-lasting antiseizure effects in the intravenous pentylenetetrazole seizure threshold test in female rats. Acute microinjection was included to verify efficacy of intrasubthalamic muscimol delivery in this seizure model and caused significant antiseizure effects at 30 and 60 ng per hemisphere with a dose-dependent increase of responders and efficacy and only mild adverse effects compared to controls. For the chronic study, muscimol was bilaterally infused into the STN over three weeks at daily doses of 60, 300, or 600 ng per hemisphere using an implantable pump and cannula system. Chronic intrasubthalamic CED of muscimol caused significant long-lasting antiseizure effects for up to three weeks at 300 and 600 ng daily. Drug responder rate increased dose-dependently, as did drug tolerance rates. Transient ataxia and body weight loss were the main adverse effects. Drug distribution was comparable (about 2-3 mm) between acute and chronic delivery. This is the first study providing proof-of-concept that not only acute, but also chronic, continuous CED of muscimol into the STN raises seizure thresholds.
Topics: Rats; Female; Animals; Subthalamic Nucleus; Muscimol; Convection; Epilepsy; Seizures
PubMed: 36736200
DOI: 10.1016/j.eplepsyres.2023.107097 -
PloS One 2022Previous studies have shown that spontaneously active cultured networks of cortical neuron grown planar microelectrode arrays are sensitive to radiofrequency (RF) fields...
Previous studies have shown that spontaneously active cultured networks of cortical neuron grown planar microelectrode arrays are sensitive to radiofrequency (RF) fields and exhibit an inhibitory response more pronounced as the exposure time and power increase. To better understand the mechanism behind the observed effects, we aimed at identifying similarities and differences between the inhibitory effect of RF fields (continuous wave, 1800 MHz) to the γ-aminobutyric acid type A (GABAA) receptor agonist muscimol (MU). Inhibition of the network bursting activity in response to RF exposure became apparent at an SAR level of 28.6 W/kg and co-occurred with an elevation of the culture medium temperature of ~1°C. Exposure to RF fields preferentially inhibits bursting over spiking activity and exerts fewer constraints on neural network bursting synchrony, differentiating it from a pharmacological inhibition with MU. Network rebound excitation, a phenomenon relying on the intrinsic properties of cortical neurons, was observed following the removal of tonic hyperpolarization after washout of MU but not in response to cessation of RF exposure. This implies that hyperpolarization is not the main driving force mediating the inhibitory effects of RF fields. At the level of single neurons, network inhibition induced by MU and RF fields occurred with reduced action potential (AP) half-width. As changes in AP waveform strongly influence efficacy of synaptic transmission, the narrowing effect on AP seen under RF exposure might contribute to reducing network bursting activity. By pointing only to a partial overlap between the inhibitory hallmarks of these two forms of inhibition, our data suggest that the inhibitory mechanisms of the action of RF fields differ from the ones mediated by the activation of GABAA receptors.
Topics: Action Potentials; Muscimol; Neurons; Radio Waves; Synaptic Transmission
PubMed: 36044461
DOI: 10.1371/journal.pone.0268605 -
Journal of Neurochemistry Dec 1983The reaction of muscimol as amino donor substrate for GABA transaminase (GABA-T) has been studied using enzyme purified from rabbit brain. Enzyme activity was assayed by...
The reaction of muscimol as amino donor substrate for GABA transaminase (GABA-T) has been studied using enzyme purified from rabbit brain. Enzyme activity was assayed by measuring the glutamate produced using glutamate dehydrogenase. Kinetic parameters determined at 37 degrees C were for GABA, Km (app) = 1.92 +/- 0.24 mM, specific activity = 7.33 +/- 0.27 mumol/min/mg (kcat = 13.7s-1), and for muscimol, Km (app) = 1.27 +/- 0.15 mM, specific activity = 0.101 +/- 0.009 mumol/min/mg (kcat = 0.19s-1). Addition of muscimol to the enzyme caused the spectral changes associated with conversion of the pyridoxaldimine form to the pyridoxamine form, and the first-order rate constant for the reaction showed a dependence on muscimol concentration that followed saturation kinetics, with a K = 1.1 +/- 0.18 mM and kmax = 0.065 +/- 0.004 s-1 (19 degrees C). The rate of spectral change observed on addition of muscimol to ornithine transaminase was extremely slow--at least an order of magnitude slower than that seen with GABA-T.
Topics: 4-Aminobutyrate Transaminase; Animals; Brain; Kinetics; Liver; Muscimol; Ornithine-Oxo-Acid Transaminase; Oxazoles; Rabbits; Spectrophotometry
PubMed: 6644308
DOI: 10.1111/j.1471-4159.1983.tb00889.x -
Neuropharmacology Sep 2023Sensorimotor gating is the ability to suppress motor responses to irrelevant sensory inputs. This response is disrupted in a range of neuropsychiatric disorders....
Sensorimotor gating is the ability to suppress motor responses to irrelevant sensory inputs. This response is disrupted in a range of neuropsychiatric disorders. Prepulse inhibition (PPI) of the acoustic startle response (ASR) is a form of sensorimotor gating in which a low-intensity prepulse immediately precedes a startling stimulus, resulting in an attenuation of the startle response. PPI is conserved across species and the underlying circuitry mediating this effect has been widely studied in rodents. However, recent work from our laboratories has shown an unexpected divergence between the circuitry controlling PPI in rodents as compared to macaques. The nucleus accumbens, a component of the basal ganglia, has been identified as a key modulatory node for PPI in rodents. The role of the nucleus accumbens in modulating PPI in primates has yet to be investigated. We measured whole-body PPI of the ASR in six rhesus macaques following (1) pharmacological inhibition of the nucleus accumbens using the GABA agonist muscimol, and (2) focal application of the dopamine D2/3 agonist quinpirole (at 3 doses). We found that quinpirole, but not muscimol, infused into the nucleus accumbens disrupts prepulse inhibition in monkeys. These results differ from those observed in rodents, where both muscimol and quinpirole disrupt prepulse inhibition.
Topics: Animals; Prepulse Inhibition; Nucleus Accumbens; Quinpirole; Reflex, Startle; Macaca mulatta; Muscimol; Dopamine Agonists; Acoustics; Acoustic Stimulation
PubMed: 37116610
DOI: 10.1016/j.neuropharm.2023.109563 -
Epilepsia Dec 2002To investigate the efficacy of in situ lipid-protein-sugar particles (LPSPs) in mitigating the epileptogenic and histologic effects of intrahippocampal pilocarpine in...
PURPOSE
To investigate the efficacy of in situ lipid-protein-sugar particles (LPSPs) in mitigating the epileptogenic and histologic effects of intrahippocampal pilocarpine in rats.
METHODS
LPSPs with and without muscimol were produced by spray-drying, sized by Coulter counter, and muscimol content determined by high-pressure liquid chromatography (HLPC). Particles, free muscimol or saline, were injected into the hippocampi of Sprague-Dawley rats before 40 mM pilocarpine, and seizure activity was scored. The trajectories of behavioral scores between groups were compared with two-way repeated measures analysis of variance. Animals were killed after 2 weeks. Brain sections were stained (Timm and thionin) and scored.
RESULTS
LPSPs were 4 to 5 microm in diameter, and contained 0 or 2% (wt/wt) muscimol. In vitro, muscimol was released over a 5-day period. Intrahippocampal injections of normal saline and blank LPSPs did not deter seizure activity from pilocarpine. The rise of the trajectory in behavior scores in animals given LPSPs containing 5 microg muscimol was significantly slower than in those receiving saline, blank particles, or 5 microg of unencapsulated muscimol. There was less apparent neuronal injury and CA3 and supragranular mossy fiber sprouting in hippocampi of animals receiving muscimol-containing particles than in animals that did not receive muscimol. Hippocampi of animals that received 5 microg of encapsulated muscimol showed less supragranular sprouting than did those receiving 5 microg of unencapsulated muscimol, but showed no difference in cell loss or CA3 sprouting.
CONCLUSIONS
Focally delivered biodegradable microparticles loaded with muscimol are effective in reducing seizure activity from pilocarpine in animals and mitigate the histologic effects.
Topics: Animals; Anticonvulsants; Drug Carriers; Drug Implants; Epilepsies, Partial; GABA-A Receptor Agonists; Hippocampus; Injections; Liposomes; Microscopy, Electron, Scanning; Muscimol; Particle Size; Pilocarpine; Rats; Rats, Sprague-Dawley; Treatment Outcome
PubMed: 12460246
DOI: 10.1046/j.1528-1157.2002.11202.x -
Neurology Jun 1980Muscimol is a potent agonist at GABA-inhibitory synapses in mammalian brain. Given systemically at 7 mumol per kilogram, it blocks topical penicillin seizures and delays...
Muscimol is a potent agonist at GABA-inhibitory synapses in mammalian brain. Given systemically at 7 mumol per kilogram, it blocks topical penicillin seizures and delays the onset of generalized metrazol convulsions in rats. It has no effect against generalized seizures caused by picrotoxin or strychnine. Higher doses of muscimol cause bradykinesia, ataxia, catatonic posturing, and slowing of the electroencephalogram. When applied topically to cortex, muscimol blocks focal penicillin, bicuculline, and picrotoxin discharges in a dose-response relationship. It has no effect against topical strychnine. Muscimol offers a potential new approach to the treatment of epilepsy.
Topics: Animals; Bicuculline; GABA Antagonists; Muscimol; Neurons; Oxazoles; Penicillins; Picrotoxin; Rats; Receptors, Drug; Seizures; Strychnine
PubMed: 7189834
DOI: 10.1212/wnl.30.6.575 -
Brain Research May 1995Effects of muscimol on the place learning in Morris water maze task were investigated in rats. Rats were given 4 training trials per day with the submerged platform at a...
Effects of muscimol on the place learning in Morris water maze task were investigated in rats. Rats were given 4 training trials per day with the submerged platform at a fixed location in the maze for 4 days. On day 4, rats were required to swim in the pool without the platform after 4 training trials (probe test). Compared to the saline-treated rats, the rats treated with muscimol on day 1-4 showed no modifications of place learning in the training trials and the probe test. However, in the rats treated with muscimol on day 1-3 and treated with saline on day 4, there was increased latency to reach the platform and reduced duration in the quadrant where the platform had been located on day 4. The increased latency in the training trials and reduced duration in the probe test on day 4 was blocked by bicuculline, when bicuculline and muscimol were co-administered on day 1-3, and saline was injected on day 4. Moreover, in the rats treated with muscimol on day 1-3, co-administration of bicuculline and muscimol on day 4 blocked place learning: increased latency in the training trials and reduced duration in the probe test was observed. These results suggest that muscimol induces state-dependent learning (SDL) in Morris water maze task, and that muscimol-induced SDL is mediated by GABAA receptors.
Topics: Animals; Bicuculline; GABA Antagonists; GABA-A Receptor Antagonists; Male; Maze Learning; Muscimol; Rats; Rats, Wistar; Time Factors
PubMed: 7552269
DOI: 10.1016/0006-8993(95)00303-8 -
Neurobiology of Learning and Memory Jul 2002Intracerebral muscimol injection is widely used to inactivate discrete brain structures during behavioral tasks. However, little effort has been made to quantify the...
Intracerebral muscimol injection is widely used to inactivate discrete brain structures during behavioral tasks. However, little effort has been made to quantify the extent of muscimol diffusion. The authors report here electrophysiological and autoradiographic results obtained after muscimol injection (1 microg/microl) either into the nucleus basalis magnocellularis (0.1-0.4 microl) or into the thalamic reticular nucleus (RE, 0.05-0.1 microl). In 52 rats, multiunit recordings were collected either in the RE or in the auditory thalamus during the 2 h following muscimol injection. Decreases in neuronal activity were observed up to 3 mm from the injection site; their time of occurrence was a function of the distance between the injection and recording sites. Because these decreases cannot be explained by physiological effects, they likely reflected muscimol diffusion up to the recording sites. Autoradiographic studies involved 25 rats and different experimental conditions. Optical density (OD) measures indicated that after a survival time of 15 min, a 0.05 microl injection produced a labeled area of 5.25 mm(2) at the injection site and a rostrocaudal labeling of 1.7 mm. Increasing the survival time to 60 min, or increasing the injected volume to 0.1 microl, systematically led to a larger labeled area at the injection site (8-12 mm(2)) and to a larger rostrocaudal diffusion (2.0-2.5 mm). Direct quantifications of radioactivity by a high-resolution radioimager validated the OD measures and even indicated a larger muscimol diffusion (up to 3.25 mm). Thus, these data point out that muscimol diffusion after intracerebral microinjection is larger than usually supposed. The relationships between these results and those obtained in behavioral studies are discussed.
Topics: Animals; Autoradiography; Biological Transport; Cerebral Cortex; Electroencephalography; Electrophysiology; GABA Agonists; Microinjections; Muscimol; Rats; Rats, Sprague-Dawley
PubMed: 12071670
DOI: 10.1006/nlme.2001.4035