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Convection-Enhanced Delivery of Muscimol Into the Bilateral Subthalamic Nuclei of Nonhuman Primates.Neurosurgery Jun 2019Muscimol is a gamma-aminobutyric acid receptor agonist that selectively and temporarily inhibits neurons. Local bolus injection of muscimol has been used experimentally...
BACKGROUND
Muscimol is a gamma-aminobutyric acid receptor agonist that selectively and temporarily inhibits neurons. Local bolus injection of muscimol has been used experimentally to inhibit neuronal populations within discrete anatomical structures and discern their physiological function.
OBJECTIVE
To determine the safety and behavioral effects of convection-enhanced delivery of muscimol into the bilateral subthalamic nuclei (STN) of nonhuman primate rhesus macaques (NHPs).
METHODS
Six awake NHPs underwent co-infusion of gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA), a surrogate magnetic resonance imaging (MRI) tracer, with increasing concentrations of muscimol for behavioral and histological assessment. Three other NHPs were co-infused with Gd-DTPA and 3H-muscimol into the STN to determine muscimol distribution by MRI and autoradiography. Two NHPs underwent microcatheter implantation without muscimol infusion for control comparison.
RESULTS
MRI revealed selective and complete perfusion of the bilateral STN in animals infused with Gd-DTPA and muscimol. No abnormal movements occurred at 0.125 mM. Muscimol doses between 0.25 and 4.4 mM resulted in transient, dose-dependent hyperkinesia. Muscimol (8.8 mM) resulted in severe bilateral dyskinesias, ballistic movements, and sedation. An 88.8 mM dose produced unresponsiveness in 1 animal. Infusion-related pathological abnormities or toxicity was not present on histological examination. MRI distribution of co-infused Gd-DTPA was similar to autoradiographic distribution of 3H-muscimol (Vd; R = 0.94). Mean Vd of infused animals was 37.9 mm3 ± 11.7 mm3 and mean Vd: Vi 7.6 ± 2.3.
CONCLUSION
Bilateral convection-enhanced delivery of muscimol into the primate STN resulted in dose-related hyperkinetic movements that resolved after stopping the infusion. Muscimol was not toxic to brain tissue. Gd-DTPA accurately tracked muscimol distribution.
Topics: Animals; Contrast Media; Convection; Female; GABA-A Receptor Agonists; Gadolinium DTPA; Macaca mulatta; Magnetic Resonance Imaging; Male; Muscimol; Subthalamic Nucleus
PubMed: 29931364
DOI: 10.1093/neuros/nyy279 -
Brain Research Dec 2022Here we studied spinal neurotransmitter mechanisms involved in the reduction of mechanical hypersensitivity by inhibition of the amygdaloid central nucleus (CeA) in male...
Here we studied spinal neurotransmitter mechanisms involved in the reduction of mechanical hypersensitivity by inhibition of the amygdaloid central nucleus (CeA) in male and female rats with spared nerve injury (SNI) model of neuropathy. SNI induced mechanical hypersensitivity that was stronger in females. Reversible blocking of the CeA with muscimol (GABA receptor agonist) induced a reduction of mechanical hypersensitivity that did not differ between males and females. Following spinal co-administration of atipamezole (α-adrenoceptor antagonist), the reduction of mechanical hypersensitivity by CeA muscimol was attenuated more in males than females. In contrast, following spinal co-administration of raclopride (dopamine D2 receptor antagonist) the reduction of hypersensitivity by CeA muscimol was attenuated more in females than males. The reduction of mechanical hypersensitivity by CeA muscimol was equally attenuated in males and females by spinal co-administration of WAY-100635 (5-HT receptor antagonist) or bicuculline (GABA receptor antagonist). The CeA muscimol induced attenuation of ongoing pain-like behavior (conditioned place preference test) that was reversed by spinal co-administration of atipamezole in both sexes. The results support the hypothesis that CeA contributes to mechanical hypersensitivity and ongoing pain-like behavior in SNI males and females. Disinhibition of descending controls acting on spinal α-adrenoceptors, 5-HT, dopamine D2 and GABA receptors provides a plausible explanation for the reduction of mechanical hypersensitivity by CeA block in SNI. The involvement of spinal dopamine D2 receptors and α-adrenoceptors in the CeA muscimol-induced reduction of mechanical hypersensitivity is sexually dimorphic, unlike that of spinal α-adrenoceptors in the reduction of ongoing neuropathic pain.
Topics: Female; Rats; Male; Animals; Muscimol; Receptors, GABA-A; Neuralgia; Amygdala; Receptors, Neurotransmitter; GABA-A Receptor Antagonists; Receptors, Adrenergic
PubMed: 36265669
DOI: 10.1016/j.brainres.2022.148128 -
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 -
Pesticide Biochemistry and Physiology May 2022Meroterpenoid compounds chrodrimanins produced by Talaromyces sp. YO-2 have been shown to act as competitive antagonists of silkworm larval GABA receptors using...
Meroterpenoid compounds chrodrimanins produced by Talaromyces sp. YO-2 have been shown to act as competitive antagonists of silkworm larval GABA receptors using electrophysiology, yet no further evidence has been provided to support such an action. We have investigated the actions of chrodrimanin B on rat brain GABA receptors by binding assays with non-competitive ligand of GABA receptors [H]EBOB and competitive ligands [H]gabazine and [H]muscimol. Chrodrimanin B did not significantly affect the binding of [H]EBOB while reducing the binding of [H]gabazine and [H]muscimol to the rat membrane preparations. Chrodrimanin B increased the dissociation constant K of [H]gabazine and [H]muscimol without significantly affecting the maximum binding, pointing to competitive interactions of chrodrimanin B with rat GABA receptors in support of our previous observation that the compound acts as a competitive antagonist on the silkworm larval GABA receptor.
Topics: Animals; Binding, Competitive; Bombyx; Brain; Larva; Muscimol; Polyketides; Rats; Receptors, GABA-A; Sesquiterpenes; gamma-Aminobutyric Acid
PubMed: 35430068
DOI: 10.1016/j.pestbp.2022.105074 -
Behavioural Brain Research Jan 2022Avoidance of sick individuals is vital to the preservation of one's health and preventing transmission of communicable diseases. To do this successfully, one must...
Avoidance of sick individuals is vital to the preservation of one's health and preventing transmission of communicable diseases. To do this successfully, one must identify social cues for sickness, which include sickness behaviors and chemosignals, and use this information to orchestrate social interactions. While many social species are highly capable with this process, the neural mechanisms that provide for social responses to sick individuals are only partially understood. To this end, we used a task in which experimental rats were allowed to investigate two conspecifics, one healthy and one sick. To imitate sickness, one conspecific received the viral mimic Polyinosinic:polycytidylic acid (Poly I:C) and the other saline. In a 5-minute social preference test, experimental male and female adult rats avoided Poly I:C treated adult conspecifics but did not adjust social interaction in response to Poly I:C treated juvenile conspecifics. Seeking a neural locus of this behavior, we inhibited the insular cortex, a region necessary for social behaviors directed toward conspecifics in distress. Insular cortex inactivation via administration of the GABA agonist muscimol to experimental rats prior to social preference tests eliminated the preference to avoid sick adult conspecifics. These results suggest that some aspect of conspecific illness may be encoded in the insular cortex which is anatomically positioned to coordinate a situationally appropriate social response.
Topics: Animals; Antiviral Agents; Avoidance Learning; Behavior, Animal; Female; GABA-A Receptor Agonists; Illness Behavior; Insular Cortex; Male; Muscimol; Odorants; Poly I-C; Rats; Social Interaction
PubMed: 34425184
DOI: 10.1016/j.bbr.2021.113541 -
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 -
Pain Jul 2022Pain is a common and debilitating symptom of inflammatory bowel disease (IBD). Based on evidence that peripheral GABAA receptor (GAR) inhibition plays an important role...
Pain is a common and debilitating symptom of inflammatory bowel disease (IBD). Based on evidence that peripheral GABAA receptor (GAR) inhibition plays an important role in establishing colonic afferent excitability and nociceptive threshold, we hypothesized that the increase in pain associated with IBD is due to, at least in part, a decrease in peripheral GAR-mediated inhibition. Acute colitis was induced with 5 days of dextran sodium sulfate (DSS, 3%) in the drinking water. Visceral sensitivity was assessed with the visceromotor response (VMR) evoked with balloon distention of the colon in control and DSS-treated mice before and after intracolonic administration of GAR agonist muscimol, the high-affinity GAR preferring agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-3-ol (THIP), the GAR positive allosteric modulator diazepam, or the GAR antagonists gabazine and bicuculline. Low concentrations of muscimol or THIP increased the VMR in DSS-treated mice but not in control mice. However, high concentrations of muscimol decreased the VMR in both control and DSS-treated mice. Diazepam decreased the VMR in both DSS-treated and control mice. By contrast, at a concentration of gabazine that blocks only low-affinity GAR, there was no effect on the VMR in either DSS-treated or control mice, but at concentrations of the antagonist that block low-affinity and high-affinity GAR, the VMR was increased in control mice and decreased in DSS-treated mice. Furthermore, bicuculline increased the VMR in control mice but decreased it in DSS-treated mice. These data suggest that activating of low-affinity GAR or blocking high-affinity GAR may be effective therapeutic strategies for the management of pain in IBD.
Topics: Animals; Bicuculline; Colitis; Colon; Dextran Sulfate; Diazepam; Disease Models, Animal; Inflammatory Bowel Diseases; Mice; Mice, Inbred C57BL; Muscimol; Pain; Receptors, GABA-A
PubMed: 34726659
DOI: 10.1097/j.pain.0000000000002526 -
Brain and Behavior May 2020Due to side effects of medications used for chronic pain, combination therapy seems to be an appropriate solution for alleviation of chronic pain and reducing the side...
INTRODUCTION
Due to side effects of medications used for chronic pain, combination therapy seems to be an appropriate solution for alleviation of chronic pain and reducing the side effects. The role of inhibitory GABA system is well proven in reducing neuropathic pain. Also, special attention has been focused on endogenous morphine (endomorphins) in reducing chronic pain originates from damage to the nervous system. The purpose of this study is to investigate the analgesic effect of simultaneous administration of GABA agonist and endomorphin-1 on neuropathic pain in rat model of spinal cord injury (SCI). The role of oxidative stress, NR1 subunits of NMDA receptors, and α subunits of GABA receptors in the spinal cord has also been investigated.
METHODS
Spinal cord at level of T6-T8 was compressed. Three weeks after spinal cord injury, muscimol and endomorphin-1 were injected (intrathecally once a day for 7 days) individually or in combination. Mechanical and cold allodynia, thermal and mechanical hyperalgesia were evaluated before injection and 15 and 60 min after injection. At the end of behavioral experiments, histological and biochemical evaluations were done on prepared spinal cord samples.
RESULTS
Isobologram results showed that combination therapy significantly increased the pain threshold comparing to injection of endomorphin-1 (EM) or muscimol alone. Histological studies indicated the increased expression of α2 subunits of GABA receptors, and NR1 subunits of NMDA receptors in the spinal cord. The combination therapy also increased the glutathione (GSH) and superoxide dismutase (SOD) level and decreased the malondialdehyde (MDA) levels in the spinal cord.
CONCLUSION
Simultaneous administration of muscimol and endomorphine-1 could be a new candidate for alleviation of pain resulting from spinal cord injury.
Topics: Animals; Hyperalgesia; Injections, Spinal; Muscimol; Neuralgia; Oligopeptides; Rats; Spinal Cord; Spinal Cord Injuries
PubMed: 32189472
DOI: 10.1002/brb3.1576 -
British Journal of Pharmacology Mar 19901. In water-loaded rats under ethanol anaesthesia, the injection of 2-4 microliters 1.54M NaCl solution (hypertonic saline:HS) into a lateral cerebral ventricle (i.c.v.)...
1. In water-loaded rats under ethanol anaesthesia, the injection of 2-4 microliters 1.54M NaCl solution (hypertonic saline:HS) into a lateral cerebral ventricle (i.c.v.) produced an antidiuretic and a pressor response, together with increased urinary excretion of vasopressin and 'oxytocin-like radioimmunoreactivity' (OLRI). In lactating rats HS also produced a milk-ejection response which was shown to be due to the release of oxytocin. 2. The injection of 20-40 micrograms gamma-aminobutyric acid (GABA) or 40-80 ng muscimol i.c.v. 2 min before HS inhibited the antidiuretic, pressor and milk-ejection responses and reduced the urinary excretion of vasopressin and OLRI. 3. The pressor response to HS was abolished by a ganglion blocking agent but it was not reduced by a vasopressin antagonist. After the antagonist, the antidiuretic response to HS was abolished and the pressor response was accompanied by a diuresis both of which were blocked by muscimol. 4. The threshold dose of HS for an antidiuretic response was 4-8 times higher on injection into the cisterna magna (i.cist.) than when injected i.c.v. GABA, i.v. or i.cist, did not inhibit the response to HS i.c.v. 5. The results confirm other evidence that, in the rat, in contrast some other species, an osmotic stimulus causes release of both vasopressin and oxytocin. This release is blocked by GABA and muscimol. These drugs and HS act at a site reached not from the subarachnoid space but from the cerebral ventricles, probably the hypothalamus. The pressor response to HS under the experimental conditions used is due entirely to central sympathetic stimulation and this effect, as well as the release of vasopressin and oxytocin, is blocked by muscimol.
Topics: Animals; Diuresis; Female; Injections, Intraventricular; Iodine Radioisotopes; Lactation; Male; Muscimol; Osmolar Concentration; Oxytocin; Pregnancy; Rats; Rats, Inbred Strains; Vasopressins; gamma-Aminobutyric Acid
PubMed: 2331582
DOI: 10.1111/j.1476-5381.1990.tb12963.x -
Journal of Neurosurgery Dec 2005The activity of gamma-aminobutyric acid (GABA), the principal inhibitory neurotransmitter, is reduced in the hippocampus in patients with complex partial seizures from...
OBJECT
The activity of gamma-aminobutyric acid (GABA), the principal inhibitory neurotransmitter, is reduced in the hippocampus in patients with complex partial seizures from mesial temporal sclerosis. To provide preliminary safety and distribution data on using convection-enhanced delivery of agents to treat complex partial seizures and to test the efficacy and safety of regional selective neuronal suppression, the authors infused muscimol, a GABA-A receptor agonist, directly into the hippocampus of nonhuman primates using an integrated catheter electrode.
METHODS
Ten rhesus monkeys were divided into three groups: 1) use of catheter electrode alone (four monkeys); 2) infusion of escalating concentrations of muscimol followed by vehicle (three monkeys); and 3) infusion of vehicle and subsequent muscimol mixed with muscimol tracer (three monkeys). Infusions were begun 5 days after catheter electrode placement and continued for 5.6 days before switching to the other agent. Head magnetic resonance (MR) images and electroencephalography recordings were obtained before and during the infusions. Brain histological studies and quantitative autoradiography were performed. Neurological function was normal in controls and when muscimol concentrations were 0.125 mM or less, whereas higher concentrations (0.5 and 1 mM) produced reversible apathy and somnolence. Fluid distribution was demonstrated on MR images and muscimol distribution was demonstrated on autoradiographs throughout the hippocampus and adjacent white matter.
CONCLUSIONS
Targeted modulation of neuronal activity is a reasonable research strategy for the investigation and treatment of medically intractable epilepsy.
Topics: Animals; Autoradiography; Brain; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Delivery Systems; Electroencephalography; Female; GABA Agonists; Hippocampus; Macaca mulatta; Magnetic Resonance Imaging; Male; Muscimol; Osmolar Concentration; Tissue Distribution
PubMed: 16381190
DOI: 10.3171/jns.2005.103.6.1035