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At least 469 records · Page 26Linked to original sources
PubMed2002

[3H]muscimol binding to gamma-aminobutyric acid(A) receptors is upregulated in CA1 neurons of the gerbil hippocampus in the ischemia-tolerant state.

BACKGROUND AND PURPOSE: Excitotoxic activation of glutamate receptors is currently thought to play a pivotal role in delayed neuronal death (DND) of highly vulnerable CA1 neurons in the gerbil hippocampus after transient global ischemia. Postischemic degeneration of these neurons can be prevented by "preconditioning" with a short sublethal ischemic stimulus. The present study was designed to test whether ischemic preconditioning is associated with specific alterations of ligand binding to excitatory glutamate and/or inhibitory gamma-aminobutyric acid (GABA)A receptors compared with ischemia severe enough to induce DND. METHODS: With the use of quantitative receptor autoradiography, postischemic ligand binding of [3H]MK-801 and [3H]alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) to excitatory N-methyl-D-aspartate (NMDA) and AMPA receptors as well as [3H]muscimol to inhibitory GABA(A) receptors in hippocampal subfields CA1, CA3, and the dentate gyrus were analyzed in 2 experimental paradigms. Gerbils were subjected to (1) a 5-minute ischemic period resulting in DND of CA1 neurons and (2) a 2.5-minute period of ischemia mediating tolerance induction. RESULTS: [3H]MK-801 and [3H]AMPA binding values to excitatory NMDA and AMPA receptors showed a delayed decrease in relatively ischemia-resistant CA3 and dentate gyrus despite maintained neuronal cell density. [3H]Muscimol binding to GABA(A) receptors in CA1 neurons was transiently but significantly increased after preconditioning but not after global ischemia with consecutive neuronal death. CONCLUSIONS: Downregulation of ligand binding to glutamate receptors in relatively ischemia-resistant CA3 and dentate gyrus neurons destined to survive suggests marked synaptic reorganization processes despite maintained structural integrity. More importantly, upregulation of binding to inhibitory GABA(A) receptors in the hippocampus indicates a relative shift between inhibitory and excitatory neurotransmission that we suggest may participate in endogenous postischemic neuroprotection.

Animals↗
PubMed1989

Growth hormone-releasing factor secretion from fetal hypothalamic cell cultures is modulated by forskolin, phorbol esters, and muscimol.

The regulation of GRF secretion was studied using a fetal rat hypothalamic cell culture system. The cells were subjected to short term release experiments on days 10-18 after plating, and GRF secretion was assessed by RIA. The identity of GRF immunoreactivity in the incubation medium was confirmed by reverse phase liquid chromatographic analysis. Depolarization of the cells with 56 mM K+ evoked a 4-fold increase in basal GRF release. When cultures were pretreated for 6 days with the adenylate cyclase activator forskolin, basal GRF release was augmented in subsequent release experiments to levels 2-fold greater than those in the control cultures. In nonpretreated cultures, forskolin (1-100 microM) and the protein kinase C activator phorbol 12-myristate 13-acetate (10 nM-1 microM), stimulated basal GRF release in a dose-dependent fashion. The Ca2+ channel blocker verapamil (100 microM) significantly inhibited the GRF response to both forskolin and phorbol 12-myristate 13-acetate. The gamma-aminobutyric acid (GABA) agonist muscimol (0.1-10 microM) inhibited forskolin-stimulated, but not K+ stimulated, GRF release in a dose-dependent manner. This inhibition was reversed by the GABA antagonists bicuculline and picrotoxinin. Muscimol (10 microM) slightly suppressed basal GRF release. The present findings suggest that GRF secretion can be evoked by agents known to increase intracellular cAMP levels or activate protein kinase-C. They also support a role for GABA in the inhibitory control of GRF secretion.

Animals↗
PubMed1978

Stimulation of prolactin and growth hormone secretion by muscimol, a gamma-aminobutyric acid agonist.

The alteration in circulating levels of PRL, GH, TSH, and cortisol was studied after the oral administration of muscimol (3-hydroxy-5-aminomethylisoxazole) to human subjects with Huntington's disease (n = 4) and chronic schizophrenia (n = 5). PRL levels rose significantly in a dose-dependent fashion within a 120-min time interval. GH rose significantly but modestly over the same time interval, whereas TSH and cortisol levels remained unchanged. Since muscimol is thought to be a potent and specific gamma-aminobutyric acid agonist, these data indicate that gamma-aminobutyric acid-mediated neural transmission may function to stimulate the release of plasma PRL and GH in human subjects.

Adult↗
PubMed1989

Blockade of enkephalinergic and GABAergic mediated locomotion in the nucleus accumbens by muscimol in the ventral pallidum.

The mu-opioid agonist, DAGO, and the indirect GABAA antagonist, picrotoxin, produced a dose-dependent increase in horizontal motor activity following injection into the nucleus accumbens that was independent of dopamine release. Injection of muscimol into the ventral pallidum antagonizes the motor stimulant effect of dopamine agonists. It was shown that muscimol abolished the locomotor stimulant effect of DAGO microinjection into the nucleus accumbens, and partially antagonized the effect of picrotoxin.

Animals↗
PubMed1981

Effect of muscimol on glucose-stimulated somatostatin and insulin release from the isolated, perfused rat pancreas.

This study examines the effect of muscimol, a high affinity, specific gamma-aminobutyric acid (GABA) agonist, on glucose-stimulated somatostatin and insulin release from the isolated, perfused rat pancreas. Perfusion with low glucose (50 mg/dl) conditions resulted in basal somatostatin release of 46 +/- 4 pg/ml. Basal insulin release was less than 20 microU/ml. High glucose (300 mg/dl) conditions stimulated somatostatin and insulin release. Steady-state levels of somatostatin and insulin release under high glucose conditions were 425 +/- 12 pg/ml and 419 +/- 18 microU/ml, respectively. Perfusion with medium containing 1 microM muscimol inhibited glucose-stimulated somatostatin release by 38%, whereas the course of glucose-stimulated insulin release was unaffected. Tentative conclusions from this study are (1) that GABA is potentially a modulator of islet somatostatin but not insulin release, and (2) the fact that somatostatin, an inhibitor of insulin, can be suppressed 38% without coincidental increase in insulin release seems to indicate that, under high glucose conditions, somatostatin is without a significant paracrine effect on the beta-cells.

Animals↗
PubMedDate not supplied

Neurotransmitter levels and [3H]muscimol binding sites in the brain of rats selectively bred for alcohol preference and non-preference.

Alcohol-naive high- (Warsaw High Preferring; WHP) and low- (Warsaw Low Preferring; WLP) preferring lines of rat were studied to determine the distribution and density of [3H]muscimol binding sites in the brain using quantitative autoradiography. The results have shown no difference in the density of [3H]muscimol binding sites in the cingulate and frontal cortex, dorsal and ventral striatum, lateral and medial septum, caudate-putamen, nucleus accumbens in the both lines of animals. In the separate experiments, the levels of neurotransimitters were measured in the frontal cortex, hippocampus and striatum of the WHP and WLP rats. The content of dopamine was significantly lower in the striatum of the WHP rats as compared to the WLP animals. The levels of serotonin and noradrenaline were without any important differences in the examined structures of both lines of rats.

Alcohol Drinking↗
PubMedDate not supplied

Lack of changes in cortical [3H]-muscimol binding in rats sensitized to nicotine-induced enhancement of dopamine metabolism.

It was proposed that chronic nicotine treatment may induce adaptive changes in GABAA receptors, thus leading to the attenuation of a GABAergic inhibition of dopaminergic neurons. This putative mechanism might underlie the sensitization to nicotine-induced increase in locomotor activity and dopamine metabolism; i.e. phenomena highly significant to the dependence-producing effects of this psychostimulant. To test this hypothesis, in the present study we have analyzed the influence of acute and repeated treatment of rats with nicotine on the binding of a highly selective and competitive GABAA receptor agonist, [3H]-muscimol. The binding was investigated by autoradiography in different brain cortical structures. It was found that nicotine given at the dose stimulating locomotor activity (0.6 mg/kg, sc), markedly increased striatal HVA concentration in the group of animals chronically pretreated (for 6 days) with this psychostimulant. Neither acute nor repeated nicotine administration changed in a significant way the [3H]-muscimol binding to brain cortical structures. Thus, the hypothesis about the role of adaptive changes in GABAA receptors in the enhancement of the biochemical and behavioral effects of nicotine was not confirmed.

Animals↗
PubMed1990

Brain ischemia increased high affinity binding of [3H]muscimol into synaptic plasma membrane receptor.

The authors investigated the high affinity binding of [3H] muscimol to the receptor of synaptic plasma membranes (SPM) isolated from a normoxic and ischemic brain. Brain ischemia enhanced the [3H] muscimol binding to the receptor, located in native (Triton X-100 untreated) membranes. Scatchard's analysis showed that the total number of binding sites (BMAX) and the KD value increased by about 60%. The higher KD value persisted during 20 min of the reperfusion period. Concomitantly, ischemia stimulated the activity of phospholipase C and phospholipase A2, acting against phosphatidylinositol (PI). The degradation of PI and a transient accumulation of docosahexaenoic and arachidonic acids may be important factors involved in the modification of high affinity agonist binding to the GABAA receptor of SPM isolated from the brain submitted to ischemia.

Animals↗
PubMed1989

Effect of GABA muscimol and picrotoxin on electrical activity of the medial preoptic area in unanesthetized rats.

Intracranial cannula along with electrodes was stereotaxically implanted in medial preoptic area of male rats. The electrical activity of mPOA was recorded before and after microinjection of GABA (0.5 micrograms/02 microliters), muscimol (0.5 micrograms/0.2 microliter), picrotoxin (0.25 micrograms/0.2 microliter) and their respective controls. Generalized slowing with an increase in amplitude appeared with GABA and muscimol, while picrotoxin produced just the reverse, i.e. fast activity. Thus the mPOA seems to be vulnerable to GABAergic compounds and supports the diversity of physiological and behavioral functions.

Animals↗
PubMedDate not supplied

Effect of GABA, muscimol and picrotoxin given in third ventricle on serum cholinesterases and monoamine oxidase and on plasma succinic dehydrogenase in rats.

Effect of injection in third ventricle of GABA, the GABA agonist muscimol, and the GABA antagonist picrotoxin on the activities of acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) and monoamine oxidase (MAO) in serum and succinic dehydrogenase (SDH) in plasma has been studied. Surprisingly, the AChE, BuChE, MAO and SDH enzymes activity were inhibited by GABA and muscimol, while they were enhanced by picrotoxin.

Acetylcholinesterase↗
PubMed1985

[Effect of muscimol (GABA-agonist) on thalamo-hypothalamic regulation by corticotropic efferents (thalamic model)].

It can be assumed from previous data that the stress-induced polyphasic adrenocortical response involves two phenomenons. First, direct hypothalamic afferents stimulate the adrenocorticotropic axis resulting in a rapid increase in plasma corticosterone levels up to a maximum of about 40 ng . ml-1 at 15 min. Then, a thalamic-hypothalamic loop generates the late rebounding components. Intravenous injection of muscimol (0.5 ml . kg-1) produces only slight and short duration (45 min) disturbances (piloerection; panting; corticosteronemia). Stress application, 1 hr after muscimol administration, elicits only the first peak of corticosterone with magnitude and delay similar to that in control. However, the late rebounding component is no more visible. Thus, GABA-ergic stimulation leads to a situation similar to that seen after section of neural connections between thalamic nuclei and infundibular complex. The hypothalamic-adrenocorticotropic reactivity itself is not affected whereas the function of the regulating thalamo-hypothalamic loop is markedly impaired.

Animals↗
PubMed1979

Muscimol antagonism of morphine analgesia in rats.

1 Muscimol, a gamma-aminobutyric acid (GABA) receptor agonist, when injected intraventricularly antagonizes the antinociceptive effect of morphine given either subcutaneously or intraventricularly. The antagonistic effect of muscimol on morphine analgesia appears to be linearly related. 2 This finding provides support for the view that a GABA-ergic system is involved in morphine analgesia.

Animals↗
PubMed1983

Simultaneous modulation of hippocampal cholinergic activity and extinction by intraseptal muscimol.

The relationship between regulation of acetylcholine metabolism in the septal-hippocampal pathway and extinction of a food reinforced lever press response was investigated by comparing the turnover rate of acetylcholine (TRACh) in the rat hippocampus with the amount of responding during extinction after intraseptal injection of the gamma-aminobutyric acid receptor agonist muscimol. Doses (0.3-3.0 nmol) which decreased the TRACh in the hippocampus also increased the responding during extinction over that of saline controls. Responding during the continuous reinforcement schedule before extinction was also increased, but to a lesser extent. Higher doses (10-30 nmol) further decreased the TRACh in the hippocampus, decreased it in the cortex and were accompanied by irregular responding and sedation. The TRACh in the hippocampus was also measured in drug-free rats undergoing extinction after training on a continuous reinforcement or variable interval 60 sec reinforcement schedule. Although the variable interval 60 sec reinforcement schedule rats responded more than the continuous reinforcement rats during extinction, there were no differences between the TRACh in the hippocampus. The present results indicate that the decrease in the hippocampal TRACh which is produced by intraseptal muscimol is accompanied by an increase in the response rate during extinction, but that operantly induced differences in this behavior are not accompanied by detectable changes in hippocampal TRACh.

Acetylcholine↗
PubMed1982

Effects of gamma aminobutyric acid (GABA) and muscimol on endocrine pancreatic function in man.

The high concentrations of gamma aminobutyric acid (GABA) in the pancreatic islets and the neurotransmitter role played by this amino acid in the central nervous system, make it plausible that GABA also intervenes in the control of endocrine pancreatic function. In 12 normal subjects, a single oral dose of 5 or 10 g GABA, as compared to placebo, caused a significant (p less than 0.01) and dose-dependent (p less than 0.01) increase of plasma levels of immunoreactive insulin, C peptide and glucagon, without affecting plasma glucose concentration. By contrast, in 15 additional subjects, a single oral dose of 5 mg muscimol, a specific GABA receptor agonist, did not consistently influence the above parameters. Although the lack of effects of muscimol might indicate that the action of GABA is not mediated through specific receptors, the results with GABA suggest that this amino acid plays a specific role in the regulation of endocrine pancreatic function.

Adolescent↗
PubMed1994

Identification of a [3H]muscimol photoaffinity substrate in the bovine gamma-aminobutyric acidA receptor alpha subunit.

An amino acid which appears to be involved in an agonist binding site of the gamma-aminobutyric acid type A (GABAA) receptor protein has been identified by photoaffinity labeling of affinity purified bovine receptor with [3H]muscimol and microsequencing of a chymotryptic fragment. Sequencing of a major purified labeled peptide gave the sequence Thr-Ile-Asp-Val-Phe with release of 3H label in the fifth cycle, corresponding to Phe. These 5 residues match the published sequence for the bovine alpha 1 subunit beginning at Thr61, following the chymotryptic substrate Tyr60. This sequence is found in the alpha 1-3 subunits of rat and cow and alpha 5 of rat, but not in any beta. Although previous evidence tentatively suggested that the beta subunit was the major [3H]muscimol-labeled subunit, homomeric expression studies have shown the potential for a functional gamma-aminobutyric acid binding site on all classes of subunits. The residue carrying the label, Phe65 on alpha 1, is conserved among all GABAA receptor alpha subunits, gamma 2, and delta. In addition, recent data indicated that a point mutation of Phe64-->Leu in rat alpha 1 subunit strongly decreased agonist and antagonist affinity when coexpressed with beta 2 and gamma 2 subunits in Xenopus oocytes (Sigel, E., Baur, R., Kellenberger; S., and Malherbe, P. (1992) EMBO J. 11, 2017-2023). The photolabeled Phe residue identified in this report is the bovine homolog to the Phe64 identified by the mutation studies of Sigel et al., to affect function in the rat GABAA receptor.

Affinity Labels↗