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PubMed2003

Distribution of muscimol, QNB, and 5HT binding in the vertebrate diencephalon: a comparative study of eight mammals and three non-mammals.

The distribution of muscimol, quinuclidinyl benzilate (QNB), and serotonin (5HT)-bound receptors in the diencephalon was examined by conventional receptor-binding methods in 11 species of amniotes including 2 reptiles, 1 bird, and 8 mammals, selected mostly on the basis of their differing last common ancestor with Anthropoids. We found that receptor binding can help define major subdivisions of the forebrain. The results show that in each of these species, the distribution of muscimol and QNB binding across the four major subdivisions of the diencephalon was consistent; densest in the dorsal thalamus, with hypothalamus and then either ventral thalamus or epithalamus with successively lesser amounts. However, the binding of serotonin (5HT) was most prevalent in the hypothalamus with equivalent amounts in the other diencephalic subdivisions. Myelin- and cell-stained materials showed that the pattern of high-density binding probably is not the secondary result of non-neurochemical factors such as differences in cell or neuropil density or in total available membrane. Perhaps more importantly, the receptor distributions suggest functional roles for major subdivisions across taxa. Results show that GABA-A and muscaranic Ach receptors are common in the dorsal diencephalon across vertebrate species and, therefore, are probably responsible for the gating of information to the cortex. Results show that serotonin is predominant in the hypothalamus. The lack of it in the dorsal thalamus indicates that it is probably not responsible for gating of information to the cortex. Results also show that in nonmammals the amount of GABA-A and muscaranic Ach differs from that found in mammals. For muscaranic Ach, the labeling in marsupials differs from that in placentals. Primates differ from other species (nonmammals and mammals combined) in the amount of 5HT found in the ventral diencephalon and the hypothalamus.

Animals↗
PubMed1981

3H-muscimol binding in synaptosomal fractions from bovine and developing rabbit retinas.

Bovine and rabbit retina synaptosomal fractions bind the potent and specific GABA agonist, [3H]-muscimol with high affinity and limited capacity. The high degree of pharmacological specificity and the subcellular distribution of these binding sites are similar to those reported for [3H]-GABA binding sites. These observations suggest that these sites represent the recognition sites for GABA receptors. The specific binding of [3H]-muscimol in retinal homogenates from different aged rabbits reveal a distinct developmental profile with a fivefold to six fold increase in binding between days 5 and 13. Thus, it appears that GABA receptor development continues after eye opening in rabbits (day 9-10) and that receptor maturation is delayed by at least two to three days with respect to published of GABA uptake and evoked release.

Animals↗
PubMed2001

Effects of linalool on [(3)H]MK801 and [(3)H] muscimol binding in mouse cortical membranes.

Linalool is a monoterpene compound reported to be a major component of essential oils of several aromatic species. Several linalool-producing species are used in traditional medical systems for sedative purposes, including the interruption and prevention of seizures. Previous studies in mice revealed that linalool modulates glutamatergic (competitive antagonism of L-[(3)H]glutamate binding, delayed intraperitoneal NMDA-induced convulsions and blockade of intracerebroventricular Quin-induced convulsions) and GABAergic transmission (protection against pentylenetetrazol and picrotoxin-induced convulsions). To further clarify the anticonvulsive mechanisms of linalool, we studied the effects of linalool on binding of [(3)H]MK801 (NMDA antagonist) and [(3)H]muscimol (GABA(A) agonist) to mouse cortical membranes. Linalool showed a dose dependent non-competitive inhibition of [(3)H]MK801 binding (IC(50) = 2.97 mM) but no effect on [(3)H]muscimol binding. The data suggest that the anticonvulsant mode of action of linalool includes a direct interaction with the NMDA receptor complex. The data do not, however, support a direct interaction of linalool with GABA(A) receptors, although changes in GABA-mediated neuronal inhibition or effects on GABA release and uptake cannot be ruled out.

Acyclic Monoterpenes↗
PubMed1997

The attenuation of kainate-induced neurotoxicity by chlormethiazole and its enhancement by dizocilpine, muscimol, and adenosine receptor agonists.

Systemically administered kainate (10 mg.kg-1) caused neuronal loss in both the hippocampus and the entorhinal regions of the rat brain. This resulted in a loss of 68.3 +/- 13.8 and 53.3 +/- 12.8% of pyramidal neurones in the hippocampal CA1 and CA3a regions, respectively. Chlormethiazole attenuated the loss of neurones in the hippocampal cell layers CA1 (cell loss 10 +/- 3.2%) and CA3a (cell loss 10 +/- 7.7%). The neuroprotective activity of chlormethiazole was apparent in the presence or absence of a low dose of clonazepam (200 micrograms.kg-1 i.p.). The kainate-induced damage could also be measured by the increase in binding of the peripheral benzodiazepine ligand ([3H]PK11195) in the hippocampus. In kainate-treated rats there was a 350-500% increase in binding indicative of reactive gliosis. Chlormethiazole prevented this elevation in a dose- and time-dependent manner, with an ED50 of 10.64 mg.kg-1 and an effective therapeutic window from 1 to 4 h posttreatment. Dizocilpine also attenuated damage significantly. The GABAA agonist muscimol was also able to attenuate the increase in [3H]PK11195 binding in a dose-dependent manner, with an ED50 of approximately 0.1 mg.kg-1. If muscimol, dizocilpine, or the adenosine A1 receptor agonist R-N6-phenylisopropyl-adenosine were administered together with chlormethiazole at their respective ED25 doses, a potentiation was apparent in the degree of neuroprotection. It is concluded that the combination of neuroprotective agents with different mechanisms of action can lead to a synergistic protection against excitotoxicity.

Adenosine↗
PubMed1993

The effect of muscimol micro-injections into the fastigial nucleus on the optokinetic response and the vestibulo-ocular reflex in the alert monkey.

Eye movements of four macaque monkeys were investigated after unilateral micro-injections of the GABA agonist muscimol (1 microgram in 1 microliter NaCl) into the caudal fastigial nucleus, i.e. the fastigial oculomotor region. Spontaneous eye movements in the dark and in the light were tested, as well as those evoked by vestibular stimulation in the dark (sinusoidal: 0.1-0.2 Hz, +/- 40-100 deg/s, velocity trapezoid acceleration 40 deg/s2, constant velocity 120 deg/s), optokinetic stimulation (sinusoidal: 0.1-0.2 Hz, +/- 40-100 deg/s, constant velocity 60-100 deg/s), and visual-vestibular conflict stimulation. With these stimuli, smooth pursuit mechanisms (fast build-up of optokinetic slow phase velocity), the vestibulo-ocular reflex (VOR) and the velocity storage mechanism were investigated. Muscimol injections consistently led to specific eye movement changes which were maximal 30-60 min after the injection and lasted 4-6 h. The fast initial rise of OKN slow phase velocity to the contralateral side decreased by 45% (range 24%-82%) of its pre-injection value, while it was virtually unaltered on the ipsilateral side (average decrease of 1%, range from a decrease of 20% to an increase of 32%). For conflict ramp stimulation, the suppression of vestibular nystagmus was less (decrease of 50%, range 12-82%) towards the contralateral side while it remained unchanged on the ipsilateral side. The VOR in the dark and the velocity storage mechanism were not altered. For the latter, the slow build-up of optokinetic nystagmus velocity, the optokinetic afternystagmus (OKAN) and the time constant of decay for the vestibular nystagmus were evaluated.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Rigidity and catalepsy after injections of muscimol into the ventromedial thalamic nucleus: an electromyographic study in the rat.

The cataleptic state induced by injection of the GABAmimetic drug muscimol into the rat's ventromedial thalamic nucleus (VM) was examined using an electromyographic (EMG) approach. Muscimol in doses up to 50 ng/0.5 microliter injected into the VM induced a tonic EMG activity in the gastrocnemius muscle which is considered to be a measure of limb rigidity. This tonic EMG activity was found to be dose-dependent, GABA specific and locus specific. By recording EMG signals from chronically implanted electrodes in awake, unrestrained rats it was shown that muscular reactions serving to maintain the animal's static equilibrium were intact in the state of VM induced catalepsy. However, animals were unable to initiate movements or locomotion even when they were forced by strong external stimuli. It was found that the animals' immobility was due to an inability to induce a phasic activation of their muscles whereas tonic activation still occurred. It is concluded that the rat's VM is part of a neuronal chain conducting information relevant for the expression of limb rigidity, the VM is involved in the central mechanisms responsible for the phasic activation of a set of muscles.

Animals↗
PubMed1980

Autoradiographic localization of 3H-GABA and 3H-muscimol binding in rat cerebellar cultures.

Autoradiographic studies were conducted on the binding of 3H-GABA and 3H-muscimol in cultures of rat cerebellum. Binding sites for both substances were observed on many cerebellar neurones, such as Purkinje cells and interneurones, but not on glial cells. Binding of 3H-GABA and 3H-muscimol was inhibited by unlabelled GABA and by the GABA antagonist bicuculline.

Animals↗
PubMed1980

Effects of sodium n-dipropylacetate, muscimol hydrobromide and (R,S) nipecotic acid amide on isolation-induced aggressive behavior in mice.

An inhibitor of GABA-T (sodium n-dipropylacetate), a GABA agonist (muscimol hydrobromide) and an inhibitor of GABA uptake (R,S) nipecotic acid amide were administered to DBA/2 isolated aggressive mice throughout three successive daily experimental sessions. Aggressive responses, measured by an automated device, were inhibited by the highest doses of the three drugs in each daily session. At the lowest doses, sodium, n-dipropylacetate and nipecotic acid amide failed to inhibit aggression in the first session while they were effective in the subsequent sessions. Muscimol was effective in the first session but did not differ significantly from saline in the second and third session. The highest doses of these three drugs did not affect spontaneous motor activity, indicating that the observed drug effects are rather specific.

Aggression↗
PubMed1981

A new method for the evaluation of benzodiazepines based on their ability to block muscimol-induced myoclonic jerks in mice.

A number of clinically used benzodiazepines were tested for their effectiveness in blocking muscimol-induced myoclonic jerks in mice. Their ED50 values were determined from their dose-response curves. These data gave the following relative potencies with respect to diazepam: diazepam = 1, medazepam = 0.24, oxazepam = 1.27, flurazepam = 1.90, lorazepam = 3.01, nitrazepam = 3.93, clonazepam = 33.14, and flunitrazepam = 116.00. Because our earlier studies indicated that muscimol-induced myoclonic jerks probably originate from the spinal cord, the present method may prove to be suitable for quantitatively evaluating the effect of benzodiazepines on the spinal cord. The present results also indicate the possible value of flunitrazepam in the management of neurologic disorders in which preferential action on the spinal cord is desired.

Animals↗
PubMed1981

Effect of muscimol, a central GABA receptor agonist, on the catalepsy, striatal homovanillic acid increase, and analgesia induced by pilocarpine in rats.

Muscimol, a structural analog of GABA, significantly potentiated pilocarpine-induced analgesia in rats, but failed to alter pilocarpine-induced catalepsy. It also failed to affect pilocarpine-elicited increase in homovanillic acid levels in the striatum. These findings suggest that the potentiation of pilocarpine-induced analgesia by muscimol is unrelated to an interaction of the GABAergic system with the striatal cholinergic or dopaminergic systems.

Analgesics↗
PubMed1986

Muscimol microinfused into the nigrotegmental target area blocks selected components of behavior elicited by amphetamine or cocaine.

We examined whether behaviors elicited by systemic administration of the stimulants amphetamine and cocaine involve the relay of outflow from basal ganglia to the target region of the GABAergic nigrotegmental pathway (nigrotegmental target area: NTT), in the region of the pedunculopontine nucleus. Bilateral microinfusions of the GABAA agonist muscimol (25 ng in each side) were administered into the NTT in stimulant-treated rats. Amphetamine- and cocaine-induced stereotyped sniffing and repetitive head movements were totally abolished by muscimol infusions. In contrast, stimulant-induced locomotion and snout contact fixation were spared or enhanced. These observations, which extend those of Childs and Gale (1983b) with apomorphine-induced gnawing, further implicate the GABAergic nigrotegmental pathway in the mediation of basal ganglia-related motor dysfunction. On the other hand, cocaine- and amphetamine-induced locomotion and snout contact fixation do not appear to depend upon mediation through GABA-receptive neurons in the NTT. Thus, the NTT may be selective for the processing of outflow from the basal ganglia.

Amphetamine↗
PubMed1983

Diazepam antagonizes GABA- and muscimol-induced changes of acetylcholine release in slices of guinea-pig cerebral cortex.

The acetylcholine (ACh) release was studied in superfused, electrically-stimulated slices of guinea-pig cerebral cortex. Muscimol and 4,5,6,7-tetrahydroisoxazolo (5-4-c)-pyridin-3-ol (THIP), as well as exogenous GABA, reduced the electrically-evoked ACh release and enhanced its spontaneous outflow. Picrotoxin antagonized these effects. In addition, picrotoxin and ethanolamine-O-sulphate (EOS) caused opposite changes in transmitter outflow, suggesting the existence of an exogenous GABAergic control on the cholinergic nerve endings. Neither flurazepam 6.6 X 10(-6)--3.3 X10(-5) mol/l nor diazepam 3.3 X 10(-6)--3.3 X 10(-5) mol/l by themselves affected ACh release. Diazepam prevented GABA-, muscimol- and EOS-induced changes in spontaneous and 1 Hz-evoked outflow. Ro 15-1788 3.3 X 10(*-6) mol/l abolished diazepam antagonism vs exogenous GABA. The ineffectiveness of flurazepam and diazepam on normal release (i.e. the lack of potentiation vs the endogenous GABAergic control) supports the view that "synaptic" GABA receptors acting upon the cholinergic nerve endings are not coupled with Benzodiazepine receptors. The unexpected diazepam antagonism vs exogenous GABA and GABA-like compounds can be explained with an unusual Diazepam negative cooperation with "extrasynaptic" GABA receptors, possibly present on the cholinergic terminals. Thus, the rule of benzodiazepine-GABA synergism does not seem always tenable, at least at certain pre-synaptic sites.

Acetylcholine↗
PubMed1992

Muscimol and flunitrazepam binding sites in a subcellular fraction enriched in rat cerebellar glomeruli.

In the internal granular layer of the cerebellar cortex the polysynaptic complexes called glomeruli consist mainly of homogeneous populations of glutamatergic and GABAergic synapses, both located on granule cell dendrites. A subcellular fraction enriched in glomeruli was prepared from rat cerebellum, and the distribution of GABAA and of benzodiazepine binding sites between membranes derived from this fraction (fraction G) and from a total cerebellar homogenate (fraction T) was studied. The benzodiazepine and GABA binding sites were measured by the binding of agonists [3H]flunitrazepam and [3H]muscimol, respectively. The results indicate that both binding sites are present, but only slightly enriched, in the glomerular synapses. We found a muscimol/flunitrazepam binding site ratio of two, which is consistent with the enrichment of muscimol binding sites in the granular layer shown by both autoradiographic with radioactive glutamatergic ligands and in situ hybridization experiments respectively.

Animals↗
PubMed1987

Binding of [3H]muscimol to calf cerebrocortical synaptic membranes and the effects of sulphur-containing convulsant and non-convulsant compounds.

Endogenous and xenobiotic sulphur-containing convulsant and non-convulsant compounds containing structural moieties of, or bearing a structural resemblance to, GABA and homocysteine were tested in binding studies for their potency in displacing the GABA-mimetic [3H]muscimol from specific, high-affinity sites (Kd = 3.6 nM; Bmax = 3.94 pmol/mg protein) on freeze-thawed, Triton-treated calf-brain synaptic membranes. The xenobiotic convulsants, 4-mercaptobutyric acid (MBA), 3-mercaptopropionic acid (3-MPA) and 2-mercaptopropionic acid (2-MPA) were found to be two-site competitive inhibitors exhibiting apparent inhibition affinity constants (Kiapp) of 5000 microM, 3750 microM, and 4800 microM, respectively; while homocysteic acid (Kiapp = 4800 microM) was shown to be a one-site partial competitive inhibitor. Intermediary metabolites of methionine: S-adenosyl-L-homocysteine, L-cysteine, the convulsant L-homocysteine, and its non-convulsant disulphide oxidation product, homocystine, were found to be one-site partial competitive inhibitors exhibiting Kiapp values of 5750 microM, 8350 microM, 5000 microM, and 510 microM, respectively. The endogenous anticonvulsant neuroeffector, taurine, and the tripeptide, reduced glutathione (GSH) were shown to be, respectively, one-site (Ki = 20 microM) and two-site (Kiapp = 4300 microM) competitive inhibitors of [3H]muscimol binding. These findings are discussed with regard to a previously proposed mechanism for the convulsant action of homocysteine.

Animals↗
PubMed1978

Isoguvacine, isonipecotic acid, muscimol and N-methyl isoguvacine on the GABA receptor in rat sympathetic ganglia.

The GABA-mimetic activities of 4 analogues muscimol, isonipecotic acid, isoguvacine and N-methyl isoguvacine have been examined at the GABA receptor in the rat isolated superior cervical ganglion. The depolarizing action of all 4 analogues could be selectively antagonized by bicuculline methochloride and isopropyl bicyclophosphate. Muscimol was the only analogue more potent than GABA (molar potency ratio = 5.08 +/- 0.707). The potency of isoguvacine was 0.23 +/- 0.026 and isonipecotic acid 0.011 +/- 0.0028. N-methyl isoguvacine was less than 0.001 GABA.

Animals↗