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PubMed1981

Localized binding of [3H]muscimol to synapses in chicken retina.

Binding sites for [3H]muscimol, an analogue of gamma-aminobutyric acid (GABA) were localized in the synaptic layers of chicken retina by light microscopic and electron microscopic autoradiography. Light microscopic autoradiography of cryostat sections incubated in [3H]muscimol or [3H]GABA revealed identical binding patterns: a band over the inner plexiform layer (IPL) and a band over the outer plexiform layer (OPL). This binding pattern differed from the uptake pattern for [3H]GABA: labeling over horizontal, amacrine, and ganglion cell bodies as well as very intense labeling over lamina 5 in the proximal IPL. Statistical analysis of electron microscopic autoradiography data from the IPL indicated that only amacrine synapses bind [3H]muscimol (i.e., make GABAergic synapses). Processes of amacrine, bipolar, or ganglion cells can be postsynaptic to these amacrine synapses. The highest concentration of synapses binding [3H]muscimol occurred in laminae 2 and 4 of the IPL and not in lamina 5 as might be expected from the density of [3H]GABA uptake. In the OPL, [3H]muscimol binding occurred over specialized junctions proximal to photoreceptor terminals. In cone receptor terminals, [3H]muscimol binding was suspected near horizontal cell dendrite/receptor terminal membranes lateral to the synaptic ribbon, supporting the hypothesis that horizontal cells are involved in a GABAergic feedback loop with cone terminals. We conclude that the synaptic binding pattern provides a more accurate concept of GABAergic synaptic interaction than does the uptake pattern for [3H]GABA because the two patterns in the IPL are not related.

Animals↗
PubMedDate not supplied

Suppression of a somatosympathetic reflex by the gamma-aminobutyric acid agonist muscimol and by clonidine.

gamma-Aminobutyric acid (GABA) and GABA agonists, e.g., muscimol, reduce blood pressure and sympathetic outflow and inhibit the "carotid occlusion reflex." In contrast, muscimol exerted only marginal effects on postural reflexes in a prior study. The somatosympathetic reflex, i.e., potentials evoked in sympathetic nerves in response to sensory nerve stimulation, is a useful model for studying centrally acting drugs. Effects of muscimol on the reflex were examined in anesthetized normotensive rats. At doses which had previously been shown to reduce blood pressure but to produce only minimal attenuation of postural reflexes in conscious hypertensive rats, muscimol, administered intracerebroventricularly, reduced blood pressure and inhibited the somatosympathetic reflex in the present study. The time course of the evoked potential was not altered. Baroreceptor activation and intracerebroventricular clonidine also suppressed the reflex. The inhibitory effect of muscimol but not that of clonidine was prevented by pretreatment with the GABA antagonist bicuculline. Thus, the marked suppression of the somatosympathetic reflex by muscimol and by clonidine, in contrast to minimal effects on postural reflexes, point to the selectivity of their central inhibitory actions.

Animals↗
PubMed1995

Contrasting baroreflex effects of muscimol versus bicuculline injected into the nucleus tractus solitarius in anesthetized rats.

To examine how the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) affects baroreflex regulation, reflex heart rate and renal nerve responses were recorded in anesthetized rats after bilateral injections of muscimol or bicuculline into the nucleus tractus solitarius (NTS). Blood pressure, heart rate, and renal nerve activity were increased by the GABA agonist muscimol and decreased by the GABA antagonist bicuculline. Control injections of the vehicle alone were ineffective. More importantly, all reflex responses later induced by infusing phenylephrine or sodium nitroprusside intravenously were reduced by muscimol. The magnitude of the reflex bradycardia and sympathoinhibition caused by phenylephrine, as well as that of the reflex tachycardia and sympathoexcitation caused by sodium nitroprusside, diminished after NTS injections of muscimol. By contrast, the same reflex responses tended to be enhanced after NTS injections of bicuculline, but most changes were not significant. If GABA acts on receptors located on second-order neurons in the NTS, then muscimol would inhibit those neurons, whereas bicuculline would prevent endogenous GABA from reaching them. Thus muscimol would reduce reflex responsiveness by inhibiting all second-order neurons, whereas bicuculline would enhance it by protecting the same neurons from inhibition by endogenous GABA.

Analysis of Variance↗
PubMed1983

Synergistic inhibition of [3H]muscimol binding to calf-brain synaptic membranes in the presence of L-homocysteine and pyridoxal 5'-phosphate. A possible mechanism for homocysteine-induced seizures.

L-Homocysteine and pyridoxal 5'-phosphate (PxyP) inhibited [3H]muscimol binding to freeze-thawed, Triton-treated calf brain membranes (containing high-affinity muscimol-binding sites: Kd 9.5 +/- 0.6 nM, Bmax 5.2 +/- 0.2 pmol/mg protein). The homocysteine--pyridoxal-5'-phosphate (Hcy-PxyP) thiazine complex had no effect. L-Homocysteine was found to be a partially competitive inhibitor, thus demonstrating an allosteric inhibition with Ki value of 1.96 mM for free receptor and Ki of 13 mM for receptor-muscimol complex. PxyP was shown to be a two-site pure competitive inhibitor of [3H]muscimol binding with cooperativity of PxyP binding such that Ki values for PxyP of 20 mM and 2.1 mM were found. L-Homocysteine and PxyP when added simultaneously to binding assays, caused a greater degree of inhibition than that observed at the same total specific concentration of either inhibitor alone. This synergistic inhibitory effect was shown to be due to a homocysteine-induced increase in the affinity of PxyP-binding sites. Three alternative models are suggested to explain the observed synergistic effects whereby it is proposed that PxyP and [3H]muscimol binding is mutually exclusive, while L-homocysteine with PxyP and L-homocysteine with muscimol, exhibit non-exclusivity. Non-linear regression analysis of binding data was undertaken in order to substantiate conclusions drawn from graphical procedures and in an attempt to ascertain which mathematical model best fitted the experimental data describing the synergistic inhibitory effects of L-homocysteine and PxyP. This synergistic inhibitory effect of PxyP and L-homocysteine on the post-synaptic gamma-aminobutyric acid receptor may provide a basis for explanation of the mechanism of homocysteine-induced seizures.

Animals↗
PubMed1980

Increase in striatal [3H]muscimol binding following intrastriatal injection of kainic acid: a denervation supersensitivity phenomenon.

The effect of intrastriatal microinjection of kainic acid (KA) on specific binding of [3h]muscimol to the particulate fractions obtained from corpus striatum (CS), globus pallidus (GP), substantia nigra (SN), and cerebral cortex (CC) was examined. Seven days after the unilateral intrastriatal microinjection of KA, the amount of specifically bound [3H]muscimol was significantly increased at the injected site, whereas no significant alteration of [3H]muscimol binding was found in GP, SN, or CC. Scatchard analysis of striatal binding revealed that microinjection of KA significantly increased the affinity (KD) of GABA receptors on the injected (lesioned) side of the CS without affecting the total number of binding sites (Bmax) therein. This significant increase in [3H]muscimol binding, however, was eliminated by pretreating particulate fractions from the CS with Triton X-100, a non-ionic detergent. No statistically significant difference in amounts of [3H]muscimol binding was detected when the preparations from the KA-treated and non-treated CS were preincubated with 0.05% Triton X-100, respectively. Scatchard analysis using CS preparations treated with 0.05% Triton X-100 revealed that the affinity of the GABA receptor was increased by treatment with Triton X-100, while the total number of binding sites (Bmax) was unchanged by this treatment. These results suggest that neuronal degeneration produced by KA in vivo and pretreatment of particulate preparations with Triton X-100 in vitro may increase the amount of specifically bound [3H]muscimol to CS preparations by a similar molecular mechanism.

Animals↗
PubMed1983

Depolarizing responses to glycine, beta-alanine and muscimol in isolated optic nerve and cuneate nucleus.

Concentration-dependent depolarizations were evoked by glycine and beta-alanine 5 X 10(-4)-10(-2)M and by the gamma-aminobutyric acid (GABA) analogue, muscimol 10(-6)-10(-4)M. The maximal response to glycine was several-fold higher than that to muscimol on optic nerve but the reverse was found on the dorsal funiculus fibres in the cuneate nucleus. beta-Alanine evoked a similar maximal response to glycine on optic nerve but a considerably higher maximum than glycine in the cuneate nucleus. Strychnine was 19.5 times more potent as a glycine antagonist (pA2 = 6.58) than as a muscimol antagonist. Bicuculline was 156 times more potent as a muscimol antagonist than as a glycine antagonist. Other antagonists of muscimol, i.e. tubocurarine, picrotoxin and leptazol, and potentiators of muscimol, i.e. pentobarbitone and flurazepam, had little or no effect on responses to glycine. Responses to beta-alanine had pharmacological properties compatible with a mixed action on both GABA and glycine receptors. The rat isolated optic nerve appears to be a useful preparation for studying the pharmacology of the neuronal glycine receptor plus chloride ionophore complex.

Alanine↗
PubMed1989

Binding of [3H]-muscimol to GABAA sites in the guinea-pig urinary bladder: biochemical assay and autoradiography.

1. The specific binding of [3H]-muscimol, a gamma-aminobutyric acidA receptor (GABAA) agonist, to whole membranes of the guinea-pig urinary bladder was examined. In addition, the distribution of specific muscimol binding sites within the bladder was visualized by autoradiography. 2. It was demonstrated that in a frozen-thawed whole membrane preparation of the organ the specific binding of [3H]-muscimol is reproducible, reversible and saturable. 3. Saturable binding was of a single component with an equilibrium dissociation constant (Kd) of 12 nM and a maximal density (Bmax) of about 80 fmol mg-1 protein. 4. In displacement experiments with several model compounds, [3H]-muscimol binding sites showed the characteristics of a GABAA receptor site. 5. Autoradiographic experiments revealed uneven distribution of specifically bound [3H]-muscimol in the bladder. The density of binding sites was high in clusters within the smooth muscle layers of the bladder fundus and of the urethra, while the apex and the neck were not specifically labelled. 6. The present findings show that GABAA type receptor sites in the guinea-pig urinary bladder may be labelled by [3H]-muscimol in a specific and reproducible manner. Moreover, the localization of these binding sites is consistent with the presence of GABAA receptors in only a subpopulation of vesical ganglia.

Animals↗
PubMed1995

Induction of a novel form of hippocampal long-term depression by muscimol: involvement of GABAA but not glutamate receptors.

1. Unlike long-term potentiation, long-term depression (LTD) in the central nervous system remains poorly understood. The present study was undertaken to investigate the role of GABAA receptors in LTD and synaptic plasticity. 2. Extracellular recordings were made in the CA1 pyramidal cell layer of rat hippocampal slices following orthodromic stimulation of Schaffer collateral fibres in stratum radiatum (0.01 Hz). 3. Muscimol induced a time- and concentration-dependent LTD of the amplitude of orthodromic potentials. Increasing the stimulation frequency from 0.01 Hz to 1 Hz for 10 s reversed the LTD induced by muscimol. Muscimol also induced LTD in the absence of electrical stimulation. 4. Adenosine decreased the spike size in a concentration-dependent manner, but failed to induce LTD. 5. Alphaxalone and 5 alpha-pregnan-3 alpha-ol-20-one at concentrations that did not have any effect themselves on the population spike (0.5 and 1 microM), potentiated the inhibitory effect of muscimol on the population spike size, including concentrations which were not effective by themselves. Both steroids were able to potentiate the ability of muscimol to induce LTD. 6. Bicuculline, 5 microM, reversed the LTD induced by muscimol, 10 microM. 7. The NMDA receptor antagonist (+/-)-2-amino-5-phosphonopentanoic acid (2-AP5), the NMDA/metabotropic antagonist 2-AP3 and selective metabotropic antagonist L-(+)-2-amino-3-phosphonopropionic acid (L(+)-AP3) failed to modify the LTD. Similarly, quisqualic acid and (1S, 3R)-aminocyclopentane dicarboxylic acid (ACPD) a selective agonist at metabotropic receptors did not induce LTD or short-term depression, whereas kynurenic acid prevented the reversal of the LTD obtained at 1 Hz. 8. It is concluded that LTD can be induced by the selective activation of GABAA receptors. The lack of involvement of glutamate receptors in our protocol confirms the unique nature of the LTD described here. The phenomenon of GABA-induced LTD and its reversal by 1 Hz stimulation may represent a novel type of long-lasting depression by which inhibitory interneurones can modulate pyramidal cell excitability in a frequency-dependent manner.

Action Potentials↗
PubMed1995

Central inhibitory effects of muscimol and bicuculline on the milk ejection reflex in the anaesthetized rat.

1. In order to determine whether GABAergic mechanisms are involved in the control of the milk ejection reflex in the rat, we examined the effects of central administration of a GABAA receptor agonist (muscimol) and antagonist (bicuculline) on the milk ejection reflex in the urethane-anaesthetized rat. 2. Intracerebroventricular (i.c.v.) injection of both muscimol (n = 17), at doses of 5, 10 and 20 ng, and bicuculline (n = 15), at doses of 0.01, 0.1 and 0.3 microgram, inhibited the milk ejection reflex in a dose-dependent manner. The bicuculline-induced inhibition was accompanied by desynchronization of the electroencephalogram and, at the highest dose, by alteration in the sensitivity of the mammary gland to oxytocin. No significant effect on the milk ejection reflex was seen with i.c.v. isotonic saline (n = 5). 3. Injection of 20 (n = 5) or 40 ng (n = 2) muscimol or 0.1 microgram bicuculline (n = 5) i.c.v. did not significantly alter the rise in intramammary pressure evoked by electrical stimulation of the neurohypophysis. 4. Bilateral 400 nl microinfusions directly into the supraoptic nuclei of either muscimol (20-100 ng microliter(-1); n = 10) or bicuculline (0.15 micrograms microliter(-1); n = 5) [corrected] resulted in an inhibition of the milk ejection reflex, which was not accompanied by desynchronization of the electroencephalogram. 5. The effects of i.c.v. injections of muscimol (15 and 20 ng) and bicuculline (0.01, 0.12 and 0.3 microgram) on the electrical activity of twenty-seven antidromically identified supraoptic magnocellular neurones were examined. Both compounds resulted in an inhibition of the background firing of oxytocinergic and vasopressinergic cells, and delayed the occurrence of high frequency bursts in oxytocin neurones. In five supraoptic neurones, bicuculline induced a transient activation before inhibition. 6. The powerful inhibitory action on the milk ejection reflex of both muscimol and bicuculline provides evidence for the importance of GABA neurones in maintaining the functional integrity of the mechanisms which allow the intermittent and pulsatile release of oxytocin during suckling.

Action Potentials↗
PubMed1988

Comparison between pentobarbital- and muscimol-induced feeding in satiated sheep.

Twenty sheep were used to study the mechanisms by which the intracerebral administration of pentobarbital and of muscimol induces feeding in ruminants. Injections of 1 mumol calcium induced a weak feeding response at 1 h postinjection compared with control values (108 vs. 63 g, p less than 0.05). Injections of 78 mumol pentobarbital and of 100 nmol muscimol elicited strong feeding responses (p less than 0.01). A preinjection of 1 mumol calcium reduced the response to pentobarbital by about 40% but did not affect the response to muscimol. Administration of 1.1 mmol sodium chloride reduced the effect to pentobarbital by about 60% but only partially decreased the effect to muscimol. Administration of picrotoxin, a GABA antagonist, slightly decreased the feeding response to pentobarbital and to muscimol. Administration of gamma-vinyl GABA, an inhibitor of the enzyme GABA transaminase, did not affect feeding behavior of sheep at any of the doses tested (0-10 mumol). Injections of gamma-vinyl GABA followed by equimolar injections of GABA failed to provoke any feeding response. The data suggest that pentobarbital and muscimol may induce feeding by acting on a similar hypothalamic receptor complex but by different mechanisms. The lack of effect of GABA itself remains unexplained.

Aminocaproates↗
PubMed1994

Effect of muscimol microinjections into the prepositus hypoglossi and the medial vestibular nuclei on cat eye movements.

1. For horizontal eye movements, previous observations led to the hypothesis that the legendary neural integrator necessary for correct gaze holding, adequate vestibuloocular reflex (VOR), and optokinetic nystagmus, was located in the region of the complex formed by the nucleus prepositus hypoglossi (NPH) and the medial vestibular nucleus (MVN). 2. The aim of the present study was to test the respective contributions of the NPH, of the rostral part of the MVN, which contains most second-order vestibular neurons, and of the central part of the MVN to the horizontal integrator. 3. An injection of muscimol was used to inactivate each of these three zones in the cat's brain. Muscimol is a gamma-aminobutyric acid (GABA) agonist. By binding to GABAA receptors, it induces a hyperpolarization of the neurons that nullifies their activity. Muscimol was injected into the brain stem of the alert cat through a micropipette by an air pressure system. 4. The search coil technique was used to record spontaneous eye movements and the VOR induced by rotating a turntable at a constant velocity. VOR was analyzed by a new method: transient analysis of vestibular nystagmus. 5. A unilateral injection of muscimol into the NPH induced a bilateral gaze-holding failure: saccades were followed by a centripetal postsaccadic drift. A vestibular imbalance was also present but it was moderate and variable. The VOR responses were distorted drastically. Through transient analysis of vestibular nystagmus, that distortion was revealed to be due more to a failure of the neural integrator than to an alteration of the vestibular input to the neural integrator. The responses to a rotation either toward the injected side or in the opposite direction were asymmetrical. The direction of that asymmetry was variable. 6. A unilateral injection of muscimol into the rostral part of the MVN caused a vestibular imbalance: in complete darkness, a nystagmus appeared, whose linear slow phases were directed toward the side of injection. 7. A unilateral injection of muscimol into the central part of the MVN induced a syndrome where a severe bilateral gaze-holding failure was combined with a vestibular imbalance. In the light, saccades were followed by a bilateral centripetal postsaccadic drift. In complete darkness, a nystagmus was observed, whose curved slow phases were directed towards the side of injection. The VOR responses were distorted drastically. Here again, that distortion was revealed by our analysis to be due more to a failure of the neural integrator than to an alteration of the vestibular input to the neural integrator.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1997

Muscimol and midazolam do not potentiate each other's effects on sleep EEG in the rat.

The interaction of a gamma-aminobutyric acid-A (GABAA) receptor agonist and a benzodiazepine-type modulator of GABAA receptors on sleep was investigated. Low doses of muscimol (0.3 mg/kg) and the benzodiazepine midazolam (1.5 mg/kg) were administered alone and in combination, in random order, to eight rats. All injections were given intraperitoneally at light onset. Electroencephalogram (EEG) and electromyogram were recorded during the first 6 h post injection. Compared with vehicle, muscimol hardly affected the time spent in non-rapid eye movement sleep (non-REMS) and REMS, but significantly enhanced EEG activity in the frequency range between 2 and 6 Hz during non-REMS. Midazolam significantly increased the time spent in non-REMS, reduced EEG activity at frequencies < 12 Hz, and elevated EEG activity in most higher frequencies during this state. The combined administration of muscimol and midazolam affected non-REMS-specific EEG activity in an unexpected fashion: the effects were intermediate between those of muscimol and midazolam. These results indicate that muscimol and midazolam have dissimilar effects on EEG within non-REMS and demonstrate that midazolam does not augment but attenuates the muscimol-induced changes in sleep EEG. Our data are at variance with established mechanisms, according to which agonistic modulators would have similar effects and should potentiate the effects of GABAA agonists. The present data suggest that application of agonists and agonistic modulators of GABAA receptors causes differential net effects on sleep parameters.

Animals↗
PubMed1998

Deficits in smooth-pursuit eye movements after muscimol inactivation within the primate's frontal eye field.

To evaluate smooth-pursuit (SP) function in the primate frontal eye field (FEF), microinjections of muscimol, a gamma-aminobutyric acid (GABA) agonist, were used to reversibly deactivate physiologically characterized sites in FEF. SP was severely impaired by deactivation at sites in the FEF's smooth eye movement region (FEFsem) located in the fundus and posterior bank of the macaque monkey's arcuate sulcus. These SP deficits were apparent immediately after the muscimol injection and persisted for several hours but recovered by the next day. SP was most drastically and consistently impaired for directions similar to the injected site's elicited smooth eye movement direction or to the optimal SP direction for its neuronal responses. Targets moving in these directions, usually ipsilateral to the injected hemisphere, were tracked primarily with saccades after the muscimol injection, the peak SP velocity being only 10-30% of preinjection velocity. SP in other directions, including contralateral, was less strongly affected. Initial SP acceleration in response to target motion onset was also significantly diminished, generally by approximately the same proportion as peak SP velocity. In contrast, saccades were largely unaffected by muscimol injections in FEFsem; nor was there an immediate effect on SP when control sites in the saccadic region of FEF (FEFsac) were deactivated, although a SP deficit often appeared 30-60 min after FEFsac injections, possibly reflecting diffusion of muscimol into neighboring FEFsem. These reversible SP deficits produced by muscimol inactivation within FEFsem are similar to permanent deficits caused by large aspiration lesions of FEF and indicate that inclusion of FEFsem is the critical factor determining whether FEF lesions impair SP. The severity of the reversible deficits found here indicates how extremely critical FEFsem is for normal highgain SP.

Animals↗
PubMed2005

Local distribution and toxicity of prolonged hippocampal infusion of muscimol.

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.

Animals↗
PubMed1990

Electrical activity and feeding correlates of intracranial hypothalamic injection of GABA, muscimol and picrotoxin in the rats.

Assemblies of electrodes and a cannula were stereotaxically implanted in the ventromedial (VMH), lateral (LHA) and paraventricular (PVH) hypothalamic areas in male albino rats. Electrical activity of these regions was recorded electrographically before and following intracranial injection (ICI) of GABA, muscimol and picrotoxin. In another set of animals, food intake and water intake were also measured. The activity of the ventromedial hypothalamus changed from slow to fast after ICI of GABA and picrotoxin and fast to slow after muscimol. The activity of the lateral hypothalamus changed from slow to fast with ICI of muscimol and picrotoxin and from fast to slow with GABA, while that of the paraventricular hypothalamic nucleus changed from slow to fast with ICI GABA and fast to slow with muscimol and picrotoxin. ICI of GABA into VMH and LHA and muscimol in VMH, LHA and PVH caused a decrease in food intake. Water intake was also decreased after ICI of GABA in PVH and muscimol in LHA and PVH. On the opposite picrotoxin increased food intake in VMA and LHA and water intake in PVH. The possible interaction of GABAergic drugs with the areas of the brain controlling feeding and drinking is being discussed.

Action Potentials↗
PubMed1990

Bilateral alterations in local cerebral glucose utilization following intranigral application of the GABAergic agonist muscimol.

Rates of cerebral glucose utilization were measured by means of the autoradiographic 2-deoxy-D-[1-14C] glucose technique in 70 anatomically discrete central nervous structures in conscious awake rats following unilateral intranigral application of the GABAergic agonist muscimol. Intranigral injection of 1.3 microliters 1 microM muscimol (0.15 ng) induced increases in glucose consumption locally in the substantia nigra reticulata (by 87%), distally in the contralateral reticulata, red nucleus, nucleus accumbens, and prefrontal cortex, and bilaterally in the pyriform cortex, as compared to values in control animals. Intranigral injection of 1.3 microliters 1 mM muscimol (150 ng) effected a local metabolic activation in the substantia nigra reticulata (by 111% compared to the control group) and in compacta (by 18%), as well as a distal activation in the contralateral reticulata (by 39%) and contralateral compacta (by 29%). Beyond the structures affected by the lower dose, the higher dose of muscimol elicited widespread bilateral increases in glucose metabolism in the rat brain. Among the principal nigral reticulata efferent projections, the deep superior colliculi displayed ipsilateral metabolic activation (by 30%), whereas the parafascicular, mediodorsal, and ventromedial thalamic projecting areas, as well as the pedunculopontine nucleus, displayed bilateral activations compared to the control animals. The ventromedial and ventrolateral thalamic nuclei contralateral to the injected substantia nigra reticulata were 20% activated compared to the ipsilateral homologous structures and 30% activated compared to the control rats. The areas that send afferent projections to the reticulata (globus pallidus, entopeduncular and subthalamic nuclei) were mainly activated contralateral to the injected reticulata compared to values for control animals. In general, following intranigral muscimol (1 mM) injection, glucose metabolism was activated to a larger extent on the side contralateral to the injection than on the ipsilateral side. It is suggested that the present findings are due to a presynaptic nigral effect of muscimol on the GABAergic autoreceptors of the striatonigral terminals and to a consequent disinhibition of the reticulata GABAergic output.

Animals↗
PubMed1984

Muscimol-scopolamine interactions in the rat brain: a study with 2-deoxy-D-[1-14C]glucose.

The 2-deoxy-D[1-14C]glucose method of Sokoloff was used to measure local cerebral glucose utilization (LCGU) in rats after injections of the GABA receptor agonist, muscimol (1.6 mg/kg and 4.0 mg/kg, i.v.); the muscarinic receptor antagonist, scopolamine (0.4 mg/kg and 2.0 mg/kg, i.v.); or combinations of both drugs. The aim was to identify brain regions where functional effects of GABAergic-cholinergic interactions could be seen. As noted previously, muscimol reduced LCGU in many brain regions. In contrast, scopolamine alone had no effect on LCGU in most brain regions; however, decreases were seen in the medial geniculate body, medial thalamic nucleus, and auditory and frontal cortical areas. Scopolamine increased LCGU in the cerebellar vermis and mesencephalic reticular formation. Although muscimol alone did not significantly affect LCGU in the external plexiform layer of the olfactory bulb or the anterior, periventricular, and parafascicular thalamic nuclei, rats treated with 0.4 mg/kg of scopolamine before 4.0 mg/kg of muscimol had LCGU decrements in those brain regions. Furthermore, the muscimol-induced decrease in LCGU in the medial cortex was enhanced by prior treatment with 0.4 mg/kg of scopolamine. In contrast, in certain brain regions where muscimol alone reduced LCGU (locus ceruleus; central gray matter; striatum; ventral, medial, reunients , and rhomboid thalamic nuclei; and the auditory cortex), scopolamine pretreatment antagonized these decrements. These findings suggest that endogenous cholinergic and GABAergic systems act antagonistically in some brain regions. However, in other brain regions, cholinergic transmission is required for full expression of GABAmimetic effects on LCGU.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Linear relationship between GABAA receptor occupancy of muscimol and glucose metabolic response in the conscious mouse brain. Clinical implication based on comparison with benzodiazepine receptor agonist.

The effect of muscimol, a GABAA receptor agonist, on the basic metabolic activity was investigated in the mouse brain and was correlated with its receptor occupancy. For the quantitative evaluation of the functional activity of the mouse brain, the cerebral glucose utilization was measured by the double tracer technique, using [14C] 2-deoxyglucose and [3H]3-O-methylglucose. The dose-dependent reduction in the cerebral glucose utilization was observed after intravenous administration of various doses of muscimol (0.3-1.5 mg/kg). On the other hand, the GABAA receptor occupancy of muscimol was determined by using the values of the unbound drug concentration in the brain tissue and the receptor dissociation constant based on the in vitro binding experiments using the dissociated brain cells. The tissue unbound concentration of muscimol was calculated by multiplying the total concentration in the brain after administration of muscimol and the tissue unbound fraction, which was measured by the equilibrium dialysis method using brain tissue homogenate. A linear relationship was observed between the GABAA receptor occupancy of muscimol and the decrease in the cerebral glucose utilization. This finding indicates that the simple receptor occupancy theory holds for this receptor-ligand system, and there is a large difference in the effect on glucose metabolic response between GABAA receptor-agonist interaction and benzodiazepine receptor-agonist interaction.

Animals↗