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PubMed1999

Reacquisition deficits in prism adaptation after muscimol microinjection into the ventral premotor cortex of monkeys.

A small amount of muscimol (1 microl; concentration, 5 microg/microl) was injected into the ventral and dorsal premotor cortex areas (PMv and PMd, respectively) of monkeys, which then were required to perform a visually guided reaching task. For the task, the monkeys were required to reach for a target soon after it was presented on a screen. While performing the task, the monkeys' eyes were covered with left 10 degrees, right 10 degrees, or no wedge prisms, for a block of 50-100 trials. Without the prisms, the monkeys reached the targets accurately. When the prisms were placed, the monkeys initially misreached the targets because the prisms displaced the visual field. Before the muscimol injection, the monkeys adapted to the prisms in 10-20 trials, judging from the horizontal distance between the target location and the point where the monkey touched the screen. After muscimol injection into the PMv, the monkeys lost the ability to readapt and touched the screen closer to the location of the targets as seen through the prisms. This deficit was observed at selective target locations, only when the targets were shifted contralaterally to the injected hemisphere. When muscimol was injected into the PMd, no such deficits were observed. There were no changes in the reaction and movement times induced by muscimol injections in either area. The results suggest that the PMv plays an important role in motor learning, specifically in recalibrating visual and motor coordinates.

Adaptation, Physiological↗

PubMed1994

Muscimol prevents neuronal injury induced by NMDA.

The effect of muscimol on N-methyl-D-aspartate (NMDA)-induced injury of primary cultured cerebral cortical neurons was examined. NMDA induced a dose-dependent leakage of LDH activity, which was significantly inhibited by (+-)-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]cyclopentan-5,10-imine (MK-801). Muscimol significantly reduced the NMDA-induced increase of lactic dehydrogenase (LDH) leakage, and bicuculline abolished this protective effect of muscimol. Similarly, muscimol reduced the NMDA-induced increase in trypan blue staining of the cells, and bicuculline suppressed this inhibitory action of muscimol. These results suggest that GABAA-receptor stimulation exerts a protective action against the neuronal injury induced by NMDA-receptor activation.

Animals↗

PubMed1989

Effect of intraventricular injection of muscimol on appetite in rats kept at high and temperate ambient temperatures.

The central mechanism controlling food intake in response to the change in environmental temperature has been little examined. The GABA agonist, muscimol, was injected into the lateral ventricle of rats which were acclimated to temperate (26 degrees C) and hot (33 degrees C) environments. Muscimol obviously stimulated the feeding behavior of rats in both environments. However, when muscimol was administered at doses of 100 and 250 ng, the food intake at 26 degrees C was greater than that at 33 degrees C. In addition, the stimulating effect of muscimol (250 ng) on food intake at 26 degrees C lasted longer than that at 33 degrees C. These findings suggested that there might be a difference in muscimol metabolism at the two temperatures.

Acclimatization↗

PubMed1999

Neuromuscular activity blockade induced by muscimol and d-tubocurarine differentially affects the survival of embryonic chick motoneurons.

To understand better how spontaneous motoneuron activity and intramuscular nerve branching influence motoneuron survival, we chronically treated chicken embryos in ovo with either d-tubocurarine (dTC) or muscimol during the naturally occurring cell death period, assessing their effects on activity by in ovo motility measurement and muscle nerve recordings from isolated spinal cord preparations. Because muscimol, a GABA(A) agonist, blocked both spontaneous motoneuron bursting and that elicited by descending input but did not rescue motoneurons, we conclude that spontaneous bursting activity is not required for the process of normal motoneuron cell death. dTC, which rescues motoneurons and blocks neuromuscular transmission, blocked neither spontaneous nor descending input-elicited bursting and early in the cell death period actually increased burst amplitude. These changes in motoneuron activation could alter the uptake of trophic molecules or gene transcription via altered patterns of [Ca(2+)](i), which in turn could affect motoneuron survival directly or indirectly by altering intramuscular nerve branching. A good correlation was found between nerve branching and motoneuron survival under various experimental conditions: (1) dTC, but not muscimol, greatly increased branching; (2) the removal of PSA from NCAM partially reversed the effects of dTC on both branching and survival, indicating that branching is a critical variable influencing motoneuron survival; (3) muscimol, applied with dTC, prevented the effect of dTC on survival and motoneuron bursting and, to a large extent, its effect on branching. However, the central effects of dTC also appear to be important, because muscimol, which prevented motoneuron activity in the presence of dTC, also prevented the dTC-induced rescue of motoneurons.

Animals↗

PubMed1989

[Effects of muscimol on aggressive behaviors induced by clonidine in mice].

A behavioral study was carried out to clarify a relationship between the GABAergic and purinergic central system in aggressive behaviors induced by clonidine in mice. Mice administered a high dose of clonidine (20 mg/kg, i.p.) exhibited aggressive behaviors such as biting and attacking. These behaviors are inhibited by L-PIA (N6-L-phenylisopropyl adenosine) and stimulated by caffeine, which suggest that a blockade of adenosine receptors is involved in these behaviors. Muscimol (0.5-2 mg/kg, i.p.), a GABA-a receptor agonist, not only markedly potentiated clonidine (20 mg/kg i.p.)-induced aggressive behaviors but also elicited characteristic behaviors such as gnawing, reinforced irritability, and self-mutilation. Bicuculline (1, 2 mg/kg, i.p.), a GABA-a receptor antagonist, or picrotoxin (1 mg/kg, i.p.), a chloride channel blocker, did not significantly affect clonidine (20 mg/kg, i.p.)-induced aggressive behaviors. The potentiating effects of muscimol (0.5, 1 mg/kg, i.p.) on clonidine-induced aggressive behaviors were antagonized by bicuculline (1, 2 mg/kg, i.p.), but not affected significantly by picrotoxin (1 mg/kg, i.p.). L-PIA (0.2 mg/kg, i.p.) reduced clonidine-induced aggressive behaviors and also reversed the potentiating effects of muscimol. Stereotyped gnawing behaviors induced by combined treatment of muscimol (0.5, 1 mg/kg, i.p.) and clonidine (20 mg/kg, i.p.) were not affected by bicuculline (2 mg/kg, i.p.). The results suggest that the potentiating effects of muscimol on clonidine-induced aggressive behaviors may be induced via the stimulation of GABA-a receptors, although not necessarily associated with chloride channel functions, and may involve certain interactions between the stimulation of GABA-a receptors and the inhibition of adenosine receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Aggression↗

PubMed1983

Changes in [3H]muscimol binding in substantia nigra, entopeduncular nucleus, globus pallidus, and thalamus after striatal lesions as demonstrated by quantitative receptor autoradiography.

A quantitative autoradiographic technique for measuring the binding of [3H]muscimol to central nervous system GABA receptors is described using tritium-sensitive film. [3H]Muscimol binding was studied in primary and secondary striatal projection areas of rat brain following kainic acid lesions of the striatum. Seven days after the lesion, binding affinities in the striatum and its projection areas were not altered significantly. There was a loss of [3H]muscimol receptors in the striatum. Receptors increased in numbers in the ipsilateral globus pallidus (19%), entopeduncular nucleus (22%), and substantia nigra pars reticulata (38%). [3H]Muscimol binding was decreased in the ipsilateral anteroventrolateral and ventromedial (8%) thalamic nuclei. [3H]Muscimol binding in other brain areas (layer IV of the cerebral cortex, central gray, superior colliculus, and stratum moleculare of hippocampus) was not affected. The findings suggest that a loss of striatal innervation resulted in increased numbers of GABA receptors in striatal projection sites. It is further suggested that loss of inhibitory striatal inputs to neurons in the entopeduncular nucleus and substantia nigra pars reticulata may activate GABAergic projections to thalamus and thus result in decreased numbers of thalamic GABA receptors.

Animals↗

PubMed1993

Pharmacodynamic interaction of clonidine and muscimol in hypertension.

The effect of the GABA agonist muscimol on the hypotensive action of clonidine in SHR was investigated. Muscimol administered before clonidine significantly (p < 0.01) intensified clonidine-induced reduction of blood pressure. This effect was achieved at muscimol doses which themselves had no influence on blood pressure. Muscimol injected after clonidine was ineffective. Our data suggest that the muscimol-clonidine interaction occurs at the level of GABAergic neurotransmission since both agents have been proved to activate the function of GABAergic neurons.

Analysis of Variance↗

PubMed1996

Muscimol acts in dorsomedial but not paraventricular hypothalamic nucleus to suppress cardiovascular effects of stress.

Both the dorsomedial hypothalamic nucleus (DMH) and the paraventricular hypothalamic nucleus (PVN) have been implicated in the neural control of the cardiovascular response to stress. We used the GABAA agonist muscimol to inhibit neuronal activation and attempted to identify hypothalamic nuclei required for the cardiovascular response to air stress. Chronically instrumented rats received bilateral injections of either 80 pmol of muscimol or 100 nl of saline vehicle into the DMH, the PVN, or an intermediate area (including the rostral edge of the DMH and the region between the two nuclei) and were placed immediately in a restraining tube and subjected to 20 min of air stress. In all rats, air stress after vehicle injections caused marked increases in heart rate (137 +/- 6 beats/min) and blood pressure (26 +/- 2 mmHg). Microinjection of muscimol into the DMH suppressed the heart rate and blood pressure response by 85 and 68%, respectively. Identical microinjection of muscimol into the intermediate area between the DMH and the PVN attenuated the increases in heart rate by only 46% and in blood pressure by 52%. In contrast, similar injections into the vicinity of the PVN failed to alter the cardiovascular response to air stress. These findings demonstrate that muscimol-induced inhibition of neuronal activity in the region of the DMH blocks air stress-induced increases in heart rate and arterial pressure, whereas similar treatment in the area of the PVN has no effect.

Air↗

PubMed1994

Effect of dorsal raphe injections of the GABAA agonist, muscimol, on ethanol intake and measures of intoxication in Wistar rats.

Peripheral administration of selective agents for GABAA receptors have been reported to modify ethanol self-administration behaviour. Recently, it has been reported that the dorsal and median raphe may represent potential brain sites for mediating these effects since injection of the GABAA agonist, muscimol, into these sites increased ethanol intake. The aim of the present study was to extend these findings and assess the effect of muscimol, injected into either the dorsal or median raphe, on a range of parameters including ethanol intake, ethanol-induced hypothermia and ethanol-induced suppression of high rates of responding. Wistar rats trained to drink 12% ethanol for 40 mins each day, increased their ethanol consumption, but not water consumption, following injection of 50 ng muscimol into the dorsal raphe. Ethanol intakes returned to baseline levels the day following drug treatment. The same dose injected into the median raphe has been shown to produce a non-selective increase in both water and ethanol intake. Further analysis of this data revealed that the rats tended to avoid the ethanol solution on the day following treatment. A further difference between the dorsal and median raphe was revealed in the ethanol-induced hypothermia experiment. Thus, 10 ng muscimol injected into the median raphe potentiated the hypothermic response induced by intraperitoneal injection of 1.5 g/kg ethanol, whereas injection into the dorsal raphe had no significant effect on this measure. Intraperitoneal injection of 0.5 g/kg ethanol suppressed operant responding for water intake and this behaviour was not altered by dorsal raphe injection of muscimol. Together these results suggest that GABAergic mechanisms within the dorsal raphe represent an important neural site for controlling the ingestion of ethanol, but not that of ethanol intoxication.

Alcohol Drinking↗

PubMed1978

Huntington's disease: treatment with muscimol, a GABA-mimetic drug.

Muscimol, a gamma-aminobutyric acid (GABA) analogue that exerts potent and specific agonist effects on GABA receptors, was administered orally to 10 patients with Huntington's disease. In this double-blind study, muscimol treatment did not result in improvement in these patients' motor or cognitive functions. However, muscimol administration did ameliorate chorea in the most severely hyperkinetic patient, and it was associated with the appearance of dystonic features, electroencephalographic changes, and behavioral alterations in some patients. These latter observations support a functional relationship between GABA-ergic activity and the genesis of both systonia and EEG abnormalities in humans. The therapeutic failure of muscimol indicates that the GABA disturbances in Huntington's disease does not alone account for the clinical features of this disorder.

Activities of Daily Living↗

PubMed1981

GABAergic synapses in the goldfish retina: an autoradiographic study of 3H-muscimol and 3H-GABA binding.

The localization of synaptic receptor sites for gamma-amino butyric acid (GABA) in the goldfish retina was studied by light microscopic (LM) and electron microscopic autoradiography (EM-ARG) of 3H-muscimol and 3H-GABA binding. Sodium-independent binding of both 3H-muscimol and 3H-GABA was localized to a uniform band throughout the inner plexiform layer (IPL) by LM-ARG of cryostat sections incubated in these compounds. No binding was observed over the outer plexiform layer. This binding pattern differs from the uptake pattern of 3H-GABA in the IPL, which shows very heavy labeling in the most proximal IPL and little labeling throughout the rest of the IPL. Statistical analysis of EM-ARGs of 3H-muscimol labeling in the IPL suggests that only amacrine synapses bind 3H-muscimol (i.e., make GABAergic synapses). Labeled amacrine-to-amacrine synapses are mostly concentrated in the 20-80% levels of the IPL, whereas amacrine-to-bipolar synapses are concentrated at about the 70-90% depth. Maximal 3H-GABA uptake, however, occurs at the 90-100% depth. This difference in the location of GABAergic synaptic binding and GABAergic uptake leads to the conclusion that the density of uptake label provides little information about the density of synaptic contacts. Thus, in order to localize GABAergic interactions, synaptic binding rather than neuronal uptake appears to provide the more appropriate description.

Animals↗

PubMed1996

Intraseptal microinfusion of muscimol: effects on hippocampal formation theta field activity and phasic theta-ON cell discharges.

The effect of intraseptal microinfusions of the GABA-A agonist muscimol on spontaneously occurring or hypothalamically induced hippocampal formation (HPC) theta field activity and the simultaneously occurring discharge properties of CA1 pyramidal and dentate granule layer phasic theta-ON cells, was investigated in urethane-anesthetized rats. The microinfusion of 5.0-12.5 nmol of muscimol into the medical septum/vertical limb of the diagonal band of Broca (MS/vDBB) resulted in a progressive reduction (beginning 5 min postinfusion) in the power (amplitude) and finally the total loss of theta field activity. In contrast, theta field frequency remained unaffected during the entire postinfusion period that theta field activity was present. In the time immediately following the first 1-min intraseptal microinfusion of 5 nmol muscimol, (before changes in theta amplitude occurred) a brief period of increased phasic theta-ON cell excitability was noted. This was manifested as an increase in the number of discharges per rhythmic burst. Associated with the progressive reduction of the amplitude of theta field activity, phasic theta-ON cell discharge rates progressively decreased for a period beginning 5 min postinfusion of 5 nmol muscimol. Despite the progressive decrease in the number of discharges and a noticeable reduction in the degree of rhythmicity, phasic theta-ON cells maintained their preferred timing of discharges in relation to the phase of theta field activity, while the latter was present. Just prior to the complete abolishment of theta field activity, phasic theta-ON cells ceased discharging. During the period when theta field activity was replaced on low amplitude asynchronous activity, phasic theta-ON cells discharged in bursts correlated with every occurrence of sharp wave field activity. The results support the following conclusions: (1) the brief excitatory effect on HPC theta-ON cell discharges may be correlated pharmacologically with an initial brief increase in HPC ACh turnover. The reduction of phasic theta-ON cell discharges and theta field activity may be correlated with the longer lasting reduction of HPC ACh turnover, controlled by MS/vDBB GABA-A inputs to MS/vDBB cholinergic septohippocampal neurons, possibly along with a direct inhibition of the GABAergic septohippocampal projection; (2) the primary contribution of the MS/vDBB nuclei, as a nodal point in the ascending brainstem HPC synchronizing system, is the modulation of the amplitude of HPC formation theta field activity and secondarily to relay frequency-coded inputs from the posterior hypothalamic region (posterior and supramammillary nuclei); (3) HPC theta and sharp wave field activity represent functionally distinct neural inputs to the same population of phasic theta-ON cells located in both the CA1 pyramidal and dentate granule cell layers.

Animals↗

PubMed1987

The relationship between hindlimb disturbances, forelimb disturbances and catalepsy after increasing doses of muscimol injected into the striatal-pallidal complex.

To establish the role of the GABA-ergic mechanism within the striatal-pallidal complex in hindlimb disturbances, forelimb disturbances and catalepsy and the relationship between these phenomena, the effects of the locally injected GABA agonist muscimol (0.5 microliter per side) were investigated in rats using several specific tests of catalepsy. The time required for retracting free-hanging hindlimbs was dose-dependently prolonged by 2-10 ng muscimol. The time required for releasing a rod that was clasped between the forelegs of otherwise free-hanging rats was dose-dependently prolonged by 5-10 ng muscimol. Likewise, the time required for retracting the free-hanging forelimbs was dose-dependently prolonged over the same dose range. Finally, the time during which standing rats kept their forelimbs on a block of 9 cm height (the dependent variable used in "classic" tests of catalepsy) was only prolonged at the highest dose (10 ng) of muscimol. The effects of the latter dose, which lasted at least 30 min, were inhibited by the GABA antagonist bicuculline (50 ng) for a minimum period of 5 min. The present data show that the GABA-ergic mechanisms within the striatal-pallidal complex are involved in hindlimb disturbances, forelimb disturbances and catalepsy, and that catalepsy requires a stronger dysfunctioning of these GABA-ergic mechanisms than do disturbances in hindlimbs and forelimbs.

Animals↗

PubMed1994

Reduction of GABAA receptor binding of [3H]muscimol in the barrel field of mice after peripheral denervation: transient and long-lasting effects.

The effect of peripheral sensory deprivation upon GABAA receptor binding of [3H]muscimol was investigated in the barrel cortex--cortical representation of mystacial vibrissae of mice--by means of in vitro quantitative autoradiography. Unilateral lesions of all vibrissae or selected rows of whiskers were performed neonatally or in adulthood. [3H]muscimol binding was examined after various survival times up to 60 days. Both types of lesions performed in adult mice resulted in a transient decrease (10-25%) of binding values in the deafferented areas of the barrel field as compared with the unoperated control side. Sixty days after denervation [3H]muscimol binding returned to control values. Similar results were found after neonatal removal of all vibrissae. Neonatal lesion of selected rows of vibrissae, however, resulted in a decrease of [3H]muscimol binding (by about 26%) lasting up to 60 days in corresponding rows of barrels. This last result was accompanied by severe cytoarchitectonic malformation of the barrel field. The results support the hypothesis that a decrease of inhibition plays a facilitatory role in the plastic reorganization of cortical circuitry.

Aging↗

PubMed1979

[Effects of muscimol and diazepam: a comparative study on behavioral inhibiton induced by novelty, punishment, and nonreward (author's transl)].

Diazepam and muscimol, a direct GABA agonist, were compared on behavioral inhibition induced in rats by (1) novelty, (2) punishment, and (3) nonreward. (1) Muscimol (0.03--0.25 mg . kg-1 i.p. 30 min before testing, or i.v. immediately before testing) failed to enhance food intake consistently in a nonfamiliar situation and (0.125--0.5 mg . kg-1 i.p. or i.v.) to increase the ingestion of an unknown food (chocolate); (2) muscimol (0.125--0.5 mg . kg-1 i.p. or 0.25 i.v. 10 min before testing) was ineffective in reducing the inhibition of lever presses for food elicited by the delivery of an electric shock at every eighth press; (3) muscimol (0.125--0.5 mg . kg-1 i.p.) failed to attenuate the inhibitory effects on responding induced by the suppression of the reinforcement during extinction. Contrastingly, diazepam (2 mg . kg-1 i.p. 30 min before testing) was found to reduce each type of behavioral inhibition. These data lend no support to the hypotheses of GABA control of behavioral inhibition and of GABA involvement in the action of benzodiazepines on inhibition induced by novelty, punishment, or nonreward.

Animals↗

PubMed1985

Subsensitivity to muscimol-induced catalepsy after long-term administration of phenytoin in rats.

Male albino rats were injected with 25 mg/kg of phenytoin (PHT) every day for 20 consecutive days and were tested on days 21 and 28 for their response to 1 or 2 mg/kg of muscimol, a GABA receptor agonist. Rats treated with PHT showed a decreased responsiveness to muscimol-induced catalepsy (2 mg/kg) on day 21 but not on day 28. Acutely administered PHT, on the contrary, had a tendency to potentiate muscimol-induced catalepsy. Muscimol-induced catalepsy was not antagonized by acute treatment with bicuculline (0.5-2.0 mg/kg). It is proposed that withdrawal after long-term administration of PHT reduces the sensitivity of a GABA receptor site not sensitive to bicuculline.

Animals↗

PubMed1981

Differential effects of IV and IP muscimol on central dopamine metabolism.

The effect of IV and IP muscimol on the concentrations of dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) in both the nigrostriatal and mesolimbic dopaminergic pathways has been studied. IV muscimol (2 mg/kg), produced significant decreases in the concentration of DA in both DA systems, while the concentration of DOPAC remained unaltered. However, IP muscimol (5 and 10 mg/kg) caused significant increases in the concentrations of DA or DOPAC in all brain regions examined. Our results suggest differential actions of muscimol on DA metabolism dependent upon the route of administration.

Animals↗

PubMed1991

Effect of typical and atypical neuroleptics on the behavioural consequences of activation by muscimol of mesolimbic and nigro-striatal dopaminergic pathways in the rat.

Direct injections of muscimol into the ventral tegmental area (VTA) or substantia nigra zona reticulata (SNR) have been used to selectively stimulate the mesolimbic and nigro-striatal dopamine pathways respectively. Such injections induced locomotor activity, rearing, sniffing and in some animals an intermittent grooming response. These responses were rapid in onset, dose-related and relatively short lasting (less than 40 min). Selective increases in dopamine turnover were seen in the nucleus accumbens and in the striatum following VTA and SNR injections of muscimol (100 ng) respectively. Haloperidol inhibited the behavioural consequences of VTA and SNR injections of muscimol with similar potency (ED50S 0.01-0.03 mg/kg IP), and fluphenazine did likewise (ED50S 0.05-0.16 mg/kg IP). However, thioridazine (ED50S VTA: 1.45-2.04 mg/kg IP, SNR 8.50-9.20 mg/kg IP) and in particular clozapine (ED50S VTA: 0.24-0.58 mg/kg IP, SNR: 6.10-9.70 mg/kg IP) were more potent at inhibiting the locomotor activity and sniffing responses due to VTA rather than SNR administered muscimol. Since dopamine D2 antagonists are believed to exert their anti-psychotic effects via an action on mesolimbic dopaminergic systems, and their ability to induce extrapyramidal side effects (EPS) is thought to be due to an action on nigro-striatal dopamine systems, these results suggest that the behavioural models described can be used to predict efficacy and side-effect liability of potential neuroleptic drugs.

Animals↗