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PubMed1991

Behavioral deficits induced by local injection of bicuculline and muscimol into the primate motor and premotor cortex.

1. The role of intracortical GABAergic inhibition in the performance of hand movements was studied in macaque monkeys while they performed two behavioral tasks: a raisin pick-up test and a visual reaction-time task. A gamma-aminobutyric acid (GABA) agonist, muscimol (MUS; 1-5 microgram), and an antagonist, bicuculline methiodide (BMI, 1-10 micrograms), were injected at various sites in the precentral motor cortex (MC), at which single-unit activity was related to the manual aspects of the performance of the reaction-time task. 2. Manual dexterity in the raisin pick-up task was severely disturbed by injections of either MUS or BMI into the hand MC. The effect was less severe after injections into the postarcuate premotor cortex (PM). 3. Performance of the reaction-time task was unstable after injection of BMI. The instability was caused by increased electromyogram (EMG) activity and by cocontractions of agonistic and antagonistic muscles of the arm during the pressing or release of the lever. 4. Reaction time was increased by injection of MUS, although the effect was temporary and decayed within 60 min. These deficits were consistent with the time course of the decrease in the total amount of EMG activity of hand muscles related to the task. As in the case of the raisin pick-up task, performance deficits were greater when MUS and BMI were injected into the hand MC and smaller when they were injected into the PM. 5. After injection of BMI, the animals gradually began to display muscle activity in response to a green warning signal that did not require a behavioral response. The muscle activity accelerated to spontaneous muscle twitches without any external stimulus, and the animals were unable to continue the task. These BMI-induced twitches were eliminated by injection of barbiturate. 6. Appropriate levels of GABAergic inhibition in the MC appear, therefore, to be important for the regulation of spatiotemporally organized ensembles of muscle activity, in particular for reciprocal contraction at the task-related joints.

Animals↗
PubMed1992

Inactivation of the DSCF area of the auditory cortex with muscimol disrupts frequency discrimination in the mustached bat.

1. The Jamaican mustached bat uses a biosonar signal (pulse) with eight major components: four harmonics each consisting of a long constant frequency (CF1-4) component followed by a short frequency-modulated (FM1-4) component. While flying, the bat adjusts the frequency of its pulse so as to maintain the CF2 of the Doppler-shifted echo at a frequency to which its cochlea is very sharply tuned. This Doppler shift (DS) compensation likely is mediated or influenced by the Doppler-shifted CF (DSCF) processing area of the primary auditory cortex, which only represents frequencies in the range of echo CF2s (60.6 to 62.3 kHz when the "resting" frequency of the CF2 is 61.0 kHz). 2. We trained four bats to discriminate between different trains of paired tone bursts that mimicked a bat's pulse CF2 and the accompanying echo CF2. The frequency of these CF2s ranged between 61.0 and 64.0 kHz. A discriminated shock avoidance procedure response was employed using a leg flexion. For one stimulus, the S+, the pulse and echo CF2s were the same frequency (delta f = 0, i.e., no Doppler shift). A leg flexion during the S+ turned off both the S+ and the scheduled shock. For a second stimulus, the S-, the echo CF2 was 0.05, 0.1, 0.3, 0.5, or 2.0 kHz higher than the pulse CF2. A delta f of 0.05 kHz was a frequency difference of 0.08%. No shock followed the S-, and leg flexions had no consequences. Correct responses consisted of a leg flexion during the S+ and no flexion during the S-; these responses were added together to compute the percentage of correct responses. When a bat correctly responded at better than 75% for all the delta f s, muscimol, a potent agonist of gamma-aminobutyric acid, was bilaterally applied to inactivate the DSCF area. Performance on each delta f discrimination was then measured. 3. Initial attempts to condition the bats to flex their legs to the CF tones mimicking part of the natural pulses and echoes failed. When broad-band noise bursts were substituted, however, the conditioned response was rapidly established. The noise band-width was gradually reduced and then replaced with the CF tones. Discrimination training with the tone burst trains then commenced. Throughout this procedure, the bats maintained their responding to the stimuli. The bats typically required approximately 20-30 sessions to perform consistently (> or = 75% correct responses) a discrimination involving a 2 kHz delta f.(ABSTRACT TRUNCATED AT 400 WORDS)

Acoustic Stimulation↗
PubMed1998

Organization of reaching and grasping movements in the primate cerebellar nuclei as revealed by focal muscimol inactivations.

Two monkeys were trained to point to targets and to retrieve fruit bits from a Kluver board, bottles, and tubes. Once proficient in the tasks, the macaques underwent aseptic surgical implantation of a recording chamber over the cerebellar nuclei on the side of their preferred hand. After recovery from surgery, a series of mapping penetrations were completed to identify task-related areas within the cerebellar nuclei. Muscimol (4- 16 microgram; 1-2 microgram/microliter) was pressure injected at different sites within the forelimb zone, and the resultant deficits were observed as the monkeys performed the behavioral tasks. Quantitative measures of task performance were supplemented by direct observation of live and videotaped performance. The locations of nuclear inactivation sites were reconstructed from marking lesions and tracks visible in histological sections. Injections placed in the cerebellar interpositus nucleus and adjacent regions of dentate caused a variety of deficits in forelimb function. A prominent anteroposterior specialization was apparent within the forelimb zone of this intermediate nuclear region. Injections into the anterior interpositus nucleus and adjacent dentate impaired preshaping of the hand and the manipulation of objects, whereas injections placed more posteriorly in posterior interpositus nucleus and adjacent dentate produced deficits in the aiming of reach and the stability of the arm. During anterior injections, the monkeys failed to adequately extend their fingers in preparation for target contact, as documented for >85% of the reaches in the pointing task of monkey J. Up to 38% of the fruit bits it attempted to retrieve from the Kluver board were dropped. In comparison, during posterior inactivations, 15% were dropped and during control conditions 3% were dropped. The monkeys made significantly greater pointing errors during posterior inactivations (11 times for monkey J and 4 times for monkey C) than during anterior inactivations (8 times for monkey J and 2 times for monkey C). We refer to the region producing hand deficits as the anterior hand zone and the region producing reaching deficits as the posterior reach zone. These results are discussed in relation to the problem of achieving spatiotemporal coordination in the large population of nuclear cells that participate in any given movement. The results do not favor the hypothesis that coordination is achieved through a selection of Purkinje cells along beams of parallel fibers. Instead, it is proposed that distal and proximal musculature is coordinated by the adaptive influences of climbing fiber input to Purkinje cells. We envision a relatively nonspecific recruitment of anterior and posterior nuclear cells due to positive feedback in the limb premotor network, which then is shaped into an appropriate spatiotemporal pattern of discharge through the inhibitory input from Purkinje cells.

Animals↗
PubMed1983

Effects of valproic acid on spinal reflexes and [3H]muscimol and [3H]diazepam binding in brain membranes in rats.

It was examined whether the anticonvulsant activity of valproic acid (di-n-propylacetic acid, DPA) was exerted via the inhibitory GABA system in the central nervous systems (CNS). Dorsal root reflexes (DR-DRR) were not augmented but intensely suppressed following the administration of DPA (50 and 200 mg/kg, i.v.). DPA did not depolarize the resting dorsal root potentials. These electrophysiological findings may indicate that DPA does not potentiate GABA system in the spinal cord of rats. DPA (1 and 10 mM) neither affected the binding of 2 or 40 nM of [3H]muscimol nor the binding of [3H]diazepam in the rat brain membranes; the same concentrations of DPA did not affect the enhancement of binding of [3H]diazepam induced by the addition of GABA (100 microM). The result obtained from binding assays indicates that DPA does not interact with the GABA-benzodiazepine receptor complex. The findings in the present study do not support the proposal that the anticonvulsant action of DPA is exerted by potentiation of the GABA system in the CNS.

Animals↗
PubMed1999

Muscimol inactivation of the dorsal hippocampus impairs contextual retrieval of fear memory.

Some models of hippocampal function have suggested a role of the hippocampus in contextual memory retrieval. We have examined this hypothesis by assessing the impact of reversible inactivation of the dorsal hippocampus (DH) on the context-specific expression of latent inhibition, a decrement in conditional responding produced by preexposure to a to-be-conditional stimulus. In Experiment 1, rats received tone preexposure either in the context that would later be used for extinction testing (context A) or in a different context (context C); a third group of rats did not receive tone preexposure. All rats then received fear conditioning, which consisted of tone-footshock pairings, in a third distinct context (context B). The following day conditional fear to the tone was assessed in one of the preexposure contexts (context A) by measuring freezing during a tone extinction test. Rats preexposed and tested in the same context exhibited less freezing to the tone than either rats preexposed and tested in different contexts or non-preexposed rats. These results indicate that the expression of latent inhibition is context specific. In Experiment 2, DH inactivation eliminated the context-specific expression of latent inhibition. Compared with saline-infused rats, rats infused with muscimol into the DH exhibited low levels of tone freezing independent of whether they had received tone preexposure in the test context or in a different context. Experiment 3 revealed normal contextual discrimination in rats after DH inactivation. These results suggest the DH is required for contextual memory retrieval in a latent inhibition paradigm.

Animals↗
PubMed1991

[Effector modeling of the action of ligands of the GABA receptor complex: functional interactions of muscimol and exogenous modulators of the complex].

In comparison with the literature data the pharmacological effects of muscimol (MS) on mice organism were studied under the condition of administration of the exogenic ligands of GABA-receptor complex GABA antagonist bicuculline (BC), chloride ionophor blocking agent pentylenetetrazole (PZ), phenazepam (BD), sodium barbital (BB) and GABA synthesis antagonist--thiosemicarbazide (TS). Antagonism of MS to the anticonvulsant effect of BB and BD at the administration of BC to the animal was observed, while no effect was observed at the administration of PZ. However at the administration of TS to the experimental animals MS exhibits anticonvulsant effect. The observed properties (partial agonism/partial reverse agonism) of MS at its effect to the whole system are probably determined by the level of endogenic GABA and its changes due to the administration of TS and functional state of GABA--receptor system modified with the exogenic ligand BC.

Animals↗
PubMed1988

[Effect of baclofen and muscimol on the evoked potentials of the tectum mesencephali in the carp in response to stimulation of the visual and somatosensory afferent inputs].

The perfusion of (+/-) 10(-5) M baclofen to the optic tectum of the carp greatly reduced evoked potential to the optic nerve stimulation and slightly inhibited evoked potential to the spinal cord stimulation. The perfusion of 10(-4) M muscimol reduced the former evoked potential as well as the latter one. The results permit supposing that tectal visual input is more sensitive to the presynaptic inhibitory influences through GABAB-receptors than the somatosensory afferent input.

Afferent Pathways↗
PubMed1984

[Differences in the mechanism of the antihypoxic action of benzodiazepine receptor agonists and muscimol].

Neuropharmacological analysis of previously revealed antihypoxic activity of benzodiazepines (BDZ) has been performed in experiments on mice exposed to hypoxia. Antihypoxic effect of diazepam is shown to be antagonized by the central BDZ receptor blocker, Ro 15-1788. A certain degree of antihypoxic activity also abolished by Ro 15-1788 is exhibited by hypothetical ligands of BDZ receptors: inosin, nicotinamide, ethyl-beta-carboline-3-carboxylate. The effect of dipyridamole, a drug with high affinity for BDZ receptors of the peripheral type is not antagonized by Ro 15-1788, another evidence of Ro 15-1788 affinity precisely to the central BDZ receptors. GABA-mimetics (muscimol and GABA cetyl ester) were also found to have marked antihypoxic activity. Unlike BDZ receptor agonists, this effect is reduced by bicuculline and not by Ro 15-1788. The data obtained suggest that antihypoxic activity of BDZ is caused by their direct interaction with the central BDZ receptors, probably with the type which is not modulated by GABAA receptors.

Animals↗
PubMed1982

[Protective effects of muscimol on acute brain ischemia in the rat (author's transl)].

Rats given i.c.v. muscimol overcome a greater number of hypoxic episodes before dying compared with controls whereas animals that receive baclofen (another GABAergic agonist) or GABA itself tolerate fewer episodes than controls. Thus, chloride ions ionophoric site activation appears to be necessary in order to obtain any GABAergic antihypoxic protection whereas GABAergic site activated by both baclofen and GABA would induce an opposite effect.

Animals↗
PubMed1981

Muscimol as an antagonist of chemical convulsants.

Muscimol (MU) was tested on mice for anticonvulsive action against chemical convulsants. 3-Mercaptopropionic acid (3-MP) was more sensitive to inhibition by MU (1.5 mg/kg) than was either pentylenetretrazol (PTZ) or bicuculline (BIC); picrotoxin (PIC) and kainic acid were not measurably antagonized; aminophylline was potentiated. The profile of action of MU closely resembles that of aminooxyacetic acid (AOAA), except that the latter strongly antagonizes kainic acid. MU distinguished more clearly than did AOAA between the action of 3-MP and that of either PTZ or BIC, inasmuch as the differences between the respective potency ratios were larger with MU than with AOAA. The results are consistent with the view that MU acts as a GABA agonist, that GABA antagonism is not a sufficient basis on which to explain the convulsive action of BIC or PIC, and that the antagonism of AOAA toward seizures induced by kainic acid may not be due to an action on the GABA system.

Animals↗
PubMedDate not supplied

Muscimol injected into the medial prefrontal cortex of the rat alters ethanol self-administration.

The role of the rodent prefrontal cortex in the regulation of ethanol self-administration has not been widely explored. Understanding the role of GABAergic transmission in this area in relation to ethanol self-administration is important, as the GABA system may be one of several targets for alcohol's actions in the brain. Rats were initiated to drink 10% ethanol from a dipper using a sucrose-substitution procedure. When baseline behavior was stable, bilateral microinjections of muscimol (a GABA(A) agonist) into the prefrontal cortex were tested at doses of 17.5, 30, 100 and 300 ng/microl. Ethanol self-administration was decreased by approximately 40% at the 30-ng dose and 30% at the 100-ng dose. No effects were observed at either the 17.5- or 300-ng dose. The effect on the pattern of self-administration was to shorten the size of the first run of drinking without affecting the rate of drinking. The hypothesis is put forward that the injections increased glutamatergic output to the nucleus accumbens (nAcc) that in turn increased accumbens output. This increased output is proposed as similar to the effects of dopaminergic (DA) manipulations within this system.

Alcohol Drinking↗
PubMed1977

Mechanisms by which diazepam, muscimol, and other drugs change the content of cGMP in cerebellar cortex.

THE CEREBELLUM CONSISTS OF TWO PARTS: the cerebellar nuclei whose connections to the various parts of the central nervous system coordinate muscle movements, and the cerebellar cortex which exerts an inhibitory influence on the cerebellar nuclei through the release of gamma-aminobutyric acid (gammaAbu) from Purkinje cells. The activity of Purkinje cells is regulated by two excitatory inputs to the cerebellar cortex-the climbing and mossy fibers-and by a neuronal network within the cortex which inhibits the activity of Purkinje cells through the release of gammaAbu from interneurons. The net activity of Purkinje cells is related to their content of guanosine 3':5'-cyclic monophosphate (cGMP) which increases or decreases according to changes in the activity of climbing and mossy fibers as well as to changes in the activation of gammaAbu receptors. When these receptors are activated, the cGMP of Purkinje cells decreases; when they are inhibited, the cGMP increases.The cGMP content of the cerebellar cortex is altered by drugs that change either the excitatory input of climbing or mossy fibers or the inhibitory input mediated by the activation of gammaAbu receptors. Mechanisms by which various drugs alter the cerebellar content of cGMP were investigated. By using various experimental designs, it was shown that diazepam and muscimol lowered the cGMP content by activating gammaAbu receptors. In contrast, morphine and haloperidol lowered the cerebellar cortex cGMP by decreasing the excitation of mossy fibers whereas harmaline increased the cGMP by increasing the excitation of the climbing fibers.

Alkaloids↗
PubMed1978

Ultrastructural localization of gamma-aminobutyric acid receptors in the mammalian central nervous system by means of [3H]muscimol binding.

This study utilizes tritiated muscimol binding and electron microscope autoradiography (Ilford L4 emulsion and phenidone development) to localize gamma-aminobutyric acid (GABA) receptor sites in the cerebellum of the rat. In the cerebellar cortex, silver grains were associated with somata and dendrites of basket and stellate cells in the molecular layer, with somata and primary and secondary dendritic shafts of Purkinje cells, axons and terminals of basket cells in the pinceau or basket, initial axonal segments and myelinated axons of Purkinje cells, and dendrites of granule and Golgi cells in the granular layer, and with somata and dendritic shafts of large and small cells in the cerebellar nuclei. These data correspond well to the light-microscope-autoradiographic observations in the cerebellum previously reported [Chan-Palay, V. (1978) Proc. Natl. Acad. Sci. 75, 1024-1028]. Label over GABA receptor sites can be localized to the plasma membranes between pre- and postsynaptic elements at synaptic junctions, of which 88.9% of the samples are axodendritic and the remaining 11.1% are axosomatic. GABA receptor sites are also found along axonal membranes of the GABA-containing basket cell within the basket surrounding Purkinje cells, where true axo-axonal synapses are rare. It is speculated that GABA receptors in the basket may suggest a possibility of the basis for synchronization, either self-inhibition or facilitation within the basket formation, or presynaptic suppression of inhibitory action of basket cell on Purkinje cell.

Aminobutyrates↗