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PubMed1981

Measurement of gamma-aminobutyric acid in human cerebrospinal fluid: radioreceptor assay using [3H]muscimol.

A method is described for the determination of gamma-aminobutyric acid (GABA) levels in human cerebrospinal fluid by modification of the radioreceptor assay utilizing [3H]muscimol as labelled ligand. This method is compared with the radioreceptor assay using [3H]GABA as labelled ligand. Although the [3H]muscimol assay is less sensitive than the [3H]GABA method, it offers the advantage of being more rapid due to the use of a filtration step instead of the usual, more time-consuming centrifugation of the samples. Samples of CSF of patients with various neurological or psychiatric disturbances were analysed. There was a satisfactory correlation between the GABA values obtained by the two assays.

Animals↗
PubMed1979

The effect of muscimol on hippocampal pyramidal cells.

The effects of muscimol on rabbit hippocampal pyramidal cell firing were studied and compared after iontophoretic, topical, and intravenous administration of the drug. All modes of application resulted in a bicuculline-sensitive, strychnine-insensitive, depression of the monosynaptically activated population spike evoked by micro-stimulation of the contralateral hippocampal field. These findings indicate that systemically administered muscimol selectively activates hippocampal GABA receptors suggesting that this compound may be useful for studying limbic system physiology.

Action Potentials↗
PubMed1981

Involvement of dopamine in circling responses to muscimol depends on intranigral site of injection.

The intensity, direction and dopamine dependence of circling behaviour were determined following stereotaxic injections of 40 ng muscimol (in 0.2 microliter over 3 min) into different regions of the rat's substantia nigra (SN). Weak, haloperidol-sensitive ipsilateral postural or locomotor asymmetries were invariably obtained from the rostral SN zona compacta (SNC), whilst robust contraversive rotational behaviour was always initiated from the SN zona reticulata (SNR) and caudal SNC. This was most rapid from the central SNR and was markedly attenuated by i.p. pretreatment with haloperidol (0.1 mg/kg) or pimozide (0.25 mg/kg), or by week-old 6-OHDA lesions of the nigrostriatal dopamine (DA) tract. Turning was significantly weaker from the lateral and ventral areas of the SNR, where it was not susceptible to DAergic blockade. Lower circling rates were also obtained if the SNR injections were made rapidly (in 30 sec), in a large volume (0.5 microliter) or at a supramaximal dose level (400 ng), possibly due to increased spread of the drug to remote neurones having an opposite effect on directional behaviour, or to exaggerated stereotypy. The variable action of muscimol at multiple sites in the SN is suggested to account for the earlier conflicting data in the literature.

Animals↗
PubMed1985

Electroencephalographic study of SR 95103, a GABAA antagonist: interaction with inhibitory amino acids and muscimol.

SR 95103 has recently been described as a selective GABAA antagonist. In this study, the electroencephalographic (EEG) effects of SR 95103 were investigated as well as its central interaction with inhibitory amino acids and muscimol. Slow intravenous infusions of SR 95103 in rats induced epileptiform EEG activities which were antagonized by intracerebroventricularly injected muscimol, GABA and taurine whereas glycine did not modify and even facilitated the effects of SR 95103. These results suggest that the EEG effects of SR 95103 are due to the specific GABAA antagonistic properties of this compound.

Animals↗
PubMed1986

Intranigral muscimol attenuates electrographic signs of seizure activity induced by intravenous bicuculline in rats.

Rats were implanted with infusion cannulas in the substantia nigra (SN), and intracranial electrodes for recording the electroencephalogram (EEG). These rats received intravenous injections of bicuculline, producing repetitive high voltage spike-and-wave complexes. Pretreatment with bilateral intranigral infusions of the GABA agonist muscimol reduced the duration of EEG epileptic activity by over 80%, as compared to the effect of pretreatment with intranigral saline in the same rats. This antiepileptic effect of intranigral muscimol may reflect a primary influence of SN outputs on brain excitability.

Animals↗
PubMed1990

Attenuation of benzodiazepine-induced passive avoidance deficit by post-training administration of muscimol: interaction with the cholinergic neuronal system.

We examined the involvement of GABAergic neuronal systems in benzodiazepine-induced passive avoidance deficit. Chlordiazepoxide impaired the passive avoidance response dose dependently when it was given prior to training. Post-training administration of muscimol improved the performance of chlordiazepoxide-pretreated mice. The effects of muscimol were antagonized completely by the GABAA antagonist, bicuculline, and the muscarinic acetylcholine receptor antagonist, scopolamine, but not by the benzodiazepine receptor antagonist, flumazenil, when the latter was administered immediately after training. It appears from these results that the GABAergic neuronal system plays an important role in the benzodiazepine-induced passive avoidance deficit by interacting with the cholinergic neuronal system.

Animals↗
PubMed1992

Intrahippocampal injections of benzodiazepine and muscimol impair working memory but not reference memory of rats in the three-panel runway task.

In a three-panel runway task, the benzodiazepine chlordiazepoxide at 3.2 and 10 mg/kg i.p. significantly increased the number of errors (attempts to pass through two incorrect panels of the three panel-gates at four choice points) in a test of working memory, but it had no effect on errors in a test of reference memory. This effect of 10 mg/kg chlordiazepoxide on working memory was blocked by the benzodiazepine receptor antagonist flumazenil at 10 mg/kg. Intrahippocampal injection of chlordiazepoxide at 10 and 32 micrograms/side significantly increased the number of working memory errors. This effect of intrahippocampal chlordiazepoxide (32 micrograms/side) was attenuated not only by flumazenil at 10 mg/kg but also by the gamma-aminobutyric acid (GABA)A receptor antagonist bicuculline at 3.2 mg/kg. Intrahippocampal injection of the GABAA receptor agonist muscimol at 100 and 320 ng/side also significantly increased working memory errors. Neither chlordiazepoxide nor muscimol affected the number of reference memory errors when injected into the hippocampus at doses up to 32 micrograms/side or 320 ng/side, respectively. These results suggest that activation of the GABAA/benzodiazepine receptor complex in the hippocampus impairs working memory, but does not affect reference memory.

Animals↗
PubMed1992

Inhibition of tetrahydroisoxazolo-pyridin-3-ol and muscimol and its mechanism on gastrointestinal transit in mice.

The effect of tetrahydroisoxazolo-pyridin-3-ol (THIP) and muscimol on gastrointestinal transit and a possible mechanism for this effect were studied using the charcoal meal test in mice. These agents inhibited transit dose relatedly. The inhibitory effect was completely reversed by yohimbine and phentolamine. A minor degree of antagonism by bicuculline was observed. There were an additive response in morphine-pretreated animals and partial antagonism in naloxone-pretreated animals. Propranolol failed to modify the inhibitory effect. The findings suggest a predominantly alpha 2-receptor-mediated inhibitory effect on gastrointestinal transit for THIP and muscimol which possibly also utilizes opioid pathways. However, it appears that beta-adrenergic and GABAergic systems might not contribute to this effect.

Animals↗
PubMed1993

Dihydroergosine: anticonflict effect in rats and enhancing effects on [3H]muscimol binding in the human brain post mortem.

The anticonflict activity of the ergot alkaloid, dihydroergosine, a drug which binds to 5-hydroxytryptamine1 (5-HT1) receptors and to gamma-aminobutyric acidA (GABAA) receptor-associated Cl- ionophore, was studied in water-deprived rats. In vitro effects of this drug on [3H]muscimol and [3H]flunitrazepam binding to the crude synaptosomal pellet of the human frontal cortex post-mortem were also investigated. Dihydroergosine, given 2 h prior to testing, enhanced drinking under punished (0.8 mA) conditions, and diminished it under unpunished conditions. The mechanism of this effect was (-)-propranolol- and pindolol-insensitive and picrotoxin-sensitive. Flumazenil either failed to affect, or at a higher dose (10 mg/kg), counteracted the dihydroergosine-induced enhancement of punished drinking. This dose of flumazenil was itself anxiogenic. Dihydroergosine had mild sedative and analgesic properties. Low concentrations of dihydroergosine (10 nM to 100 microM) enhanced the binding of [3H]muscimol but not of [3H]flunitrazepam. The results suggest that dihydroergosine may possess anxiolytic properties presumably mediated by its specific action at the GABA/benzodiazepine/chloride channel complex.

Animals↗
PubMed1993

Early postnatal treatment with muscimol transiently alters brain GABAA receptors and open-field behavior in rat.

The long-term effects of treatment with muscimol, a GABAA agonist, and with ethanol, also shown to have a GABAergic profile of action, on subsequent behavior and on the binding parameters of GABAA receptors were studied in Wistar rats. Rats were given two daily injections of muscimol (0.1 mg/kg M1 group of 0.2 mg/kg M2 group) or ethanol (1.5 g/kg) between the 1st and 21st postnatal days, with saline-treated animals serving as controls. At the age of one month, the activity of the M2 rats was decreased in the open-field arena. At the age of four months, ethanol-treated rats consumed less 10% ethanol solution in a free choice situation. No changes were seen in the elevated plus-maze test. Maximal GABA stimulation of [3H]flunitrazepam binding was decreased in the cerebellum and hippocampus in M2 rats at the age of one month but not four months. A significant positive correlation was found in all rats between maximal GABA-stimulated [3H]flunitrazepam binding in the cerebellum and ambulation in the open-field arena at the age of one month. Ethanol intake correlated negatively with maximal GABA stimulation of [3H]flunitrazepam binding in the cerebral cortex. None of the treatments affected the cerebellar binding of an imidazobenzodiazepine, [3H]Ro 15-4513. There was an age-dependent decline in the efficacy and potency (EC50) of the GABA enhancement of [3H]flunitrazepam binding in the cerebellum in all treatment groups. Basal binding of [3H]flunitrazepam to hippocampal and cerebellar membranes as well as binding of [3H]Ro 15-4513 to cerebellar membranes was also decreased as a function of age.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1993

delta 9-Tetrahydrocannabinol and anandamide enhance the ability of muscimol to induce catalepsy in the globus pallidus of rats.

Doses of 3 or 30 micrograms of delta 9-tetrahydrocannabinol markedly increased the ability of 25 ng of muscimol to delay the descent of rats from a horizontal bar (descent latency) when these drugs were coadministered bilaterally into the globus pallidus. Intrapallidal injections of 30 micrograms of the putative endogenous cannabinoid, anandamide, also increased the effect of muscimol on descent latency. These data indicate that the production of catalepsy by cannabinoids may depend at least in part on an ability to enhance GABAergic transmission in the globus pallidus and support the hypothesis that anandamide is indeed an endogenous ligand for the cannabinoid receptor.

Amides↗
PubMed1988

Comparative studies of the ingestive behaviors produced by microinjections of muscimol into the midbrain raphe nuclei of the ventral tegmental area of the rat.

Microinjection of the GABA-A agonist muscimol into the median (MR) or dorsal (DR) raphe nuclei or the ventral tegmental area (VTA) of non-deprived rats induced intense feeding and drinking in a dose-dependent and site-specific manner. Lower doses of muscimol were required to increase food intake, spillage and water intake with injections into the MR than with injections into the other two sites. These data demonstrate that the MR is a more sensitive site for the elicitation of ingestive behavior than either the DR or the VTA.

Animals↗
PubMed1990

Effects of muscimol and flurazepam on the sleep EEG in the rat.

In order to assess the possible role of GABA receptor function in the hypnotic property of benzodiazepines, we have examined the sleep EEG in rats given the GABA agonist muscimol, alone and in combination with flurazepam. Muscimol 0.05 and 0.1 mg/kg IP failed to alter sleep latency or total sleep time, and did not interact with the sleep-enhancing properties of flurazepam 20 mg/kg IP. These observations, in conjunction with a previous study of bicuculline, suggest that the hypnotic property of benzodiazepines may not be mediated by alteration of GABAergic activity.

Animals↗
PubMed1983

Disinhibition of muricide and irritability by intraseptal muscimol.

In two experiments we have found and replicated the observation that intraseptal muscimol profoundly facilitates muricide. It also increases irritability (response to handling). These effects are specific to aggressive behaviors in that the drug affects neither activity nor chocolate chip acceptance. The effects of the GABA synthesis inhibitor thiosemicarbazide depend upon the site of injection within the septum; in more anterior loci the drug produces the expected increase in muricide latency; in more posterior sites it produces an anomalous facilitation of muricide. The serotonergic agents quipazine and metergoline have no significant effect when injected into any of these sites. These results suggest that the septal neurons mediating the muricide-inhibitory effect of electrical stimulation [29] are subject to local, GABAergic, control. Inhibition of these neurons by muscimol produces a net disinhibition of muricide.

Aggression↗
PubMed1992

Muscimol facilitates sexual receptivity in hamsters when infused into the ventral tegmentum.

Progestogenic stimulation of both the ventral medial nucleus of the hypothalamus (VMH) and the ventral tegmental area (VTA) within the midbrain is critical for normal receptivity in female hamsters. However, few estrogen-induced progestin receptors have been found in the midbrain. In addition, recent evidence suggests that progestin's action in the VTA is mediated nongenomically at the membrane. The present experiment investigated the possible role of GABAA receptors in mediating the effects of progesterone in this brain region. Ovariectomized female hamsters were bilaterally implanted with chronic cannulae aimed toward the ventral mesencephalon. Five days after surgery, animals were injected with 10 micrograms estradiol benzoate SC. Forty hours later, the same animals were injected with either 25 or 100 micrograms progesterone and at hour 43.5, 50 ng muscimol was infused in 0.5 microliters. Control animals received 0.5 microliters vehicle, sterile saline, or no infusion. At hour 44, animals were tested for sexual receptivity by placing them in an observation arena with a sexually experienced male for 10 min, during which lordosis duration was recorded. The following week, the same regimen was given with the alternate dose of progesterone. Histology revealed that only those animals that were infused with muscimol into the VTA had total lordosis durations that were significantly longer than the controls. Implants that missed the ventral tegmental area were much less effective. These results indicate that GABA might play a facilitatory role in enhancing the efficacy of threshold doses of progesterone. Whether this interaction is due to a direct effect of progestins on the GABAA receptor complex awaits further study.

Animals↗
PubMed1992

Effects of alcohol dependence on shock-induced fighting: action of muscimol and homotaurine.

We have applied the electroshock-induced fighting behavior to the study of experimental alcohol dependence. Adult Wistar rats were intoxicated chronically with ethanol (10 g/kg/24 h) for 13 days. Electroshock-induced fighting behavior was studied during chronic intoxication and withdrawal in comparison with normal rats receiving a water-carbohydrate solution isocaloric to ethanol. Rats were divided into groups receiving respectively muscimol (0.25 mg/kg), a GABAA agonist; homotaurine (140 mg/kg) a GABA mimetic; and physiological saline (10 ml/kg), intraperitoneally. During chronic intoxication, rats showed an increase in defensive-fighting behavior. Withdrawal accentuated the aggressive behavior and muscimol and homotaurine inhibited it. These results confirm the relevance of the electroshock-induced defensive fighting behavior test in chronic intoxication with alcohol, but to show the involvement of GABAergic transmission in the behavioral effects of alcohol withdrawal, additional experiments with other GABA mimetics and with GABA antagonists should be considered.

Aggression↗
PubMed1991

Oxotremorine attenuates retrograde amnesia induced by post-training administration of the GABAergic agonists muscimol and baclofen.

These experiments examined the involvement of cholinergic influences in the effects of GABAergic drugs on 24-h retention of an inhibitory avoidance response by mice. A first set of experiments confirmed previous findings indicating that post-training injections (ip) of the GABAergic agonists muscimol (1.0 and 2.0 mg/kg) and baclofen (10.0 and 20.0 mg/kg) impaired retention, as well as previous findings indicating that injections of the cholinergic agonist oxotremorine (5.0 and 10.0 micrograms/kg) enhanced retention. The findings of a second set of experiments indicated that the memory-impairing effects of muscimol and baclofen were attenuated by concurrent injections of a low, and otherwise ineffective, dose of oxotremorine (2.5 micrograms/kg). These findings are interpreted as suggesting that GABAergic drugs affect memory storage through influences on cholinergic systems.

Animals↗
PubMed1992

Ontogeny of GABAA/benzodiazepine receptor subunit mRNAs in the murine inferior olive: transient appearance of beta 3 subunit mRNA and [3H]muscimol binding sites.

The GABAA/benzodiazepine receptor consists of at least four subunits, alpha, beta, gamma and delta, each comprised of several variants. The developmental expression of the alpha 1, beta 1-3, gamma 2 and delta subunits was studied in the murine inferior olivary nucleus by in situ hybridization with antisense cRNA probes. The postnatal appearance and distribution of [3H]flunitrazepam and [3H]muscimol binding sites, alpha and beta subunit-specific ligands respectively, were also studied autoradiographically. The beta 3 subunit was transiently expressed in each of the subnuclei of the inferior olive: The signal was strong at birth, increased throughout postnatal week 1 and rapidly declined thereafter to low adult levels. A similar pattern of labeling was observed with [3H]muscimol. Detectable levels of alpha 1 subunit mRNA hybridization signal and [3H]flunitrazepam binding sites were also present in the inferior olive at birth, decreasing thereafter. Low to moderate levels of beta 1, beta 2, and gamma 2 subunit mRNAs were present in olivary neurons throughout postnatal development, while delta mRNAs were largely absent. It has been reported previously that, during the 2nd postnatal week, the ratio of climbing fiber terminals to Purkinje cells is reduced from 3:1, as observed in neonates, to the 1:1 relationship observed in the adult cerebellar cortex. Our results raise the possibility that the subunit composition of the GABAA/benzodiazepine receptor in inferior olivary neurons undergoes changes during development, and that this process may be related to the elimination of multiple climbing fiber innervation of cerebellar Purkinje cells.

Animals↗