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PubMed1990

Ontogeny of muscimol effects on locomotor activity, habituation, and pain reactivity in mice.

Three hundred and twenty mouse pups of both sexes of the CD-1 outbred strain received IP muscimol and were subsequently assessed for locomotor activity (single Varimex 30-min session) and for hot-plate responding. Muscimol doses were 0.05, 0.1, or 0.2 mg/kg at 8 and 14 days, and 0.1, 0.5, or 1.0 mg/kg at 21, 28, and 35 days. Activity data showed a shift from an immature pattern at 8 and 14 days to an adult-like pattern from day 21 onwards (high initial activity followed by a marked within-session decrement). Muscimol was ineffective on day 8, and depressed activity from day 14 onwards. At 28 days, however, the higher-dose male group showed a non-monotonic trend of activity; that is an initial depression followed by a marked rebound hyperactivity. With regard to hot-plate exposure, muscimol was ineffective at 8 days, while it produced maximal analgesic effects on day 14, followed by a progressive decrease in drug sensitivity. Around day 70, mice of the former 0.1 mg/kg and saline groups were re-tested for locomotor activity and pain reactivity without additional drug treatment. Activity was generally higher in males than in females, and two groups habituated significantly less than the others (females tested in the muscimol state at 8 days and males tested in the saline state at 35 days). Moreover, prior testing at the earliest ages and prior muscimol exposure had additive attenuating effects on pain reactivity.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1980

Potentiation by intraventricular muscimol of the anticonflict effect of benzodiazepines.

The anticonflict action of muscimol (a potent GABA receptor agonist) and its ability to potentiate the anticonflict action of the benzodiazepines was studied in rats using VOgel's procedure. Rats were injected intraventricularly with a dose of muscimol from 50 to 200 ng to study whether the anticonflict action was dose-related. The potency of a 200 ng dose of muscimol is comparable to the potency of an anticonflict dose of 0.5 mg i.v. of diazepam. THIP (a muscimol analogue with weaker intrinsic GABA-mimetic activity) is active in doses 10 times higher than muscimol. The threshold dose of diazepam (0.2 mg/kg i.v.) to elicit anticonflict action was markedly potentiated when it was injected 5 min after intraventricular muscimol (150 ng). These data support the concept that GABA receptors may be involved in the anticonflict effects of the benzodiazepines.

Animals↗
PubMed1980

GABA receptors in bovine cerebral blood vessels: binding studies with [3H]muscimol.

[3H]Muscimol, a potent GABA agonist used to label GABA receptor sites in brain and invertebrate striated muscle, was found to bind specifically to sites in a crude membrane fraction prepared from bovine cerebral blood vessels. Specific [3H]muscimol binding was saturable of high affinity (Kd = 41 nM), and was selectively inhibited by GABA, specific GABA agonists, and the antagonist bicuculline with potencies similar to what has been found for GABA receptors in mammalian brain. GABA and several GABA agonists including muscimol have been reported to dilate isolated cerebral arteries, but not peripheral blood vessels. The pharmacology of the [3H]muscimol binding site correlated well with that of the vasodilatory response. No significant specific [3H]muscimol binding was detected in aorta and mesenteric arteries. The characteristics of the cerebrovascular muscimol binding site thus are indicative of a physiologically relevant GABA receptor associated with cerebral blood vessels. These findings suggest a direct role for GABA in cerebral vascular function.

Animals↗
PubMed1984

Extrastriatal circuits activated by intrastriatal muscimol: a [14C]2-deoxyglucose investigation.

The quantitative autoradiographic [14C]2-deoxyglucose technique has been employed in conscious, lightly restrained rats to investigate the functional consequences (which are reflected as alterations in local rates of glucose utilization) of unilateral intrastriatal administration of the GABAergic agonist, muscimol. Intrastriatal injections of muscimol (500 ng) effect a widespread, homogeneous reduction (by 33%) in glucose utilization throughout the ipsilateral striatum. Increased glucose utilization following intrastriatal muscimol injection was observed in each region to which the principal striatal efferent projections are directed (ipsilateral globus pallidus increased by 29%; ipsilateral entopeduncular nucleus increased by 33%; ipsilateral pars reticulata increased by 46%). Significant focal alterations in glucose utilization occurred in a number of other regions ipsilateral to the injection, including lateral habenular nucleus (increased by 16%), pars compacta of the substantia nigra (increased by 28%), ventrolateral nucleus of the thalamus (decreased by 40%), sensory-motor cortex (decreased by 47%), deep layer of the superior colliculus (decreased by 18%), and subthalamic nucleus (decreased by 18%). In the overwhelming majority of brain regions examined, glucose utilization was unaltered by intrastriatal administration of muscimol. All regions which displayed significant alterations in glucose use with intrastriatal muscimol are known to have direct connections with the striatum (e.g. pallidus and nigra), or to be anatomical components in polysynaptic striatal outflow pathways (e.g. striatal-pallidal-ventral thalamic-neocortical circuit). The present results indicate that activity within striatal efferent circuits can be differentially modified by the effects of the GABAergic agonist, muscimol, within the caudate nucleus.

Animals↗
PubMed1995

Effect of muscimol on haloperidol-induced alteration of neurotensin gene expression in the striatum and nucleus accumbens in the rat.

Acute neuroleptic administration increases the expression of neurotensin/neuromedin (NT/N) gene in rat dorsolateral striatum and shell sector of the nucleus accumbens. The purpose of this study was to examine modulation of neuroleptic induction of NT/N and the proto-oncogene c-fos expression by the GABAA agonist muscimol. Adult male Sprague-Dawley rats were treated with saline, haloperidol (1 mg/kg); muscimol (3.2 mg/kg); or haloperidol (1 mg/kg) plus muscimol (3.2 mg/kg). Animals were sacrificed 1 h after drug administration. Expression of NT/N and c-fos mRNA was examined by in situ hybridization using 35S-antisense probes. Muscimol alone had no measurable effect on basal levels of NT/N or c-fos mRNA in either the dorsolateral striatum or the nucleus accumbens. However, co-administration of muscimol with haloperidol reduced haloperidol-induced increases in NT/N as well as c-fos mRNA in the dorsolateral striatum. In contrast, NT/N mRNA expression in accumbal shell induced by haloperidol was not modulated by co-administration of muscimol. These data suggest that GABAA receptors may be involved in regulation of NT/N gene expression in the DLSt, but not in the nucleus accumbens.

Animals↗
PubMed1981

Correlation of [14C]muscimol concentration in rat brain with anticonvulsant activity.

Muscimol, an in vivo and in vitro GABA agonist, has anticonvulsant activity against bicuculline-induced seizures when given systemically to rats. To determine whether parent compound or a metabolite possessed the anticonvulsant activity, experiments were performed with [14C]muscimol. Anticonvulsant activity was determined by the percent of animals protected against tonic forelimb extension induced by bicuculline. Brain and urine were analyzed for unchanged [14C]muscimol by thin-layer chromatography. The time course of anticonvulsant activity and [14C]muscimol concentration in brain after intravenous injection were similar. Peak brain concentration of [14C]muscimol and maximal protection against bicuculline-induced seizures occurred simultaneously. These data suggest that intravenously administered [14C]muscimol rapidly penetrates brain tissue and parent compound is responsible for antagonism of bicuculline-induced convulsions.

Animals↗
PubMed1982

BehavioraL and biochemical changes caused by muscimol in mice withdrawN from haloperidol administration.

This study was designed to determine the behavioral and biochemical effects of the gamma-aminobutyric acid (GABA) agonist, muscimol, in mice withdrawn from chronic haloperidol administration. Mice received either haloperidol or vehicle In their drinking water for 35 days, after which the haloperidol was replaced with vehicle. Seven days after withdrawal from chronic treatment with haloperidol, the effect of apomorphine on the climbing behavior of haloperidol-withdrawn mice was markedly enhanced as compared to control mice that received only vehicle. Muscimol produced a dose-related reduction in the intensity of climbing behavior induced by apomorphine in both control and haloperidol-withdrawn mice. However, the inhibition of climbing behavior induced by muscimol was significantly greater in haloperidol-withdrawn animals. In addition, in haloperidol-withdrawn mice, muscimol produced a significant reduction in striatal homovanillic (HVA) levels with no change in striatal dopamine (DA) levels, suggesting a decrease in DA turnover. In support of this conclusion, muscimol decreased the disappearance of dopamine in haloperidol-withdrawn mice that were injected with alpha-methyl-p-tyrosine. Both the behavioral and biochemical effects of muscimol were blocked by the GABA antagonist, picrotoxin. These results indicate that after chronic haloperidol administration there is not only an enhanced response to dopaminergic agonists but also to GABAergic agonists.

Animals↗
PubMed1987

Behavioural and electrocortical changes induced by muscimol in rats withdrawn from chronic treatment with diazepam.

In rats withdrawn from a chronic treatment with diazepam, the effects of muscimol, given into the III cerebral ventricle, on behaviour and spectrum power of activity in the electrocorticogram (ECoG) were studied. In comparison to control rats which received only muscimol, in rats pretreated with diazepam (1 mg/kg/day for 30 consecutive days) the behavioural and ECoG effects of muscimol were significantly reduced or abolished. In fact, in rats pretreated with diazepam a small dose (50 ng) of muscimol did not affect behaviour or ECoG activity, in contrast to control animals in which the same dose produced, after a period of locomotor stimulation and ECoG desynchronization, typical and long-lasting behavioural sedation or sleep accompanied by a significant increase in total voltage power and in the lower frequency bands in the ECoG. In addition, larger doses (100 and 200 ng) of muscimol, which in control rats produced a typical biphasic pattern of ECoG and behavioural changes, i.e. an initial period of ECoG desynchronization and behavioural stimulation, followed by a second period of behavioural and ECoG sleep, in animals pretreated with diazepam, produced only an increase in total voltage power and in the lower frequency bands in the ECoG resembling the effects of the smaller (50 ng) dose. The present experiments suggest that, after chronic stimulation of benzodiazepine receptors a decrease in sensitivity of receptors for gamma-aminobutyric acid (GABA) occurs, since the effects of muscimol on behaviour and spectrum power were significantly reduced or abolished.

Animals↗
PubMed1990

Modulation by estrogen and progesterone of the effect of muscimol on nociception in the spinal cord.

The GABAA agonist, muscimol, administered intrathecally (IT) to the spinal cord at a dose (1 microgram) that was subthreshold for affecting pain thresholds (vocalization-threshold-to-tail-shock: VTTS, and tail-flick latency: TFL) in ovariectomized, hormonally untreated rats, showed a significant increase in VTTS up to 30 min postinjection in intact females only in proestrus or estrus. This treatment produced no significant effect on TFL at any stage of the estrous cycle. IT muscimol produced a significant increase in VTTS (but not TFL) in ovariectomized rats primed with estradiol benzoate (EB) for 2 days and tested 40 hr after the second injection but had no effect in females primed with a single EB injection and tested 15 min later. By contrast, ovariectomized females primed with progesterone (P) for 15 min exhibited a significant increase in pain thresholds after IT muscimol in both the VTTS and TFL tests. When EB-primed females (2 days) received P 4 hr prior to muscimol there was no analgesia produced by IT muscimol, in contrast to EB-primed females receiving P 15 min prior to IT muscimol in which there was significant analgesia. These results suggest a mechanism for antagonistic effects of estrogen and progesterone.

Animals↗
PubMed1996

Maintenance of muscimol-induced long-term depression by neurosteroids.

1. The present study was undertaken to expand investigations of the interaction between neurosteroids and long-term depression (LTD) induced by muscimol 10 mu M. 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. As previously reported, muscimol at 10 mu M induced a time, frequency of stimulation and concentration-dependent LTD of the amplitude of orthodromic potentials. Alphaxalone, at concentrations that had no significant effect themselves on the population spike (0.5 and 1 mu M) potentiated the inhibitory effect of muscimol on the population spike size. 4. It is now reported that low concentrations of alphaxalone are able to potentiate the ability of muscimol to induce LTD. In addition, concentrations of muscimol as low as 1 mu M which are not themselves able to induce LTD, as well as aiphaxalone and 5 alpha-pregnan-3 alpha-ol-20-one 1 mu M were able to maintain the LTD induced by muscimol 10 mu M 5. It is suggested that the ability of such low concentrations of GABA receptor agonists to maintain LTD could be of physiological importance.

Anesthetics↗
PubMed2006

Microinjection of muscimol into caudal periaqueductal gray lowers body temperature and attenuates increases in temperature and activity evoked from the dorsomedial hypothalamus.

Microinjection of the neuronal inhibitor muscimol into the midbrain lateral/dorsolateral periaqueductal gray (l/dlPAG) suppresses increases in heart rate (HR) and mean arterial pressure (MAP) evoked by microinjection of the GABA(A) receptor antagonist bicuculline methiodide (BMI) into the dorsomedial hypothalamus (DMH) in rats. Injection of BMI into the DMH also increases body temperature (Tco) and motor activity. Here, our goal was to extend previous findings by examining the effect of microinjection of muscimol into the PAG on these thermogenic and behavioral responses in conscious freely moving rats. Microinjection of muscimol (300 pmol and 1 nmol) alone into the l/dlPAG reduced baseline Tco without affecting activity, HR, or MAP. Similar injection of a dose that failed to alter baseline Tco (100 pmol) suppressed the increases in Tco evoked from the DMH and significantly attenuated DMH-induced increases in locomotor activity. Whereas microinjection of 1 nmol muscimol into the ldlPAG abolished the increases in Tco evoked from the DMH and in fact lowered body temperature to a degree similar to that seen after this dose of muscimol alone, 1 nmol muscimol at adjacent sites outside the targeted region of the PAG had no significant effect on DMH-induced increases in Tco or any other parameter. These results indicate a role for neuronal activity in the l/dlPAG in (1) the temperature and behavioral responses to disinhibition of neurons in the DMH, and (2) the maintenance of basal body temperature in conscious freely moving rats.

Animals↗
PubMed2005

Ventilatory effects of muscimol microdialysis into the rostral medullary raphé region of conscious rats.

We hypothesized that inhibition of the rostral medullary raphe region (MRR), a putative central chemoreceptor location, with the GABA(A) receptor agonist muscimol would decrease ventilatory responses to hypercapnia and hypoxia in conscious rats, and that its known effect at this site on body temperature might alter its effect upon these ventilatory responses. At ambient temperatures of 24.5-26.5 degrees C (Cool), microdialysis of 1mM muscimol into the MRR significantly decreased body temperature by approximately 0.5 degrees C, increased the ventilatory response to 7% CO(2) and decreased the response to 10% O(2). At ambient temperatures of 29.5-30.5 degrees C (Warm), 1 mM muscimol microdialysis no longer decreased body temperature and increased the ventilatory response to hypercapnia and to hypoxia. Muscimol did not significantly affect the VE/VO2 ratio at either temperature. Muscimol significantly increased the hypercapnic ventilatory responses in Cool and Warm conditions and the hypoxic response in Warm conditions, which indicates the presence of an inhibitory effect of rostral MRR neurons sensitive to muscimol. In the Cool condition the ventilatory response to hypoxia is inhibited but appropriately so for the lower VO2 .

Analysis of Variance↗
PubMed2003

Effects of spinal administration of muscimol on C- and A-fibre evoked neuronal responses of spinal dorsal horn neurones in control and nerve injured rats.

Neuropathic pain is a common clinical problem with complex aetiology, mechanisms and symptoms. Alterations in spinal gamma-aminobutyric acid (GABA) receptors may contribute to persistent pain states. The aim of the present study is to investigate potential changes of spinal GABA(A)-receptor function following peripheral nerve injury. Effects of spinal administration of the GABA(A)-receptor agonist muscimol (0.1-30 microg/50 microl) on electrically-evoked responses of spinal neurones in control, spinal nerve ligated and sham operated halothane-anaesthetised rats were studied. Spinal muscimol significantly (10 microg/50 microl) reduced evoked Abeta-, Adelta- and C-fibre responses of spinal neurones in control rats (58+/-22% of control, P<0.05; 3+/-2% of control, P<0.001; and 8+/-7% of control, P<0.001; respectively). Muscimol produced significantly greater inhibition of Adelta- and C-fibre evoked neuronal responses compared to Abeta-fibre evoked neuronal responses in control rats (P<0.001). C-fibre mediated post-discharge responses and the non-potentiated C-fibre evoked responses were significantly inhibited by muscimol in control rats. Inhibitory effects of muscimol (10 microg/50 microl) were blocked by pre-application of spinal bicuculline (10 microg/50 microl). Following either sham surgery, or spinal nerve ligation, spinal muscimol inhibited Abeta-, Adelta- and C-fibre evoked responses of spinal neurones to a similar extent, however significant inhibitory effects on the post-discharge response were not observed in nerve injured rats. Our data demonstrate that GABA(A)-receptor control of Abeta- and Adelta-fibre evoked responses are not altered in nerve injured or sham operated rats, compared to control. However, following nerve injury we report a reduction in GABA(A)-receptor control of C-fibre responses, in particular in relation to post-discharge responses.

Animals↗
PubMed2001

Lack of robust anticonvulsant effects of muscimol microinfusions in the anterior substantia nigra of kindled rats.

The substantia nigra pars reticulata is thought to control the spread of seizures in various seizure models. Potentiation of gamma-aminobutyrate (GABA)-mediated transmission in this region by intranigral administration of drugs such as muscimol has been shown to inhibit seizure propagation in such models, including the kindling model of epilepsy. More recent studies have shown that the effects on seizures are site-specific within the substantia nigra pars reticulata. Using flurothyl to induce clonic seizures, it was reported that bilateral microinfusions of muscimol into the anterior substantia nigra pars reticulata were anticonvulsant, while similar infusions into the posterior pars reticulata were proconvulsant. This prompted us to reevaluate the effects of intranigral muscimol in the kindling model with particular emphasis on the anterior substantia nigra pars reticulata. In amygdala kindled rats, muscimol was bilaterally infused into the anterior pars reticulata at doses of either 60 or 120 ng. Thirty minutes later, the threshold for induction of afterdischarges in the amygdala and the threshold for generalized seizures were determined in each rat. Furthermore, severity and duration of seizures at threshold currents were recorded. Unexpectedly, muscimol failed to increase seizure thresholds or to significantly reduce seizure severity or duration of motor seizures, although there was a moderate reduction in motor seizure duration in several rats. The data indicate that, in contrast to flurothyl seizures, in kindled rats the anterior pars reticulata of the substantia nigra is not a site at which muscimol causes robust anticonvulsant effects.

Amygdala↗
PubMed2000

Excitation of nigral dopamine neurons by the GABA(A) receptor agonist muscimol is mediated via release of glutamate.

Previous electrophysiological studies have shown that the GABA(A)-receptor agonist muscimol is able to markedly increase the firing rate of rat nigral dopamine (DA) neurons. This action of the drug is paradoxical since local microiontophoretic application of the drug is associated with a clearcut inhibition of this neurons. In the present electrophysiological study, an attempt was made to analyze the mechanism of this action of the drug. Administration of muscimol (0.25-4.0 mg/kg, i.v.) was associated with a dose-dependent increase in firing rate as well as an increased bursting activity of the nigral DA neurons. Both these effects of muscimol were clearly antagonised by intravenous administration of the NMDA receptor antagonist MK 801(1 mg/kg) or by intracerebroventricular administration of the broad-spectrum excitatory amino acid receptor antagonist kynurenic acid. Furthermore, pretreatment with PNU 156561A (40 mg/kg, i.v., 5-8h), a compound that raised endogenous kynurenic acid levels about 9 times, also clearly antagonised the actions of muscimol. Indeed, this treatment reversed the excitatory action of muscimol into an inhibitory effect on the nigral DA neurons. Here, we report that the excitatory action of muscimol is mediated indirectly by release of glutamate.

Animals↗
PubMed1994

Effect of the infusion of the GABA-A receptor agonist, muscimol, on the role of the entorhinal cortex, amygdala, and hippocampus in memory processes.

Rats were bilaterally implanted with cannulae in the entorhinal cortex, amygdala, and hippocampus; after recovery, they were trained in a step-down inhibitory avoidance task and tested for retention 24 h later. Muscimol (0.03 microgram) or D-amino-5-phosphonovalerate (5.0 micrograms) infused in the entorhinal cortex 20 min prior to training inhibited the amnestic effect of the same dose of muscimol infused into this area 100 min after training. Thus, memory-relevant information must be processed by the entorhinal cortex at the time of training in order that this cortex may play a late post-training role in memory processing. Pretraining intraentorhinal muscimol administration did not affect the amnestic effect of the post-training infusion of muscimol into the amygdala and hippocampus, or the inhibition of memory expression induced by a pretest infusion of CNQX into the amygdala and hippocampus or into the entorhinal cortex. Pretest intraentorhinal muscimol also did not influence the effect of pretest intra-amygdala and intrahippocampal CNQX administration. These data indicate that the cells of the entorhinal cortex that are sensitive to pretraining muscimol are not part of the inputs that lead to post-training processing by the amygdala and hippocampus, or to the intervention of the amygdala, hippocampus, and entorhinal cortex in memory expression. The present findings are compatible with the possibility that, instead, the entorhinal cortex may be an output of the amygdala and hippocampus at the time of memory expression.

2-Amino-5-phosphonovalerate↗
PubMed2003

Rescue of developing spinal motoneurons from programmed cell death by the GABA(A) agonist muscimol acts by blockade of neuromuscular activity and increased intramuscular nerve branching.

Blockade of neuromuscular activity in the chick embryo during the period of programmed cell death of motoneurons results in a complete rescue of these cells. Understanding the cellular mechanisms that mediate this counterintuitive effect is of considerable interest with respect to the regulation of motoneuron survival during development as well as for understanding why motoneurons die pathologically. Although considerable evidence supports the role of a peripheral site of action at the neuromuscular junction in mediating the rescue of motoneurons following activity blockade, some evidence also supports a role for central nervous system (CNS) neurons. For example, the rescue of motoneurons by curare has been reported to be blocked by the GABA(A) agonist muscimol via its actions on CNS neurons. We have carried out a series of studies to further investigate this interesting observation. Surprisingly, we find that: (1) muscimol blocks activity and rescues MNs in a dose-dependent manner, similar to curare; (2) muscimol's effects on MN survival appear to be mediated by its action on intramuscular nerve branching, similar to curare; and (3) although muscimol acts centrally, the effects of muscimol on MN survival and axon branching are mediated peripherally at the neuromuscular junction, similar to curare. Because muscimol reduces MN depolarization these data also suggest that the depolarization of MNs by afferents is not required for promoting MN survival. Taken together, these data provide further evidence in support of a peripheral site of action of activity blockade in rescuing motoneurons from developmental cell death.

Animals↗
PubMed1978

gamma-Aminobutyric acid receptors visualized in spinal cord cultures by [3H]muscimol autoradiography.

gamma-Aminobutyric acid (GABA) receptors were visualized in mouse spinal cord explant cultures by [3H]muscimol autoradiography over certain small neurons of the dorsal horn grey matter, in the interneuronal neuropil of dorsal and ventral horns, and (rarely) in small clusters on processes of anterior horn cells. Specificity was indicated in control experiments by inhibition of binding by [3H]muscimol after pretreatment with GABA or a GABA analogue, 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP, isoxazole 16), or with receptor antagonists bicuculline and picrotoxin. Unlabeled muscimol exchanged effectively with [3H]muscimol and produced autoradiographic label in locations indistinguishable from those found in experiments with [3H]muscimol alone. Pretreatment with the GABA uptake and transport inhibitors (-)-nipecotic acid and guvacine did not affect binding with [3H]muscimol. These experiments indicate that explant culture systems can be used for demonstration of functional receptors.

Animals↗