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PubMedDate not supplied

Acid metabolite of progabide pharmacokinetics following single administration in the rabbit with special references to HPLC and (3H) muscimol radioreceptor assay.

The aim of the present study was to monitor plasma levels of progabide and its metabolites in the rabbit following single oral administration of 20 mg.kg-1. The plasma levels were determined selectively using high performance liquid chromatography (HPLC) and then correlated with a global estimation by a (3H) muscimol radioreceptor assay (RRA). In our "in vitro" binding conditions progabide itself was virtually ineffective (IC50 greater than 100 microM) so only RRA active materiel plasma concentrations were studied. A good enough correlation (r = 0.71) has been established between HPLC and RRA plasma concentrations from 0 to 3 hours following oral administration specially considering the absorption phase. But with closed regards to the elimination pharmacokinetic parameters specially the elimination half-life values (t1/2el (RRA) = 1.67 h and t1/2el (HPLC) = 0.70 h) that correlation should be weaker than the former instead metabolites including GABAmide and GABA itself are probably present in amounts likely to affect the displacement of specific binding in the (3H) muscimol radioreceptor assay.

Animals↗
PubMed1999

Defensive reactions are counteracted by midazolam and muscimol and elicited by activation of glutamate receptors in the inferior colliculus of rats.

The inferior colliculus is involved in conveying auditory information of an aversive nature to higher cortical structures. Gradual increases in the electrical stimulation of this structure produce progressive aversive responses from vigilance, through freezing, until escape. Recently, we have shown that microinjections of NMDA into the inferior colliculus mimic these aversive effects and that the neural substrates responsible for learned escape behavior in the inferior colliculus are regulated by GABA-benzodiazepine mechanisms. In the present study, we extend these observations showing that unlearned aversive responses are also depressed by muscimol and midazolam, both GABA-benzodiazepine agonists, and that microinjection of glutamate, an excitatory amino acid, into the inferior colliculus can trigger freezing responses. Electrical stimulation of the inferior colliculus of rats placed inside an open field allowed the determination of thresholds for the aversive responses, alertness, freezing and escape. Systemic administration (3 and 5.6 mg/kg) as well as microinjections into the inferior colliculus of the anxiolytic compound midazolam (10, 20 and 40 nmol) caused increases in threshold for these aversive responses. Similar results were obtained following microinjections of the GABA-A agonist muscimol (0.1, 1 and 5 nmol) into this brainstem structure. Microinjections of low doses of glutamate (5 nmol), presumed to activate mainly AMPA/kainate receptors, into the ventrolateral division of the central nucleus of the inferior colliculus of rats placed inside a circular arena induced aversive reactions, characterized by freezing responses. However, higher doses of glutamate caused no apparent effects. GDEE, an AMPA/kainate receptor antagonist, inhibited, whereas AP7, a NMDA receptor antagonist, did not influence these responses. It is suggested that GABA-benzodiazepine processes modulate the expression of defensive reactions in the inferior colliculus and that activation of fast-acting excitatory amino acid receptors in this midbrain region can trigger the initial steps of the defense reaction without eliciting the motor explosive behavior usually seen following the activation of NMDA receptors.

Animals↗
PubMed1999

The effects of muscimol inactivation of small regions of motor and somatosensory cortex on independent finger movements and force control in the precision grip.

This study investigated the effects of inactivating small regions of the primary somatosensory (SI) and motor (MI) cortex on the control of finger forces in a precision grip. A monkey was trained to grasp and lift a computer-controlled object between the thumb and index finger and to hold it stationary within a narrow position window for 2 s. The grip force applied perpendicular to the object surface, the lifting or load force applied tangentially in the vertical direction, and the vertical displacement were sampled at 100 Hz. Also, the ability of the monkey to extract small pieces of food from narrow wells of a Klüver board was analyzed from video-tape. Preliminary single-unit recordings and microstimulation studies were used to map the extent of the thumb and index-finger representation within SI and MI. Two local injections of 1 microl each (5 microg/microl) of the GABA(A)-agonist muscimol were used to inactivate the thumb and index region of either the pre- or post-central gyrus. The precision grip was differently affected by muscimol injection into either SI or MI. MI injections produced a deficit in the monkey's ability to perform independent finger movements and a general weakness in the finger muscles. Whole-hand grasping movements were inappropriately performed in an attempt to grasp either the instrumented object or morsels of food. Although the effect seemed strongest on intrinsic hand muscles, a clear deficit in digit extension was also noted. As a result, the monkey was unable to lift and maintain the object within the position window for the required 2 s, and, over time, the grip force decreased progressively until the animal stopped working. Following SI injections, the most obvious effect was a loss of finger coordination. In grasping, the placement of the fingers on the object was often abnormal and the monkey seemed unable to control the application of prehensile and lifting forces. However, the detailed analysis of forces revealed that a substantial increase in the grip force occurred well before any deficit in the coordination of finger movements was noted. This observation suggests that cutaneous feedback to SI is essential for the fine control of grip forces.

Animals↗
PubMed2000

D-Amphetamine potentiates muscimol-induced disinhibition of A10 dopaminergic neurons in the rat.

UNLABELLED: Evidence suggests that sensitisation to the behavioural effects of d-amphetamine involves a late-onset (>3 hrs), long-term potentiation (LTP)-like change at medial prefrontal cortex (mPFC)-regulated synapses on A10 dopaminergic (DA) neurons. Since muscimol-induced excitation of A10 DA neurons is dependent on mPFC-regulated afferents, this assay was used to assess whether d-amphetamine enhances the driving of A10 DA neurons by the mPFC, as would be predicted if it resulted in the conditions necessary for LTP. Animals were administered d-amphetamine or saline, 3-4.5 hrs prior to recording. In the acute condition, animals were drug-naïve prior to d-amphetamine, whilst in the challenge condition, animals had previously received d-amphetamine (or saline) each day for 6 days. Recording took place on withdrawal day 2. Muscimol produced significantly less inhibition of A10 DA neurons from animals administered d-amphetamine (rather than saline), but only when d-amphetamine had been chronically administered beforehand (i.e. in the challenge condition). Hence, although the studies fail to provide evidence that acute d-amphetamine administration produces the conditions necessary for LTP, chronic d-amphetamine administration appears to potentiate the impact on A10 DA neurons of mPFC-regulated excitatory activity, thus strengthening the link between this potentiation and the sensitisation process. KEYWORDS: Ventral tegmental area, excitatory amino acids, medial prefrontal cortex, non-DA neurons, synaptic plasticity, behavioural sensitisation.

Analysis of Variance↗
PubMed1980

Reduction of [3H]muscimol binding sites in rat dorsal spinal cord after neonatal capsaicin treatment.

Two-day-old rats were pretreated with 50 mg/kg of capsaicin. After 3--4 months, specific binding of [3H]muscimol and [3H]strychnine was measured in membrane preparations from dorsal spinal cord. A 20-30% decrease of the number of [3H]muscimol binding sites was observed after capsaicin treatment. In contrast, [3H]strychnine binding was unchanged. The results provide indirect evidence for a presynaptic location of GABA receptors on capsaicin-sensitive primary afferent neurons.

Animals↗
PubMed1981

Autoradiographic localization of [3H]muscimol in the cat retina.

In the cat retina, [3H]muscimol is localized in 5 morphologically distinct subpopulations of neurons with cell bodies in the amacrine layer and in other neurons located in the ganglion cell layer. Müller cells are unlabeled. The labeled subpopulations in the amacrine layer correspond to the subpopulations which also exhibit preferential uptake of [3H]GABA. The [3H]muscimol-labeled cells include interplexiform cells and type-AI reciprocal amacrine cells.

Animals↗
PubMed1983

Differential modulation of etazolate or pentobarbital enhanced [3H] muscimol binding by benzodiazepine agonists and inverse agonists.

Flunitrazepam, a benzodiazepine agonist increases, and DMCM, an inverse agonist decreases the stimulation by etazolate or pentobarbital of [3H] muscimol binding to membranes of rat cerebral cortex. Ro 15-1788 has no marked effects but antagonizes the action of both flunitrazepam and DMCM. The investigation of several drugs acting on benzodiazepine receptors on etazolate enhancement of [3H] muscimol binding suggests that their receptor interaction reflects a spectrum from agonists to inverse agonists.

Animals↗
PubMed1983

In vivo release of [3H]GABA in cat caudate nucleus and substantia nigra. I. Bilateral changes induced by a unilateral nigral application of muscimol.

Push-pull cannulae were implanted in both caudate nuclei and both substantiae nigrae (SN) of halothane-anesthetized cats and the release of [3H]GABA, continuously synthesized from [3H]glutamine, was measured in these structures during 4 h of superfusion. In some experiments, multi-unit neuronal activity was recorded at the tip of the nigral push-pull cannulae, using a bipolar electrode. Two hours after the onset of superfusion with [3H]glutamine, 10(-6)M of muscimol was added (for 1 h) in the superfusion medium delivered to one SN. This treatment increased locally the release of [3H]GABA and enhanced the neuronal activity of the nigral cells in the zona reticulata. An increased release of [3H]GABA was also observed in the contralateral SN, in association with an inhibition of the activity of the zona reticulata cells. The unilateral nigral application of muscimol also induced asymmetric changes in the release of [3H]GABA in both caudate nuclei, since [3H]GABA release was increased ipsilaterally and reduced on the contralateral side. The present findings are considered in relation to possible GABAergic neuronal populations affected by this local pharmacological treatment.

Animals↗
PubMed1983

The effects of the GABAergic agonist muscimol upon the relationship between local cerebral blood flow and glucose utilization.

The relationship between cerebral blood flow and glucose utilization was studied in conscious rats using the [14C]iodoantipyrine and [14C]2-deoxyglucose quantitative autoradiographic techniques respectively. Both blood flow and glucose use decreased in parallel in the 38 areas of the brain analyzed following administration of the GABA agonist muscimol, thus maintaining the relationship observed in control rats. The present study offers no evidence for a direct vasodilatatory action for muscimol in the conscious rat, but points to underlying regional metabolic activity as the primary determinant of cerebral blood flow.

Animals↗
PubMed1986

[3H]muscimol binding of GABA receptors in the visual cortex of normal and monocularly deprived cats.

In vitro receptor binding techniques were used to compare the total number, affinity and regional distribution of GABA receptors in visual cortex, as revealed by [3H]muscimol binding, in 5 normal and 5 monocularly deprived (MD) cats. Analysis of saturation kinetics and pharmacological specificity indicated that binding was to a single site having the characteristics of the GABAA receptor. No differences were found between normal and MD cats in either number or affinity of receptors. Within visual cortex, there were laminar differences in the density of binding, but no evidence for a lateral (columnar) organization. Label was densest in the superficial layers (I-IV), lowest in layer V and intermediate in layer VI. This pattern of label varied with incubation parameters with layer IV showing the densest label when high concentrations of [3H]muscimol and short rinse times were used. There were no differences between normal and MD cats in regional distribution of receptors under any incubation condition.

Animals↗
PubMed1987

Cerebral glucose utilization following striatal lesions: the effects of the GABA agonist, muscimol, and the dopaminergic agonist, apomorphine.

Local cerebral glucose utilization was measured in 21 discrete regions of the rat CNS following unilateral kainic acid lesions of the caudate nucleus, and subsequent pharmacological challenge with GABAergic or dopaminergic agonists. The most pronounced increases in glucose use were observed in those ipsilateral areas of the brain to which the lesioned striatum normally projects (globus pallidus, entopeduncular nucleus and substantia nigra pars reticulata), although several other brain regions with known anatomical connections to the striato-pallido-nigral system were also affected, most notably in the thalamus and epithalamus. These effects were similar to those reported previously from a different group of animals in which the injection protocol was slightly different. The consequences of striatal lesion, in terms of alterations in local rates of glucose use, were attenuated by i.v. administration of the putative GABA agonist, muscimol. In one area, the ventromedial thalamus, glucose use was more markedly affected by muscimol treatment bilaterally in lesioned animals than in intact animals. The consequences of striatal lesions upon the response to the putative dopaminergic agonist apomorphine, were both complex and profound. In some regions (e.g. globus pallidus), striatal lesion eliminated, or masked the normal response to apomorphine. Elsewhere, the apomorphine response, although in evidence, was significantly attenuated by striatal lesion (e.g. entopeduncular nucleus), but in only two brain areas, substantia nigra pars reticulata and ventrolateral thalamus, the apomorphine response was significantly potentiated by striatal lesion. These studies add further weight to the concept of disinhibition, mediated via striatal GABA fibres, as an organizing principle in striatonigral function and indicate a complex interaction of intrinsic GABAergic pathways with dopaminergic systems in the integrated response to stimulation of dopaminergic receptors in the extrapyramidal motor system.

Animals↗
PubMed1987

Facilitation of premotor cortical seizure development by intranigral muscimol.

The role of the substantia nigra in seizure development was investigated using a chronic model of partial onset generalized seizure induced by low frequency cortical stimulation. Unilateral intranigral micro-injection of muscimol, a GABA receptor agonist, was found to facilitate partial onset seizure development, but did not affect developed seizures. This finding suggested that a non-dopaminergic, presumably GABAergic, mechanism was involved since the facilitatory effect of intranigral muscimol was not modified by haloperidol pretreatment.

Animals↗
PubMed1988

Microinjection of muscimol into entopeduncular nucleus suppresses pilocarpine but not maximal electroshock seizures in rats.

Microinjection of muscimol (406 pmol) into the rat entopeduncular nucleus, the analogue of the primate globus pallidus pars interna, significantly suppressed pilocarpine but not maximal electroshock seizures in a spatially specific manner. In contrast to its lack of efficacy in the entopeduncular nucleus, microinjection of muscimol into the substantia nigra suppressed maximal electroshock seizures. These findings suggest that the neural networks and/or the neurotransmitters that subserve the propagation of pilocarpine and maximal electroshock seizures differ with regard to the entopeduncular nucleus. The data also underscore the powerful regulatory role of the substantia nigra in diverse models of seizures.

Animals↗
PubMed1991

Anti-pentylenetetrazol effect of intranigral 2-amino-7-phosphonoheptanoate attenuated by muscimol.

Bilateral injection of 2-amino-7-phosphonoheptanoate (2-APH), a selective N-methyl-D-aspartate (NMDA) receptor antagonist, into substantia nigra pars reticulata (SNpr) significantly and dose-dependently suppressed tonic pentylenetetrazol (PTZ) seizures (100 mg/kg, i.p.). The results confirm the anticonvulsant effectiveness of 2-APH and the capacity of SNpr to modulate PTZ seizure activity. The anti-PTZ effect of 2-APH was significantly attenuated by muscimol, co-infused into SNpr. This result supports the hypothesis, drawn from earlier studies, that intranigral muscimol can interfere with the anti-PTZ actions of other intranigral treatments.

2-Amino-5-phosphonovalerate↗
PubMed1991

Ovarian steroid modulation of [3H]muscimol binding in the spinal cord of the rat.

[3H]Muscimol binding was measured in the lumbar spinal cord of female rats by in vitro quantitative autoradiography. Ovariectomized rats were treated subcutaneously with either oil, estradiol benzoate (EB) or EB plus progesterone (P) in a regime known to reliably induce sexual receptivity. The level of [3H]muscimol binding was highest in laminae I-III and in the region around the central canal. Binding was lower in laminae IV-VI and was frequently undetectable in the ventral horn. There was a significant increase in the level of binding in laminae I-III after EB treatment. There was also a significant increase after treatment with EB+P in comparison to both the ovariectomized and EB-treated groups in this same region of the spinal cord.

Animals↗
PubMed1992

Muscimol infused into the medial septal area impairs long-term memory but not short-term memory in inhibitory avoidance, water maze place learning and rewarded alternation tasks.

These experiments investigated the effects of injections of muscimol (1 or 5 nmol), administered into the medial septal area prior to training, on memory tested at different retention delays after training in 3 tasks: an inhibitory avoidance task, a one-trial place learning task, and a rewarded alternation task. In all 3 tasks, intraseptal injections of muscimol did not impair memory performance at short retention delays, but impaired memory at the longer retention delays. These findings are consistent with the view that GABAergic regulation of the septohippocampal cholinergic system plays a selective role in the establishment of long-term memory.

Animals↗
PubMed1993

Decreased forebrain [35S]TBPS binding and increased [3H]muscimol binding in rats that do not develop stress-induced behavioral depression.

Recent evidence suggests that anxiety and its biological concomitants may be involved in the pathophysiology of depression. In the present study, the in vitro radioligand binding of [3H]flunitrazepam, [3H]muscimol and [35S]t-butylbicyclophosphorothionate (TBPS) sites on the benzodiazepine/GABA chloride ionophore receptor complex (BGRC) was examined using the learned helplessness paradigm. Only rats which did not develop the syndrome showed a significant increase in [3H]muscimol binding in cerebral cortex and a decrease in [35S]TBPS binding in cerebral cortex and hippocampus in comparison to naive controls. For both ligands, this represented a change in Bmax rather than a change in affinity. Adrenalectomy had no impact on these alterations indicating that critical endogenous factors are not manufactured by the adrenal glands. These findings suggest that the BGRC in the forebrain may be a site mediating the 'coping' ability of rats that do not develop the learned helplessness syndrome. The possible involvement of neurosteroids in this effect is discussed.

Adrenalectomy↗
PubMed1996

Involvement of GABAB receptor systems in action of antidepressants. II: Baclofen attenuates the effect of desipramine whereas muscimol has no effect in learned helplessness paradigm in rats.

Involvement of GABAergic systems in action of antidepressants was examined in the learned helplessness paradigm in rats. Rats were treated with desipramine, baclofen or muscimol for 14 days. On day 14, the rats were subjected to 90 inescapable shocks. On day 15, the rats received the 40-trial escape test. The inescapable shocks induced the subsequent increase in escape failures in the escape test. Desipramine dose-dependently improved the increased escape failures induced by the inescapable shocks. Baclofen attenuated the escape failures-improving effect of desipramine, although baclofen had no effects on the increased escape failures when it was injected alone. Muscimol at any dose failed to influence the increased escape failures. Therefore, it is suggested that the long-term decrease in GABAB neurotransmission may be involved in the action of antidepressants. Our present results do not support the hypothesis that activation of GABAA receptors may contribute to the action of antidepressants.

Animals↗