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PubMed1992

Bilateral cerebral metabolic effects of pharmacological manipulation of the substantia nigra in the rat: unilateral intranigral application of the inhibitory GABAA receptor agonist muscimol.

Rates of cerebral glucose utilization were measured by means of the autoradiographic 2-deoxy-D[1-14C]glucose technique in the rat brain in order to determine the metabolic effects of unilateral intranigral application of the GABAA agonist muscimol upon the substantia nigra and its targets. Intranigral injection of 1.5 microliters 0.3 M muscimol (52 micrograms total dose) induced local metabolic activation in the injected substantia nigra reticulata (by 87% as compared to the control group), and distal metabolic depressions in the nucleus accumbens, striatum, globus pallidus and subthalamic nucleus only ipsilaterally to the injected nigra. The remaining basal ganglia components, including the substantia nigra compacta and the entopeduncular nucleus were bilaterally unaffected. Among the principal efferent projections of the substantia nigra reticulata, the ventromedial and centrolateral thalamic nuclei as well as the deep layers of the superior colliculi were metabolically depressed bilaterally, whereas the ventrolateral, parafascicular and mediodorsal thalamic nuclei as well as the pedunculopontine nucleus displayed metabolic depressions ipsilateral to the muscimol-injection nigra. The ventromedial and centrolateral thalamic nuclei were depressed by 41 and 42%, respectively, in the ipsilateral side, and by 30 and 26% in the contralateral side, when compared to the respective values of the control group of rats. Furthermore, unilateral intranigral injection of 0.3 M muscimol induced metabolic depressions in reticular, intralaminar and prefrontal thalamocortical areas mostly ipsilateral to the injected nigra, as well as in limbic areas bilaterally. It is suggested that the present findings are due to a postsynaptic effect of muscimol on the nigral GABAergic cells and to a consequent metabolic depression of the basal ganglia and associated thalamocortical areas, in contrast to an earlier suggested presynaptic nigral effect of lower doses of intranigrally injected muscimol which induced metabolic activations within the same network. This suggestion is further supported by the fact that intranigrally injected substrate P19 induced similar effects to those elicited by the lower doses of intranigral muscimol and opposite to those induced at present by the higher muscimol dose. Moreover, it is further substantiated that the nigrothalamic GABAergic system is responsible for considerable transfer of information from one substantia nigra reticulata to the ipsilateral basal ganglia and associated thalamocortical components as well as to bilateral motor, intralaminar and limbic areas.

Animals↗
PubMed1997

Microinjections of muscimol into lateral superior colliculus disrupt orienting and oral movements in the formalin model of pain.

An important reaction in rodent models of persistent pain is for the animal to turn and bite/lick the source of discomfort (autotomy). Comparatively little is known about the supraspinal pathways which mediate this reaction. Since autotomy requires co-ordinated control of the head and mouth, it is possible that basal ganglia output via the superior colliculus may be involved; previously this projection has been implicated in the control of orienting and oral behaviour. The purpose of the present study was therefore, to test whether the striato-nigro-tectal projection plays a significant role in oral responses elicited by subcutaneous injections of formalin. Behavioural output from this system is normally associated with the release of collicular projection neurons from tonic inhibitory input from substantia nigra pars reticulata. Therefore, in the present study normal disinhibitory signals from the basal ganglia were blocked by injecting the GABA agonist muscimol into different regions of the rat superior colliculus. c-Fos immunohistochemistry was used routinely to provide regional estimates of the suppressive effects of muscimol on neuronal activity. Biting and licking directed to the site of a subcutaneous injection of formalin (50 microliters of 4%) into the hind-paw were suppressed in a dose-related manner by bilateral microinjections of muscimol into the lateral superior colliculus (10-50 ng; 0.5 microliter/side); injections into the medial superior colliculus had little effect. Bilateral injections of muscimol 20 ng into lateral colliculus caused formalin-treated animals to re-direct their attention and activity from lower to upper regions of space. Muscimol injected unilaterally into lateral superior colliculus elicited ipsilateral turning irrespective of which hind-paw was injected with formalin. Oral behaviour was blocked when the muscimol and formalin injections were contralaterally opposed; this was also true for formalin injections into the front foot. Interestingly, when formalin was injected into the perioral region, injections of muscimol into the lateral superior colliculus had no effect on the ability of animals to make appropriate contralaterally directed head and body movements to facilitate localization of the injected area with either front- or hind-paw. These findings suggest that basal ganglia output via the lateral superior colliculus is critical for responses to noxious stimuli which entail the mouth moving to and acting on the foot, but not when the foot is the active agent applied to the mouth. The data also suggest that pain produces a spatially non-specific facilitation of units throughout collicular maps, which can be converted into a spatially inappropriate signal by locally suppressing parts of the map with the muscimol.

Animals↗
PubMed2000

The medial prefrontal cortex plays an important role in the excitation of A10 dopaminergic neurons following intravenous muscimol administration.

Intravenous muscimol administration increases the activity of dopaminergic neurons of the A10 cell group, located in the ventral tegmental area. Evidence suggests that this increase in activity is produced by disinhibition following the inhibition of GABAergic ("non-dopaminergic") cells in the ventral tegmental area. We hypothesized that the activation of A10 cells by muscimol is likely to be at least partly caused by the action of excitatory afferents. To verify this, A10 cells were isolated from ipsilateral afferent sources which utilise excitatory amino acids (which play an important role in the activity of these neurons), using hemisections at the level of the subthalamic nucleus (or just anterior to the subthalamic nucleus), electrolytic lesions of the pedunculopontine tegmental nucleus, or a combination of both. Following hemisections, and hemisections combined with lesions of the pedunculopontine tegmental nucleus, muscimol inhibited rather than excited A10 dopaminergic neurons. The pedunculopontine tegmental nucleus itself appeared to make little intrinsic contribution to muscimol-induced excitation, although the results suggested that part of the excitation which originates in the forebrain may be conducted to A10 cells via the pedunculopontine tegmental nucleus. The source of the effective forebrain excitation was investigated using electrolytic lesions of documented sources of excitatory amino acidergic afferents to the ventral tegmental area: the medial prefrontal cortex, certain nuclei of the amygdalar complex and the lateral habenular nucleus. In the medial prefrontal cortex-lesioned group, muscimol again produced inhibition, an effect qualitatively and quantitatively similar to that in the hemisected groups. Habenular lesions blocked muscimol-induced excitation without producing inhibition, whilst amygdalar lesions produced no significant change in the effects of muscimol. The results suggest that under normal circumstances, an active excitation counteracts and exceeds the direct inhibitory effects of muscimol on the activity of A10 dopaminergic neurons. Furthermore, this activation appears to be produced by the action of excitatory (probably excitatory amino acidergic) afferents arising from the medial prefrontal cortex, and possibly the lateral habenular nucleus. Insofar as the excitation of A10 dopaminergic neurons, which is produced by certain drugs of abuse, and which may play a crucial role in their sustained use, has its basis in excitation following disinhibition, this excitation may provide a novel target for therapeutic intervention in addiction.

Amygdala↗
PubMed2003

Septal infusions of glucose or pyruvate, but not fructose, produce avoidance deficits when co-infused with the GABA agonist muscimol.

Although glucose typically enhances memory or reverses memory deficits, glucose can also produce memory deficits when co-infused with the gamma-aminobutyric acid (GABA) agonist muscimol into the medial septum (Parent & Gold, 1997; Parent, Laurey, Wilkniss, & Gold, 1997). To date the mechanisms underlying the memory-impairing interaction between GABA and glucose remain unknown. Here we investigate whether this effect is the result of hyperosmolar conditions or may involve glucose metabolism. Male Sprague-Dawley rats were given one-trial inhibitory avoidance training after receiving septal infusions of vehicle (phosphate-buffered saline, 0.5 microl), the GABA(A) agonist muscimol (3 nmol), glucose (16.5, 33, or 66 nmol), fructose (33 nmol), pyruvate (33 nmol), or a solution containing muscimol combined with glucose, fructose, or pyruvate. Retention performance was tested 48 h later. Infusions of glucose, pyruvate, fructose, or muscimol alone did not affect retention performance. However, co-infusions of all doses of glucose (16.5, 33, or 66 nmol) or the glycolytic end product pyruvate with muscimol impaired retention performance. Co-infusions of fructose with muscimol did not affect retention performance. These results suggest that the memory-impairing interaction between glucose and muscimol does not result from hyperosmolar conditions, because equiosmolar concentrations of fructose do not mimic the effects of glucose and the memory deficits do not vary as a function of glucose concentration. The finding that pyruvate mimicked the effects of glucose and impaired memory when combined with muscimol suggests that glucose metabolism may be involved in the memory-impairing interaction between glucose and GABA(A) receptors in the medial septum.

Animals↗
PubMed2002

Muscimol diffusion after intracerebral microinjections: a reevaluation based on electrophysiological and autoradiographic quantifications.

Intracerebral muscimol injection is widely used to inactivate discrete brain structures during behavioral tasks. However, little effort has been made to quantify the extent of muscimol diffusion. The authors report here electrophysiological and autoradiographic results obtained after muscimol injection (1 microg/microl) either into the nucleus basalis magnocellularis (0.1-0.4 microl) or into the thalamic reticular nucleus (RE, 0.05-0.1 microl). In 52 rats, multiunit recordings were collected either in the RE or in the auditory thalamus during the 2 h following muscimol injection. Decreases in neuronal activity were observed up to 3 mm from the injection site; their time of occurrence was a function of the distance between the injection and recording sites. Because these decreases cannot be explained by physiological effects, they likely reflected muscimol diffusion up to the recording sites. Autoradiographic studies involved 25 rats and different experimental conditions. Optical density (OD) measures indicated that after a survival time of 15 min, a 0.05 microl injection produced a labeled area of 5.25 mm(2) at the injection site and a rostrocaudal labeling of 1.7 mm. Increasing the survival time to 60 min, or increasing the injected volume to 0.1 microl, systematically led to a larger labeled area at the injection site (8-12 mm(2)) and to a larger rostrocaudal diffusion (2.0-2.5 mm). Direct quantifications of radioactivity by a high-resolution radioimager validated the OD measures and even indicated a larger muscimol diffusion (up to 3.25 mm). Thus, these data point out that muscimol diffusion after intracerebral microinjection is larger than usually supposed. The relationships between these results and those obtained in behavioral studies are discussed.

Animals↗
PubMed1991

Differential effects of bicuculline and muscimol microinjections into the vestibular nuclei on simian eye movements.

1.) Eye movements were recorded in four Java monkeys (M. fascicularis) after unilateral microinjections (1 microliter, concentration 1 micrograms/microliter) of the GABA antagonist, bicuculline, and the GABA agonist, muscimol, into oculomotor related regions of the vestibular nuclei. Eye movements were investigated in the dark and light during spontaneous eye movements, vestibular stimulation (sinusoidal: 0.2 Hz, +/- 40 deg/s, and velocity trapezoid: 40 deg/s2 acceleration, 120 deg/s constant velocity), and visual-vestibular conflict stimulation. 2.) Bicuculline and muscimol injections consistently led to specific eye movement changes, which were maximal 5-10 min after bicuculline injection (muscimol 10-30 min), and lasted 90-120 min (muscimol 2-4 h). Control injections with NaCl (0.9%) into the responsive area and with bicuculline 2-3 mm more lateral showed no effect. 3.) Bicuculline induced a spontaneous nystagmus of 40.9 deg/s (average, range 10.5-93 deg/s), beating in 60% of the cases to the contralateral and in 40% to the ipsilateral side. The analysis of the slope of the slow phase gave no evidence for an additional gaze holding deficit. The VOR gain in the dark showed a slight decrease (pre: 0.96; post: 0.86) on average. The time constant of decay for slow phase nystagmus velocity after vestibular ramp stimulation was reduced, reflecting a 'velocity storage' deficit. After bicuculline injections nystagmus suppression in the light and during visual-vestibular conflict stimulation was generally well preserved. 4.) After muscimol injections horizontal gaze holding was severely affected. Each saccade was followed by an exponentially decreasing postsaccadic drift with a time constant as short as 250 ms (average 414 ms). The eyes always drifted towards a null-position, which generally did not coincide with the midposition of the eye. The null-position could move up to 35 deg to the contralateral or ipsilateral side. The highly distorted eye movements after muscimol injections prevented VOR-measurements based on eye velocity. Instead vestibular stimulation led to a shift of the null-position with an amplitude corresponding to a gain (eye position/stimulus position) of 0.17 (average) at 0.2 Hz (+/- 40 deg/s). Vertical eye movements did not show a major gaze holding deficit. 5.) From the experiments it can be concluded that the inhibitory transmitter GABA plays an important role for eye movement generation within the vestibular nuclei. Bicuculline induces mainly a vestibular imbalance with little evidence for a neural integrator deficit. In contrast unilateral muscimol injections lead to a complete, reversible loss of function for the common horizontal neural integrator, which converts eye velocity into eye position signals. The accompanying shift of the null-position reflects an additional vestibular imbalance.

Animals↗
PubMed1981

The effects of muscimol and picrotoxin injections into the cat substantia nigra.

The behaviour of cats after unilateral injections of muscimol, picrotoxin and bicuculline into the posterior and lateral parts of the substantia nigra was observed. The antagonism between muscimol and picrotoxin was limited to some effects of the drugs: (1) muscimol-induced sniffing, licking and enhanced locomotor activity was attenuated by picrotoxin in contrast to the muscimol-induced contralateral turning which was even enhanced by picrotoxin; (2) picrotoxin-induced balance disorders as well as characteristic motor disturbances in the hind legs remained unaffected following an additional treatment with muscimol. Furthermore, subcutaneously given apomorphine did not affect the picrotoxin-induced balance and hind leg disorders, although the apomorphine-induced stereotyped behaviour itself was enhanced and suppressed by intranigral administration of muscimol and picrotoxin respectively. The conclusion is reached that there are at least two distinct populations of GABA receptors within the substantia nigra: one group controlling or being controlled by dopaminergic neurons and one group operating fully independently of the former neurons. The similarities to experiments on rats are stressed. The mechanism underlying the muscimol-resistant picrotoxin-induced effects (balance disorders and motor disturbance of the hind legs) is discussed.

Animals↗
PubMed1986

Involvement of the midbrain reticular formation in self-injurious behavior, stereotyped behavior, and analgesia induced by intranigral microinjection of muscimol.

Bilateral microinjection of muscimol (60 ng), a gamma-aminobutyric acid (GABA) agonist, into the central region of the substantia nigra (pars reticulata) produced self-injurious behavior (SIB), stereotyped behavior and analgesic-like effects in rats. Bilateral electrolytic lesions of the midbrain reticular formation ventrolateral to the periaqueductal gray matter completely blocked the SIB but had little effect on stereotyped behavior produced by intranigral muscimol. Lesions of the midbrain reticular formation reduced the antinociceptive effect of intranigral muscimol on the tail-flick but not on the hot-plate test. Bilateral microinjection of muscimol (10-100 ng) into the midbrain reticular formation produced intense stereotyped behavior and had an analgesic-like effect on the hot-plate test but not on the tail-flick test. Stereotyped behavior appeared to interfere with the paw-lick response on the hot-plate test. These data suggest that the antinociceptive effect of intranigral muscimol on the tail-flick test is mediated by fibers that project to or pass through the midbrain reticular formation and that analgesia may play an important role in muscimol-induced SIB. The midbrain reticular formation does not appear to be involved in the stereotyped behavior produced by intranigral muscimol.

Animals↗
PubMed1995

Muscimol injected into the right or left amygdaloid complex differentially affects retention performance following aversively motivated training.

The effects of intra-amygdala infusion of the GABAA agonist, muscimol, prior to retention testing was examined. In Expt. 1, rats were trained in a one-trial inhibitory-avoidance task and given bilateral intra-amygdala infusions of vehicle or muscimol or simultaneous unilateral infusions of each, 5 min before the retention test 24 h after training. Expt. 2 used the same procedures as those in Expt. 1 but two retention measures were taken: initial step-through latency and the number of trials to reach criterion during continuous multiple-trial inhibitory-avoidance (CMIA) training. Groups given bilateral infusions of muscimol or unilateral infusion of muscimol into the right amygdala had significantly shorter latencies to enter the dark compartment than groups given bilateral infusions of vehicle or unilateral infusion of muscimol into the left amygdala. Bilateral muscimol infusions impaired acquisition of CMIA relative to bilateral vehicle infusions or unilateral muscimol infusion into the left amygdala. These results suggest differential involvement of the right and left amygdala in memory.

Amygdala↗
PubMed1983

Effects of barbiturates and ethanol on muscimol-induced release of [3H]-D-aspartate from rodent cerebellum.

The K+-stimulated release of [3H]-D-aspartate and [14C]-GABA from synaptosomal (P2) fractions prepared from rat cerebellum was studied. Muscimol enhanced the release of [3H]-D-aspartate by 60-75% and the release of [14C]-GABA by 20-35%. Muscimol also enhanced the release of [3H]-D-aspartate from P2 fractions prepared from swine and mouse cerebellum. Pentobarbital, an anesthetic barbiturate, had no effect on basal or K+-stimulated release of [3H]-D-aspartate or [14C]-GABA but potentiated the enhancement of [3H]-D-aspartate release by muscimol. The EC50 was approx. 50 microM. The S(-)-isomer of pentobarbital was more potent than the R(+)-isomer in potentiating the action of muscimol, in agreement with the anesthetic potencies of the isomers. Phenobarbital, an anticonvulsant barbiturate, enhanced release of [3H]-D-aspartate and [14C]-GABA in the absence of muscimol. In contrast, the convulsant barbiturate 5-ethyl-5-(2'-cyclohexylidene-ethyl)barbituric acid (CHEB) caused a significant increase in basal release of [3H]-D-aspartate and [14C]-GABA in the absence of muscimol. Diazepam and ethanol had no effect on the release of [3H]-D-aspartate and did not potentiate the action of muscimol. These experiments provide biochemical evidence for an enhancement of the action of GABA by anesthetic barbiturates. This effect appears to be mediated through a benzodiazepine-insensitive presynaptic GABA receptor.

Animals↗
PubMed1982

Intra-raphe muscimol induced hyperactivity depends on ascending serotonin projections.

Acute microinjections of the GABA agonist, muscimol (100 ng), into either the dorsal (DR) or the median (MR) raphe nucleus of etherized rats induced post-anesthesia hyperactivity as measured in photocell chambers. The increased activity counts seen after MR injections, furthermore, were 4 times greater than those following DR injections. In animals implanted with chronically indwelling cannulae, a muscimol (25-400 ng) dose-response analysis confirmed the greater sensitivity of the MR site. Subsequent experiments thus employed only MR cannulae. The benzodiazepine, chlordiazepoxide, in a subataxic dose (3.8 mg/kg, IP) by itself did not affect activity level, but enhanced the locomotor response to low doses (25-50 ng) of muscimol. Conversely, a sub-convulsant dose of the GABA antagonist, bicuculline (1.1 mg/kg, IP), completely blocked the hyperactivity produced by muscimol (50-100 ng). Bilateral electrolytic destruction of the ventral tegmental nuclei of Gudden produced hyperactivity, but failed to alter the effect of muscimol. Forebrain 5-hydroxytryptamine (5-HT, serotonin) depletion following administration of 5,7-dihydroxytryptamine did not affect baseline activity level, but markedly attenuated the locomotor response produced by intra-MR injections of muscimol. These data suggest that midbrain GABA neurons modulate activity level through a direct action on 5-HT neurons, and indicate that intra-MR muscimol induced hyperactivity depends on intact ascending 5-HT fibers.

Animals↗
PubMed2000

Brain allopregnanolone regulates the potency of the GABA(A) receptor agonist muscimol.

Allopregnanolone (ALLO), a potent positive-allosteric modulator of the action of GABA at GABA(A) receptors, is synthesized in the brain from progesterone by the sequential action of two enzymes: 5alpha-reductase and 3alpha-hydroxysteroidoxidoreductase. The concentration of ALLO in various parts of the mouse brain varies substantially, from 15 pmol/g in the olfactory bulb, to approximately 6 pmol/g in the frontoparietal cortex, and 2.7 pmol/g in the cerebellum. The systemic administration of 48 micromol/kg of the Type I and Type II 5alpha-reductase inhibitor, (17beta)-17-[bis (1-methylethyl) amino carbonyl)] androsta-3, 5-diene-3-carboxylic acid (SKF 105,111), reduced brain ALLO content by 80-90% in 30 min; the rate constant (k) of ALLO decrease in each brain area can be utilized to establish the rate of ALLO biosynthesis, which is higher in the olfactory bulb (62 pmol/g/h) than in the frontoparietal cortex (24 pmol/g/h) or cerebellum (11 pmol/g/h). The duration of the righting reflex loss elicited by the potent GABA(A) receptor agonist muscimol was reduced in SKF 105,111-treated ALLO-depleted mice. SKF 105,111 treatment had no effect on muscimol metabolism or on brain levels of pregnenolone and progesterone; however, the brain levels of 5alpha-DHP, the precursor of ALLO, were also decreased. Administration of ALLO at a dose of 15 micromol/kg i.p. by itself did not alter the muscimol-induced loss of the righting reflex; but it completely blocked the effect of SKF 105,111. To elucidate the possible molecular mechanism by which a decrease of brain ALLO content can shorten the duration of the righting reflex loss elicited by muscimol, we patch-clamped neocortical pyramidal neurons of mice pretreated with SKF 105,111 or vehicle, and studied the efficiency of muscimol in eliciting Cl- currents. The current amplitude was significantly smaller in neurons from SKF 105,111-treated mice, especially at lower doses (0.1-1 microM) of muscimol, and the muscimol dose-response (0.1-10 microM) relationship displayed cooperativity (nH=1.4). These data suggest that ALLO synthesized in brain plays an important physiological permissive role in the modulation of GABA-gated Cl- channel function.

5-alpha-Dihydroprogesterone↗
PubMed2002

Effects of subcutaneous administration of the gamma-aminobutyric acid(A) receptor agonist muscimol on water intake in water-deprived rats.

The effects of the gamma-aminobutyric acid(A) (GABA(A)) receptor agonist muscimol were investigated on water intake in rats that had been deprived of water for 16 h. Muscimol (0.5-2.0 mg/kg sc) produced a dose-related inhibition of water consumption in both male (n=8) and female (n=8) rats, with maximal suppression of drinking occurring during the first 30 min after administration. Doses of 1 and 2 mg/kg produced significant decreases in water intake (P<.01), while a lower dose of 0.5 mg/kg was without effect. The hypodipsic effect of muscimol (1.0 mg/kg sc) was abolished by pretreatment of the animals with the GABA(A) receptor antagonist bicuculline (1 mg/kg sc). Furthermore, muscimol (2 mg/kg sc) did not produce aversion in a two-bottle conditioned taste aversion test, indicating that the suppressant effects of muscimol on water intake are not due to drug-induced malaise. The results suggest that systemic administration of muscimol produces a behaviourally specific suppression of primary drinking in rats by a GABA(A) receptor-mediated mechanism. Moreover, this action of muscimol appears to be independent of the gender of the animals.

Animals↗
PubMed1985

Modification of saccadic eye movements by GABA-related substances. I. Effect of muscimol and bicuculline in monkey superior colliculus.

Our previous observations led to the hypothesis that cells in the substantia nigra pars reticulata (SNr) tonically inhibit saccade-related cells in the intermediate layers of the superior colliculus (SC). Before saccades to visual or remembered targets, cells in SNr briefly reduce that inhibition, allowing a burst of spikes of SC cells that, in turn, leads to the initiation of a saccadic eye movement. Since this inhibition is likely to be mediated by gamma-aminobutyric acid (GABA), we tested this hypothesis by injecting a GABA agonist (muscimol) or a GABA antagonist (bicuculline) into the superior colliculus and measured the effects on saccadic eye movements made to visual or remembered targets. An injection of muscimol selectively suppressed saccades to the movement field of the cells near the injection site. The affected area expanded over time, thus suggesting the diffusion of muscimol in the SC; the area never included the other hemifield, suggesting that the diffusion was limited to one SC. One of the monkeys became unable to make any saccades to the affected area. Saccades to visual targets following injection of muscimol had longer latency and slightly shorter amplitudes that were corrected by subsequent saccades. The most striking change was a decrease in the peak velocity of the saccade, frequently to less than half the preinjection value. Saccades to remembered targets following injection of muscimol also showed an increase in latency and decrease in velocity, but in addition, showed a striking decrease in the accuracy of the saccades. The trajectories of saccades became distorted as if they were deflected away from the affected area. After muscimol injection, the area over which spontaneous eye movements were made shifted toward the side ipsilateral to the injection. Saccades toward the contralateral side were less frequent and slower. In nystagmus, which developed later, the slow phase was toward the contralateral side. In contrast to muscimol, injection of bicuculline facilitated the initiation of saccades. Injection was followed almost immediately by stereotyped and apparently irrepressible saccades made toward the center of the movement field of the SC cells at the injection site. The monkeys became unable to fixate during the tasks; the fixation was interrupted by saccadic jerks made to the affected area of the visual field and then back to the fixation point.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Effect of gamma-aminobutyric acid and muscimol on corticosterone secretion in rats.

The effect of gamma-aminobutyric acid-receptor agonists, GABA and muscimol on the pituitary-adrenocortical activity, measured indirectly through corticosterone secretion, and the receptors involved were investigated in conscious rats. GABA given ip induced a dual effect, in lower dose (10 mg/kg) it significantly decreased the resting serum corticosterone levels while in higher doses (100-500 mg/kg) it considerably raised that level. Muscimol (0.5 mg/kg ip) also increased the corticosterone concentration. Both GABA and muscimol given intracerebroventricularly (icv) induced a significant, dose-related increase in serum corticosterone levels. Bicuculline, a GABAA-receptor antagonist, totally abolished the corticosterone response to GABA but did not influence the response to muscimol. Pretreatment with atropine did not affect the corticosterone response to GABA but significantly diminished the response to muscimol. These results suggest that GABA moderately inhibits the pituitary-adrenal axis at the pituitary level but significantly stimulates it at the hypothalamic level. The stimulatory effect of GABA, but not muscimol, is mediated by hypothalamic GABAA-receptors, and in the effect of muscimol hypothalamic cholinergic, muscarinic receptors are involved to a significant extent.

Animals↗
PubMed1996

Reversible inactivations of the cerebellum with muscimol prevent the acquisition and extinction of conditioned nictitating membrane responses in the rabbit.

Lesions of the cerebellum severely impair the classically conditioned nictitating membrane response (NMR) in rabbits. Thus, the cerebellum is essential for the production of conditioned responses (CRs), either because it is actively involved in NMR conditioning or because damage to it causes motor or other general deficits. To distinguish between these alternatives, the cerebellum may be inactivated during training. Inactivation of the cerebellum during acquisition training might result in the absence of CRs on initial trials of subsequent training without the neuronal blockade. The blockade may have prevented learning but it may have produced other deficits that require time or further training to overcome. This problem can be addressed by inactivating the cerebellum during extinction training. If inactivation during extinction training results in the immediate production of CRs when training is resumed without the blockade, then it may be concluded that extinction learning was prevented by the blockade-the presence of CRs argues against any deficits not associated with learning. We used muscimol to inactivate the cerebellum and test its involvement in acquisition and extinction of NMR conditioning in the same subjects. We injected muscimol close to the interpositus nucleus of the cerebellum 1 h before each of four daily training sessions of delay conditioning. Almost no CRs were produced in these training sessions-there was little or no acquisition of NMR conditioning during cerebellar inactivation. The subjects were then trained for four daily sessions without injections of muscimol. There were no CRs on initial trials of the first session of retraining, but all subjects produced CRs by the end of this session. The subjects then received four daily sessions of extinction training with muscimol inactivation of the nuclei-no CRs were produced. Extinction training then continued for four daily sessions without muscimol inactivation. On the first of these sessions, all subjects immediately produced high levels of CRs. These responses then extinguished within and between sessions with characteristic beginning-of-session spontaneous recovery. There was little or no extinction of NMR conditioning during cerebellar inactivation. After inactivation, the muscimol- inactivated subjects went on to acquire and extinguish NM responses at rates similar to those of appropriate controls. We conclude that cerebellar circuitry is essential for, and actively engaged in, both acquisition and extinction of this simple form of motor learning.

Animals↗
PubMed1979

Baclofen and muscimol: behavioural and neurochemical sequelae of unilateral intranigral administration and effects on 3H-GABA receptor binding.

Log dose-response curves for induction of contralateral rotational behaviour in the rat by unilateral intranigral injections of the GABA agonist muscimol and the GABA analogue baclofen have been compared. Baclofen, 5--1000 ng, produced a maximal rotational response that was only 40% of that produced by 0.25--100 ng muscimol, and log dose-response curves failed to show parallelism. The behavioural effects of both drugs were only weakly antagonised by haloperidol and were not antagonised by 6-hydroxydopamine lesions of ipsilateral dopamine (DA) neurons, indicating that these responses were independent of DAergic mechanisms. The effects of baclofen were weakly antagonised by picrotoxin. Intranigral muscimol and baclofen substantially elevated striatal DA concentrations. While muscimol also substantially elevated striatal dihydroxyphenylacetic acid (DOPAC) but not homovanillic acid (HVA), bactofen did not significantly effect either DOPAC or HVA. Baclofein, GABA and muscimol displaced specific 3H-GABA binding in vitro with IC50's of 40 micron, 400 nM and 40 nM respectively. These results indicate that muscimol and baclofen do not act via a unitary GABAergic mechanism, but suggest that baclofen may be a partial GABA agonist, at least at nigral GABA receptors.

Aminobutyrates↗
PubMed1989

Central administration of muscimol phase-shifts the mammalian circadian clock.

The suprachiasmatic nucleus (SCN) of the hypothalamus contains a neural oscillatory system which regulates many circadian rhythms in mammals. Immunohistochemical evidence indicates that a relatively high density of GABAergic neurons exist in the suprachiasmatic region. Since intraperitoneal injections of the benzodiazepine, triazolam, have been shown to induce phase shifts in the free-running circadian rhythm of locomotor activity in the golden hamster, the extent to which microinjections of muscimol, a specific agonist for gamma-aminobutyric acid (GABA), may cause phase-shifts in hamster activity rhythms was investigated. Stereotaxically implanted guide cannulae aimed at the region of the SCN were used to deliver repeated microinjections in individual animals. A phase-response curve (PRC) generated from microinjections of muscimol revealed that the magnitude and direction of permanent phase-shifts in the activity rhythm were associated with the time of administration. The PRC generated for muscimol was characterized by maximal phase-advances induced 6 h before activity onset and by maximal phase-delays which occurred 6 h after activity onset. The PRC for muscimol had a shape similar to a PRC previously generated for the short-acting benzodiazepine, triazolam. Single microinjections of different doses of muscimol given 6 h before activity onset induced phase-advances in a dose-dependent fashion. Histological analysis revealed that phase shifts induced by the administration of muscimol were associated with the proximity of the injection site to the SCN area. These data indicate that a GABAergic system may exist within the suprachiasmatic region as part of a central biological clock responsible for the regulation of the circadian rhythm of locomotor activity in the golden hamster.

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