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PubMed1995

Injections of muscimol into the median raphe nucleus produce hippocampal theta rhythm in the urethane anesthetized rat.

It has previously been shown that serotonergic [5-hydroxytryptamine (5-HT)] neurons of the median raphe nucleus (MR) are critically involved in the control of the hippocampal electroencephalogram (EEG). Activation of MR 5-HT neurons desynchronizes the hippocampal EEG, whereas inhibition of MR 5-HT activity produces hippocampal theta rhythm. The MR contains an intrinsic population of gamma-aminobutyric acid (GABA) containing neurons that synapse on 5-HT cells of the MR. The present study examined the effects on the hippocampal EEG of injections of the GABAA agonist muscimol hydrobromide into the MR. Low doses of muscimol (0.5 microgram) produced hippocampal theta rhythm at a mean latency of 6.81 min and for a mean duration of 23.6 min. Higher doses (1.0 microgram and 3.0 micrograms, respectively) produced theta at mean latencies of 2.24 min and 3.2 min and for mean durations of 31.84 min and 24.88 min. Injections of muscimol into regions adjacent to the MR generated theta at significantly longer latencies or were without effect. The present results indicate that MR injections of muscimol produce theta by inhibiting the activity of MR 5-HT neurons. It is concluded that MR GABAergic systems, via their influence on MR 5-HT cells, serve an important role in the control of the hippocampal EEG.

Anesthesia↗
PubMed1999

Effects of transient inactivation of the subthalamic nucleus by local muscimol and APV infusions on performance on the five-choice serial reaction time task in rats.

Within the basal ganglia circuitry, recent conceptions of the subthalamic nucleus are that it fulfils integrative functions. We have previously shown that bilateral excitotoxic lesions of the subthalamic nucleus induce behavioural deficits in a five-choice serial reaction time task in the rat, consistent with attentional impairments and suggesting important roles of this basal ganglia structure in mechanisms of behavioural control. In the present study, we tested the effects of (i) blocking its excitatory inputs (originating mainly in the cerebral cortex and the parafascicular nucleus of the thalamus) via the NMDA receptors and (ii) stimulating its GABA receptors to mimick the influence of its inhibitory inputs (mainly from the globus pallidus). Bilateral microinfusions of APV (NMDA receptor antagonist) or muscimol (GABA-A receptor agonist) into the subthalamic nucleus were administered to rats trained in the same five-choice serial reaction time task. Both APV (0.125-0.5 microg) and muscimol (1-3 ng) reduced choice accuracy, slowed correct responses and increased omissions and perseverative responses. Premature responses tended to increase after APV but decrease after muscimol. Increased perseverations at the food magazine occurred only after muscimol infusions. These results reproduce many of the effects of lesions of the STN and are consistent with an integrative role for this structure in pallidal and thalamo-cortical processing.

2-Amino-5-phosphonovalerate↗
PubMed1978

Contralateral turning evoked by the intranigral microinjection of muscimol and other GABA agonists.

Contraversive turning was evoked by the microinjection of GABAergic agents into the substantia nigra (SN) of the rat. Muscimol, the most potent GABA agonist, evoked contralateral turning when injected into the SN in doses of 0.005, 0.05, 0.5 and 5 microgram, whereas 0.5 microgram of muscimol applied at extranigral sites produced no turning. A shorter lived contraversive turning response was evoked by the intranigral micro-injection of imidazole acetic acid (10 or 50 microgram), ethanolamine-O-sulphate (25 or 50 microgram), or GABA (50 microgram). No increase in GABA-induced turning was produced by local pretreatment with pipecolic acid (5 microgram). When injected into the SN, neither picrotoxin, in doses of 0.1, 0.5, 1.0 or 2.0 microgram, nor bicuculline methiodide (Bm), in doses of 0.1 or 0.2 microgram, elicited a significant amount of turning. Picrotoxin, however, partially blocked the turning evoked by the intranigral injection of muscimol, both via the i.p. and intranigral routes of administration whereas Bm did not. In addition, haloperidol (1 mg/kg i.p.) antagonized the muscimol-induced turning. Hence, we feel GABA mimetic substances injected within the SN might evoke contralateral turning via activation of a heretofore undescribed neural system arising from the SN or by activating the ipsilateral dopaminergic neurons projecting from the SN.

Animals↗
PubMed1980

Effects of muscimol and picrotoxin on single unit activity of substantia nigra neurons.

Intravenous administration of the GABA agonist, muscimol, caused dose-dependent increases in the unit activity of substantia nigra pars compacta (dopamine) neurons and an inhibition of nigral pars reticulata cells. The depressant effects of the drug upon reticulata neurons were reversible by subsequent administration of the GABA antagonists, picrotoxin and bicuculline HCl. However, the stimulatory effects of i.v. muscimol upon dopamine neurons were not abolished by these agents. Intravenous administration of picrotoxin alone caused only moderate increases in the activity of dopamine neurons (31% over baseline at 7.0 mg/kg), but markedly stimulated the firing of pars reticulata cells (154% over baseline at 7.0 mg/kg). In spite of the stimulation of dopamine neurons after i.v. muscimol, microiontophoresis of GABA and muscimol could inhibit the firing of both pars compacta and pars reticulata cells, although the reticulata neurons were much more sensitive to the inhibitory actions of these agents than the dopamine neurons. Considered together, these studies suggest that a population of neurons in the substantia nigra pars reticulata have the capacity to be more affected by a major GABA input to the nigra than the pars compacta dopamine neurons. The results further suggest that if the dopamine cells are regulated by GABAergic neurons of the striatonigral pathway, their regulation must be indirect and could involve a second inhibitory neuron within the nigra.

Animals↗
PubMed1981

GABA and muscimol open ion channels of different lifetimes on cultured mouse spinal cord cells.

Intracellular recordings of cultured mouse spinal neurons were used to examine the effects of gamma-aminobutyric acid (GABA) and the GABA analog muscimol on neuronal excitability. Muscimol was about twice as effective as GABA in increasing membrane conductance to C1-ions. Fluctuation analysis of membrane current responses showed that muscimol activated ion channels with the same conductance as GABA but with about the average duration. The results provide an economical explanation for the greater potency of muscimol in depressing excitability.

Animals↗
PubMed1983

Anisatin modulation of temperature-dependent inhibition [3H]muscimol binding by chloride ion.

We investigated the effects of anisatin, a pure toxic substance isolated from Illicium anisatum, and chloride ion on [3H]muscimol binding to rat brain membranes at various temperatures (0-16 degrees C). Chloride ion (100 mM) itself slightly inhibited specific [3H]muscimol binding at 0-4 degrees C and this inhibition was more marked at 10 or 16 degrees C than at 0-4 degrees C. Anisatin further decreased [3H]muscimol binding inhibited by 100 mM chloride at 16 degrees C without affecting the basal specific binding. These effects of anisatin were also dependent on the temperature. Scatchard analysis revealed that the effects of chloride and chloride plus anisatin on [3H]muscimol binding were mainly due to reduction in the number of binding sites. The temperature- and chloride-dependent effects of anisatin were similar to those of picrotoxinin. Pre-treatment of membranes with 0.05% Triton X-100 markedly decreased the inhibitory effects of chloride and chloride plus anisatin. Our results indicate that anisatin affects the number of GABA receptor sites probably through the picrotoxin sensitive sites and that chloride ion not only modifies the GABA receptors but also plays an important role in the action of anisatin and picrotoxinin.

Animals↗
PubMed1988

Locomotor hyperactivity in the rat after infusion of muscimol and [D-Ala2]Met-enkephalin into the nucleus basalis magnocellularis. Possible interaction with cortical cholinergic projections.

Locomotor activity in the rat was studied after infusion of GABAergic and enkephalinergic agonists into the nucleus basalis magnocellularis (NBM) of the forebrain. The experiments were designed to find out whether pharmacological blockade of cholinergic neurons in the NBM had similar behavioral effects to those observed after lesion of the same structure. Three experiments were carried out. In the first experiment, infusion of the GABAergic agonist muscimol (50 ng) into the NBM led to a marked locomotor hyperactivity. In the second experiment, it was shown that muscimol-induced locomotor response was reduced by pretreatment with the GABAergic antagonist picrotoxin (3 mg/kg). Further, locomotor hyperactivity was also observed after injection of the indirect GABA agonist, ethanolamine-o-sulfate (50 micrograms) into the NBM. The third experiment was designed to investigate the relationship between the blockade of NBM cholinergic neurons and the development of locomotor hyperactivity. The locomotor hyperactivity produced by the cholinergic antagonist scopolamine (0.4 mg/kg) was increased two-fold after infusion of 10 ng muscimol into the NBM. This dose of muscimol on its own had no effect on locomotor behavior. Similar enhancement of the locomotor response to that found with GABAergic agonists was observed after infusion of [D-Ala2]Met-enkephalinamide (2.5 micrograms) into the NBM. This enkephalin mediated locomotor response was blocked by the opiate antagonist naloxone (2 mg/kg). Pharmacological manipulations of the afferent inputs to the NBM could therefore be of value in studies on the behavioral role of cholinergic neurons in the NBM.

Animals↗
PubMed1989

Suppressive effects of intranigral injection of muscimol in three models of generalized non-convulsive epilepsy induced by chemical agents.

The involvement of intranigral gamma-aminobutyric acid (GABA) receptors in the control of generalized non-convulsive epilepsy was investigated in the rat in 3 models of petit mal epilepsy induced by systemic administration of gamma-butyrolactone, pentylenetetrazol and 4,5,6,7-tetrahydroisoxazolo [5,4-c]pyridin 3-ol (THIP). Bilateral intranigral injection of muscimol (2 ng/0.2 microliters/side), a GABAA receptor agonist, significantly reduced the duration of EEG-recorded spike-and-wave discharges induced by gamma-butyrolactone (100 and 200 mg/kg i.p.), pentylenetetrazol (20 mg/kg i.p.) and THIP (7.5 mg/kg i.p.). This treatment had no effect on the electroencephalographic discharges observed after injection of THIP (10 mg/kg i.p.). Bilateral injection of muscimol (2 and 4 ng/side) into the substantia nigra did not modify the latency of onset nor the duration of clonic seizures induced by pentylenetetrazol at the dose of 40 mg/kg i.p. Bipolar depth electrode recording indicated that intranigral injection of muscimol did not alter nigral electroencephalographic activity. Autoradiography following intranigral injection of [3H]muscimol indicated a diffusion not exceeding 400 microns from the injection site. These results confirm that activation of GABA receptors in the substantia nigra suppresses the occurrence of spike-and-wave discharges in animal models of generalized non-convulsive epilepsy.

4-Butyrolactone↗
PubMed1991

Muscimol-associated changes in local cerebral glucose use following chronic diazepam administration.

Local cerebral glucose use (LCGU) was determined in parallel groups of conscious rats receiving muscimol (1.5 mg/kg i.v.) after either saline pretreatment (28 days i.p.), saline pretreatment (27 days i.p.) followed by a single dose of diazepam (5 mg/kg i.p.) 24 h prior to muscimol administration, or chronic diazepam pretreatment (5 mg/kg i.p. daily for 28 days). Acute administration of muscimol produced a significant reduction in LCGU in 25 out of 66 structures examined compared with vehicle-treated controls. The pattern of reductions was heterogeneous. Thalamic and most cortical areas showed reductions of the order of 30-45%, whereas more modest depressions of 15-20% were observed in some limbic structures (e.g. basolateral amygdala, anterior thalamic nuclei, nucleus accumbens, subiculum). This contrasts with the more extensive and homogeneous pattern of LGCU reductions (around 20%) produced by diazepam. Neither acute diazepam treatment the previous day nor chronic diazepam pretreatment altered the LGCU response to muscimol. These data suggest that high-affinity GABA receptor-mediated responses are unchanged by both acute and chronic benzodiazepine pretreatment. It would appear unlikely that alterations in these responses contribute to the mechanism of benzodiazepine tolerance.

Animals↗
PubMed1980

Antinociceptive effects of baclofen and muscimol upon intraventricular administration.

The effects of intraventricularly administered baclofen and muscimol were investigated on tail-flick responding and on vocalization and motor responses to nociceptive pinch. Baclofen (1 microgram) and muscimol (0.1 microgram) strongly reduced responding to pinch, particularly vocalization, without altering tail-flick responding. When given systemically, however, baclofen markedly attenuated tail-flick as well as pinch responding. Muscimol produced only weak antinociception by systemic administration, suggesting that it may have poor access to brain. At antinociceptive doses, i. vent. muscimol produced less apparent muscle relaxation than did baclofen. These results suggest that baclofen's antinociceptive action may be mediated in part by a supraspinal, GABAergic substrate, in addition to a spinal component which may not directly involve GABA.

Analgesics↗
PubMed1982

Anion-dependent modulation of [3H]muscimol binding and of GABA-stimulated [3H]flunitrazepam binding by picrotoxin and related CNS convulsants.

Picrotoxin, isopropylbicyclophosphate (IPTBO) and related CNS-convulsants have allosteric effects on the binding of ligands to the GABA/benzodiazepine receptor complex. When binding experiments were performed at 23 degrees C and at 35 degrees C, these drugs inhibited [3H]muscimol binding and muscimol- or GABA-stimulated [3H]flunitrazepam binding, respectively. Both effects required the presence of C1-, Br-, I- but not of F- or SO4(2-). Picrotoxin and IPTBO could only partially inhibit [3H]muscimol binding. In contrast other GABA antagonists and convulsants like bicuculline, 3 alpha-hydroxy-16-imino-5 beta-17-aza-androstan-11-one (R 5135), strychnine and d-tubocurarine interferred completely with [3H]muscimol binding, also in the absence of those ions mentioned above which were essential for the effects of picrotoxin. Our results support the notion that drugs like picrotoxin and IPTBO which interfere with the GABA receptor effector system, may lead to an allosteric perturbation of GABA-recognition sites.

Animals↗
PubMed1992

Effect of the beta-adrenoceptor antagonist, propranolol, on feeding induced by noradrenaline and muscimol in rats kept at high and temperate-ambient temperatures.

Both the gamma-aminobutyric acid (GABA) receptor agonist, muscimol, and noradrenaline stimulated the feeding behavior of rats in the two environments. When noradrenaline or muscimol was administered, however, the food intake at 26 degrees C was greater than that at 33 degrees C. In addition, the stimulatory effect of noradrenaline on food intake was significantly depressed by propranolol pretreatment at both temperatures. The stimulatory effect of muscimol on food intake was significantly depressed by the propranolol pretreatment at 33 degrees C but not at 26 degrees C. Some eating-stimulatory subsystems associated with feeding behavior induced by noradrenaline or muscimol might have been depressed in the hot environment, thus the food intake increased by these drugs in rats acclimated to the hot environment was less than that in rats acclimated to the temperate environment.

Animals↗
PubMed1995

Effect of delta 9-tetrahydrocannabinol on circling in rats induced by intranigral muscimol administration.

Unilateral injection of 25 ng of muscimol into the rat substantia nigra pars reticulata induced contralateral circling. Circling induced by 25 ng of muscimol was increased by simultaneous administration of 1 microgram of delta 9-tetrahydrocannabinol and abolished by 10 micrograms. Previous experiments have shown that delta 9-tetrahydrocannabinol enhances muscimol-induced catalepsy in the globus pallidus. These results identify another brain area in which synergism between delta 9-tetrahydrocannabinol and muscimol can occur and show that delta 9-tetrahydrocannabinol can enhance an excitatory as well as inhibitory GABAergic motor effect. The data support the hypothesis that cannabinoids can facilitate transmission along central gamma-aminobutyric acid (GABA) releasing pathways.

Animals↗
PubMed1982

Suppression of apomorphine-induced oral stereotypy in rats by microinjection of muscimol into midbrain.

Rats with large lesions of the superior colliculus do not display the oral stereotypy normally induced by high systemic doses of dopamine-agonists. It has been suggested that collicular lesions have such an effect because they destroy the GABAergic nigrotectal pathway. This suggestion was investigated by observing the effects of bilateral microinjections of the GABA-agonist muscimol into midbrain sites in rats given 8 mg/kg subcutaneous apomorphine. A low dose of muscimol (25 ng in 0.5 ul saline/side) injected into regions of the superior colliculus with nigrotectal innervation almost abolished apomorphine-induced licking and gnawing. Control microinjections of saline into the superior colliculus, or of muscimol into overlying cerebral cortex, were ineffective. This result is consistent with the GABAergic nigrotectal projection being important for the expression of dopamine-related oral stereotypy. It was also found, however, that 25 ng of muscimol suppressed oral stereotypy when microinjected into the mesencephalic reticular formation underlying the superior colliculus. The anatomical basis of this latter effect is uncertain.

Animals↗
PubMed1983

Evidence that the nigrotegmental GABAergic projection mediates stereotypy induced by apomorphine and intranigral muscimol.

The substantia nigra plays a pivotal role in the relay of output from the striatum. One neural pathway from substantia nigra projects GABAergic fibers to the caudal mesencephalic tegmentum, terminating in the vicinity of the pedunculopontine nucleus (PPN). To evaluate the functional importance of this projection in the mediation of stereotyped behaviors of striatal and nigral origin, we microinjected low doses of the GABA agonist, muscimol, bilaterally into the vicinity of the PPN. This muscimol treatment resulted in a total blockade of all stereotyped behaviors normally elicited by systemic apomorphine or by intranigral muscimol. Blockade was not observed in animals microinjected with muscimol into the dorsal reticular formation, 1 mm above the level of the PPN. Our results indicate that the nigrotegmental projection may play a crucial role in the expression of stereotyped and dyskinetic behaviors of basal ganglia origin.

Animals↗
PubMedDate not supplied

Median and dorsal raphe injections of the 5-HT1A agonist, 8-OH-DPAT, and the GABAA agonist, muscimol, increase voluntary ethanol intake in Wistar rats.

Low doses of the selective 5-HT1A agonist 8-OH-DPAT increase ethanol intake in a limited access paradigm following peripheral injection. This may be due to a reduction in 5-HT neurotransmission following activation of raphe somatodendritic autoreceptors. In order to test this hypothesis, and to determine the effects of selective reductions in raphe 5-HT activity, experiments examined the effects of injecting 8-OH-DPAT into the dorsal raphe (0, 0.02, 0.1, 1 and 2.5 micrograms) or the median raphe (0, 0.1, 1 and 5 micrograms) in rats trained to drink 12% ethanol for 40 min each day. The effects of the GABAA agonist, muscimol, on ethanol intake were also examined. Ethanol intake was increased at the highest dose of 8-OH-DPAT following injection into either site, with no change in water intake. Thus, the effects of 8-OH-DPAT are selective for ethanol. The selective 5-HT1A antagonist, (+)-WAY100135 (0.3, 1 and 3 mg/kg), blocked the effect of 8-OH-DPAT, showing that activation of 5-HT1A receptors underlies the ethanol drinking induced by 8-OH-DPAT. These results are consistent with the idea that reduced 5-HT function increases ethanol intake. Several behavioral mechanisms for this effect are discussed. Muscimol (50-100 ng) also increased ethanol drinking. Following injection into the median raphe, muscimol also stimulated water intake. These effects are probably due to non-specific behavioural activation induced by this treatment. However, the effect of muscimol in the dorsal raphe was specific for ethanol since water intake was not altered.(ABSTRACT TRUNCATED AT 250 WORDS)

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1989

Reduced behavioral responses to intranigral muscimol following chronic ethanol.

Increased biochemical measures of GABA activity are observed after acute administration of ethanol and decreased activity has sometimes been observed after chronic ethanol exposure. Since chronic alterations in neurotransmitter activity may result in changes in receptor function, it is possible that changes in GABA-receptive neurons may accompany chronic ethanol treatment. In the present study we examined the incidence of muscimol-induced motor behaviors in ethanol-naive and chronic ethanol-treated animals. Male Sprague-Dawley rats received bilateral cannula implants into substantia nigra pars reticulata for subsequent administration of muscimol or saline. After recovery from surgery, rats received chronic treatment in ethanol-vapor inhalation chambers for 15 days. Animals were then removed from the chambers and examined 10 hours after removal. Muscimol resulted in a general increase in motility in both control and ethanol-treated animals. Animals withdrawn from chronic ethanol exposure, however, exhibited significantly less muscimol-stimulated, repetitive 9 Hz movements. These results suggest that GABA receptive cells within the substantia nigra or its vicinity may be functionally less responsive to GABAergic stimulation after chronic ethanol administration.

Animals↗
PubMed1990

Effects of intracerebroventricular injection of muscimol or GABA on operant feeding in pigs.

Young pigs were prepared with lateral intracerebroventricular (ICV) cannulae. They were housed individually in cages fitted with operant panels and could obtain food and water ad lib. The GABA-A receptor agonist muscimol (25-200 nmol) ICV produced an increase in food intake in which the dose-response relation was most obvious 30-60 min after dosing. The 25-nmol dose had no effect on feeding. However, muscimol (50 nmol) caused a significant increase in feeding (p less than 0.01) during the first 30 min after injection, while the 100- and 200-nmol doses increased food intake (p less than 0.01) during the first 60 min. The effect of muscimol (100 nmol) on food intake was completely abolished by the simultaneous administration of the GABA-A receptor antagonist bicuculline (100 nmol). GABA (40-1600 nmol) ICV also produced a dose-related increase in food intake (p less than 0.01) in the 15 min after injection. Only doses of 800 nmol and above were effective. The effects of GABA (1600 nmol) were completely abolished by the simultaneous administration of bicuculline (50 nmol). Neither muscimol nor GABA influenced food intake for the 24-hr time period or water intake during any time period. The results indicate that stimulation of central GABA-A receptors induces operant feeding in the satiated pig.

Animals↗