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PubMed1983

Monoamine involvement in the overeating caused by muscimol injection in the rat nucleus raphe dorsalis and the effects of d-fenfluramine and d-amphetamine.

Injections of 5,7-dihydroxytryptamine in the nucleus raphe dorsalis did not significantly modify the eating caused by muscimol (100 ng) injected in the same area of freely fed rats 11 days later. Eating caused by muscimol, like food intake in starved rats, was significantly reduced by phenoxybenzamine (5, 10 and 20 mg/kg i.p.). Penfluridol (2.5 and 5 mg/kg p.o.), a dopamine receptor blocker, markedly reduced muscimol-induced eating, but had no effect on the food intake of starved rats. d-Fenfluramine (2.5 mg/kg i.p.), a releaser of serotonin from nerve terminals, significantly reduced eating in muscimol-injected and starved animals whereas d-amphetamine 1.25 and 2.5 mg/kg i.p. only inhibited the food intake of starved rats. Eating elicited by muscimol injected in the nucleus raphe dorsalis appears to constitute a catecholamine-mediated model of hyperphagia selectively inhibited by agents which increase serotonin transmission.

5,7-Dihydroxytryptamine↗
PubMed1985

Relations between muscimol, quinuclidinyl benzilate and nicotine binding sites in brain after very long treatment with ethanol in rats.

Rats were treated with ethanol in the drinking fluid 2 X 1 h daily for 83 weeks. [3H]Muscimol, [3H]quinuclidinyl benzilate ( [3H]QNB) and [3H]nicotine binding was measured in selected brain areas 7, 14 and 21 days after withdrawal of ethanol. A significant increase (P less than 0.05) when compared to controls was found on day 7 in both [3H]-QNB binding in the cortex and high affinity [3H]muscimol binding in the cerebellum. Furthermore, on day 7 of abstinence there was a positive correlation in number of binding sites between [3H]muscimol (high affinity sites; cerebellum) and [3H]QNB (cortex) while a negative correlation was found between [3H]muscimol (low affinity sites; cerebellum) and [3H]nicotine (cortex). The first correlation might indicate a relation between increased excitation (QNB) and increased inhibition (muscimol) in two brain areas.

Animals↗
PubMed1987

Evidence that muscimol acts in the forced swimming test by activating the rat dopaminergic system.

Muscimol as well as catecholaminergic drugs reduce immobility time in the forced swimming test. In view of the fact that GABAergic drugs may facilitate some brain catecholaminergic functions, we investigated as to whether or not muscimol would reduce immobility time through activation of catecholaminergic mechanisms. The effect of muscimol (2 mg/Kg i.p.) on reduction of immobility time was prevented by intraperitoneal alpha-methyl-para-tyrosine (250 mg/Kg i.p.), which reduces brain catecholamine content, haloperidol (0.5 mg/Kg) and sulpiride (100 and 50 mg/Kg), antidopaminergic drugs, and meta-chlorphenyl-piperazine (0.6 and 1.25 mg/Kg), a serotonergic agonist, but not by clonidine (0.1 mg/Kg), an alpha2-adrenoceptor agonist, d, 1-propranolol (5 mg/Kg), an antagonist of beta-adrenergic receptors, or subcutaneous prazosin (3 mg/Kg), an alpha1-adrenolytic drug. Our findings indicate that a) muscimol reduces immobility time by stimulating dopaminergic neurons and b) activation of the serotonergic system antagonizes muscimol effect.

Animals↗
PubMed1993

Intrahypothalamic, but not hippocampal, administration of muscimol suppresses hyperglycemia induced by hippocampal neostigmine in anesthetized rats.

We investigated the effects of intrahypothalamic or hippocampal injection of GABA receptor agonists on hyperglycemia induced by hippocampal neostigmine. Prior to the injection of neostigmine (50 nmol) into the hippocampus (HPC), muscimol (0.01-1 nmol) or baclofen (1 nmol) was injected into the bilateral ventromedial hypothalamus (VMH). Muscimol suppressed the hyperglycemia in a dose-dependent manner, but baclofen affected it only minimally. In contrast, neither hippocampal muscimol (1 or 2.5 nmol) nor baclofen (1 nmol) suppressed the hippocampal neostigmine-dependent hyperglycemia. Intrahypothalamic muscimol (1 nmol) also decreased the changes in hepatic venous plasma glucagon and epinephrine significantly. These results indicate that intrahypothalamic muscimol suppresses hyperglycemia caused by cholinergic neurons originating from the HPC, indicating existence of the location specificity.

Analysis of Variance↗
PubMed1982

Chronic benzodiazepine treatment increases [3H]muscimol binding in mouse brain.

High affinity [3H]muscimol receptors were analyzed in the forebrain and cerebellum of mice that had been treated on a chronic regimen with chlordiazepoxide and clonazepam. In the forebrain, only clonazepam induced an increase in the number of muscimol binding sites 2 hr after drug treatment. In the cerebellum, both the chlordiazepoxide and clonazepam-treated animals showed an increased number of muscimol binding sites 2 hr after drug treatment. At 26 hr after drug treatment, only the clonazepam-treated animals still revealed an increased number of cerebellar muscimol binding sites. Chronic benzodiazepine administration, therefore, induced an increase in the apparent number of high affinity muscimol binding sites in both the forebrain and cerebellum.

Animals↗
PubMed1983

Muscimol inhibits ADH release induced by hypertonic sodium chloride in rats.

The effect of the GABA-agonist muscimol on ADH release induced in rats by administration of hypertonic sodium chloride solutions was studied by means of intracerebroventricular and intraperitoneal injections of the drug. Injected by the intracerebroventricular route, muscimol produced a significant reduction of plasma ADH concentration not only in animals treated with hypertonic sodium chloride, but also in unstimulated animals. Following intraperitoneal administration larger doses were required to produce such an effect, thus suggesting a central site of action for the effect of muscimol on ADH release. Bicuculline, given intraperitoneally before muscimol injection, completely blocked ADH inhibition induced by muscimol, thus suggesting a specific involvement of GABAergic receptors. These findings indicate that GABAergic mechanisms may be involved in the regulation of body fluids in the rat by affecting ADH release.

Animals↗
PubMed1986

Selective involvement of dopamine in the nucleus accumbens in the feeding response elicited by muscimol injection in the nucleus raphe dorsalis of sated rats.

Muscimol injection (100 ng) in the nucleus raphe dorsalis (NRD) caused intense eating in non-food-deprived rats. At a dose (10 micrograms) blocking dopamine mediated responses (examined by increased locomotion or stereotypy caused by systemically injected d-amphetamine), fluphenazine injected in the n. accumbens, but not in the striatum, significantly reduced the eating response elicited by muscimol in the NRD while food intake of deprived rats was not significantly modified by fluphenazine injected in either area. Fluphenazine (20 micrograms) in the striatum reduced eating in both conditions, but the animals showed marked sedation which obviously interfered with the feeding response. Dopamine release and synthesis, measured respectively by 3-methoxytyramine and accumulation of dihydroxyphenylalanine after aromatic amino acid decarboxylase inhibition, were significantly reduced in the n. accumbens, but not in the striatum, of muscimol treated animals. The metabolism of serotonin was reduced in both areas of muscimol treated rats. It is suggested that changes in dopamine receptor sensitivity, together with changes in serotonin function, might be involved in the feeding response caused by muscimol injection in the NRD.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1987

Evidence against serotonin involvement in the hyperactivity produced by injections of muscimol into the median raphe nucleus.

Microinjections of muscimol into the median raphe nucleus were found to result in pronounced hyperactivity which could not be attenuated by the serotonin depletion produced either by systemic treatment with p-chlorophenylalanine or by intra-raphe injections of 5,7-dihydroxytryptamine. Furthermore, hyperactivity could not be produced by intra-median raphe injections of serotonin or of fenfluramine, compounds which would be expected to inhibit serotonergic raphe cells. These results argue strongly against an essential involvement of serotonin in mediating the effects of intra-median raphe muscimol injections. Muscimol failed to produce hyperactivity, however, when injected into rats who had previously received an electrolytic median raphe lesion. This finding suggests that muscimol injected into the median raphe produces hyperactivity as a result of an action on local cell bodies, rather than by diffusion to a distant site. The simplest explanation of the current results is that muscimol injected into the median raphe produces hyperactivity as a result of an inhibition of nonserotonergic cells within the median raphe nucleus.

5,7-Dihydroxytryptamine↗
PubMed1987

An investigation of the role played by the superior colliculus and ventromedial thalamus in self-injurious behavior produced by intranigral microinjection of muscimol.

Bilateral injection of muscimol (30 or 60 ng) into the substantia nigra (pars reticulata) of rats produced a variety of stereotyped acts, self-injurious behavior (SIB), and antinociception. Bilateral electrolytic lesions of the superior colliculus strongly suppressed SIB without reducing the antinociceptive effects of intranigral muscimol. Electrolytic lesions of the ventromedial thalamus had no effect on behavioral responses to intranigral muscimol. These studies suggest that the SIB produced by intranigral muscimol is mediated by neuronal pathways that terminate in or pass through the superior colliculus. The ventromedial thalamus does not appear to play a role in mediating behavioral responses to intranigral muscimol.

Animals↗
PubMed1991

Muscimol injections into the median raphe nucleus increase serum ACTH and corticosterone concentrations via a nonserotonergic mechanism.

Midbrain raphe serotonin (5-HT) neurons can influence the pituitary-adrenal axis. The midbrain raphe nuclei also contain a number of non-5-HT neurons, including gamma-aminobutyric acid (GABA) interneurons which can modulate 5-HT neuronal activity. We investigated the effects of intraraphe injections of the GABAA agonist, muscimol, on serum adrenocorticotropin hormone (ACTH) and corticosterone concentrations. Rats were infused with muscimol (0, 25, 50, and 100 ng in 0.5 microliters saline) into the median raphe nucleus (MR). The animals were killed 30 min later, and trunk blood was collected for measurement of serum concentrations of ACTH and corticosterone by radioimmunoassay. Muscimol dose dependently increased plasma concentrations of these two pituitary-adrenal hormones. In order to determine the role of MR 5-HT neurons in these effects, separate groups of implanted animals were infused with either the serotonergic neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT) or ascorbic acid vehicle into the MR. Two weeks later, the animals were infused with muscimol (100 ng in 0.5 microliters) and sacrificed as above. Treatment with 5,7-DHT, which markedly reduced hippocampal concentrations of 5-HT (-83%) and 5-HIAA (-73%), did not block intra-MR muscimol-induced elevations in ACTH and corticosterone. Thus, 5-HT neurons within the MR apparently do not mediate the increased activity of the pituitary-adrenal axis produced by stimulation of MR GABAA receptors.

5,7-Dihydroxytryptamine↗
PubMed1996

Effects of ventral tegmental microinjections of the GABAA agonist muscimol on self-administration of ethanol and sucrose.

Two groups of Long-Evans rats were trained to lever press on a fixed-ratio 4 (FR4) schedule of reinforcement with ethanol (10% v/v) or sucrose (75% w/v) presented as the reinforcer. After implantation of guide cannulae aimed at the ventral tegmental area (VTA), weekly bilateral injections of muscimol (10, 30, and 100 ng) were tested. During control conditions, response patterns for both groups were characterized by high rates that began shortly after the start of the session and terminated after approximately 10 min. Muscimol (10 ng) administration in the VTA increased the number of sucrose- but had no effect on the total number of ethanol-reinforced responses. Muscimol (30 ng) shifted the response patterns of both groups from high initial rates with early termination to slow initial rates with delayed termination, suggesting the possibility of nonspecific locomotor effects. These data suggest that ethanol- and sucrose-reinforced response totals are differentially sensitive to changes in GABAergic transmission in the VTA. The similar muscimol-induced changes in response patterns with the two reinforcers supports the hypothesis that GABAA receptors in the VTA are involved similarly in the maintenance of ethanol- and sucrose-reinforced responding. However, the failure of muscimol to increase ethanol-reinforced responding suggests that GABAergic systems in other brain regions may also be involved in the changes in ethanol intake seen following peripheral administration of GABAmimetic drugs.

Alcohol Drinking↗
PubMedDate not supplied

Intra-median raphe infusions of muscimol and the substance P analogue DiMe-C7 produce hyperactivity: role of serotonin neurons.

Injections into the midbrain median raphe nucleus (MR) of the metabolically stable substance P analogue, DiMe-C7, produce dose-dependent increases in locomotor activity (LMA). Ibotenic acid (8.0 micrograms in 2.0 microliter vehicle) lesions of the MR block the hyperkinetic effects of optimal doses of both DiMe-C7 (1.0 microgram in 0.5 microliter vehicle) and the GABAA agonist, muscimol (100 ng in 0.5 microliter vehicle). This observation indicates that the increases in LMA produced by intra-MR DiMe-C7 and muscimol infusion are not due to diffusion to sites outside the MR. Intra-MR administration of the selective serotonin (5-HT) neurotoxin, 5,7-dihydroxytryptamine (6.0 micrograms in 1.5 microliter vehicle), following pretreatment with the norepinephrine and dopamine reuptake inhibitor, nomifensine maleate (15 mg/kg, i.p.), blocked the hyperactivity induced by intra-MR infusions of DiMe-C7 (1.0 microgram) but not that of muscimol (100 ng). These observations suggest that the LMA effects of intra-MR DiMe-C7 and muscimol administration are mediated by different neural mechanisms. The LMA effects of DiMe-C7 depend on intact 5-HT neurons in the MR, whereas the effects of muscimol depend on intact non-5-HT MR cells.

5,7-Dihydroxytryptamine↗
PubMed1991

Autoradiographic estimation of the extent of reversible inactivation produced by microinjection of lidocaine and muscimol in the rat.

We used autoradiography to examine the extent of reversible inactivation produced by microinjection of lidocaine (40 micrograms/microliters saline) and muscimol (1 microgram/microliter saline). We measured intracortical spread of tracer amounts of labelled drug and local changes in uptake of [1-14C]glucose produced by the microinjection. The maximal average radii of regions of drug spread were 1.7 mm for both [14C]lidocaine and [3H]muscimol and were achieved within the first 20 min postinjection. The width of lidocaine injections decreased at longer postinjection times (30-60 min) but the width of muscimol injections remained relatively constant (30-120 min). Lidocaine radioactivity decreased faster from the injection site than muscimol radioactivity. Glucose autoradiograms showed a discrete region of maximally reduced glucose uptake (1.4 mm for lidocaine and 1.0 mm for muscimol) surrounded by a region of less reduced glucose uptake (up to approximately 3 mm). These findings suggest that, in the cortex, the effects of focal inactivation extend beyond the region of drug spread. Diffuse effects may be mediated of disfacilitation of cortico-cortical circuits.

Animals↗
PubMed1994

Comparison of effects of bilateral injections of bicuculline and muscimol into the caudate-putamen of amygdaloid-kindled rats.

Bicuculline is an antagonist of gamma-aminobutyric acid (GABA) receptors, and muscimol is an agonist of GABA receptors. In this study, the effects of bilateral injections of bicuculline and muscimol into the caudate-putamen (CP) were compared in amygdaloid-kindled rats. Thirty minutes after the injection of bicuculline (1, 10 and 100 pmol per CP) or muscimol (10, 50 and 100 nmol per CP), the kindled amygdala was stimulated at the previously established generalized seizure triggering threshold (GST). Most doses of bicuculline caused no significant alteration either in the seizure stage or in the afterdischarge duration. Only the 100-pmol dose produced a marked reduction in the afterdischarge duration. With 10 nmol of muscimol, there was no significant change in the kindled seizure stage or in the afterdischarge duration. However, 50 and 100 nmol of muscimol markedly suppressed both parameters. These findings suggest that CP efferent pathways are involved in the mechanism that underlies the development of kindled amygdaloid seizures, and support the concept that GABA acts as an anticonvulsant in the brain.

Amygdala↗
PubMed1994

GABAA receptor agonist muscimol can reset the phase of neural activity rhythm in the rat suprachiasmatic nucleus in vitro.

We investigated the phase-resetting effect of muscimol, gamma-amino butyric acid (GABA)A receptor agonist, on the circadian neural activity rhythm of the rat suprachiasmatic nucleus (SCN), which contains a circadian pacemaker. Acute application of muscimol inhibited the neural activity of the SCN in a dose-dependent manner. Under the tissue culture condition, the treatment with 10 microM muscimol during the early- to mid-subjective day on the first day (day 1) in vitro produced the largest phase advance in neural activity rhythm of the SCN on day 2. By contrast, the administration of muscimol during the subjective night produced no change. These phase changes were similar to those reported for dark pulses in constant light. These findings indicate that muscimol can directly affect SCN neurons and reset the circadian pacemaker in the SCN. The GABA neural function through the activation of GABAA receptors may play a role in modulating the phase of the SCN clock, especially during the subjective day.

Animals↗
PubMed1984

Ontogenesis of muscimol binding sites in cat visual cortex.

In vitro receptor binding techniques were used to study the characteristics, distribution, and ontogenesis of muscimol binding sites in cat visual cortex. [3H] Muscimol, a GABA agonist, labelled a single population of binding sites with a KD of 18 nM in adult cats. Specific binding was saturable, reversible and was blocked by the addition of GABA or (+) bicuculline. Autoradiograms revealed that the highest density of [3H] muscimol binding occurred in cortical layer IV. Similar patterns of [3H] muscimol binding were observed at all ages examined, although the binding densities differed. The peak [3H] muscimol binding density, corrected for amount of protein, occurred at 3 months postnatally. In 3 day old and adult cats binding density was 41% and 69%, respectively, of the peak value.

Animals↗
PubMed2005

Chronic stimulation of GABAA receptor with muscimol reduces amyloid beta protein (25-35)-induced neurotoxicity in cultured rat cortical cells.

The present study was performed to examine how the stimulation of gamma-aminobutyric acid (GABA) receptor affects amyloid beta protein (25-35) (Abeta (25-35)), a synthetic 25-35 amyloid peptide, -induced neurotoxicity using cultured rat cortical neurons. Abeta (25-35) produced a concentration-dependent reduction of cell viability, which was significantly reduced by (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine (MK-801), an N-methyl-d-aspartate (NMDA) receptor antagonist, verapamil, an L-type Ca(2+) channel blocker, and N(G)-nitro-l-arginine methyl ester (l-NAME), a nitric oxide synthase inhibitor. Pretreatment with muscimol, a GABAA receptor agonist, over a concentration range of 0.1-10microM 24h before the treatment with 10microM Abeta (25-35) showed concentration-dependent inhibition on the Abeta (25-35)-induced neuronal apoptotic death. However, baclofen (1 and 10microM), a GABAB receptor agonist, failed to inhibit the Abeta (25-35)-induced neuronal death. In addition, pretreatment with muscimol (1microM) for 24h inhibited the Abeta (25-35) (10microM)-induced elevation of cytosolic Ca(2+) concentration ([Ca(2+)]c) and glutamate release, generation of reactive oxygen species (ROS), and caspase-3 activity in cultured neurons. These neuroprotective effects of muscimol (1microM) were completely blocked by the simultaneous treatment with 10microM bicuculline, a GABAA receptor antagonist, indicating that the protective effects of muscimol were due to GABAA receptor stimulation. When, however, treated just 15min before the treatment with Abeta (25-35), muscimol (1microM) did not show any protective effect against Abeta (25-35) (10microM)-induced neurotoxicity in cultured neurons. These results suggest that the chronic activation of GABAA receptor may ameliorate Abeta-induced neurotoxicity by interfering with the increase of [Ca(2+)]c, and then by inhibiting glutamate release, generation of ROS and caspase-3 activity.

Amyloid beta-Peptides↗
PubMed1999

Excitotoxic basolateral amygdala lesions potentiate the memory impairment effect of muscimol injected into the medial septal area.

In rats, the septo-hippocampal system is important for memory encoding. Previous reports indicate that muscimol, a specific GABAergic agonist induces learning and memory deficits when infused into the medial septal area. The basolateral nucleus of the amygdala (BLA) modulates memory encoding in other brain areas, including the hippocampus. To explore the interactions between the septo-hippocampal system and amygdala in memory, we studied the effects of intra-medial septal infusions of muscimol in rats with BLA lesions. Animals received sham surgery or excitotoxic BLA lesions and were given infusions of either vehicle or muscimol (5 nmol) into the medial septal area 5 min prior to training sessions in inhibitory avoidance and water maze tasks. In the inhibitory avoidance task, muscimol-induced memory impairment was potentiated by BLA amygdala lesions. Additionally, in the water maze task, BLA-lesioned rats given muscimol infusions into the medial septal also showed memory impairment. These findings indicate that the MSA interacts with the BLA in the processing of memory storage.

Amygdala↗