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PubMed1983

Effects of nigral application of muscimol on release of [3H] gamma-aminobutyrate and on multiunit activity in various cat thalamic nuclei.

The release of [3H] gamma-aminobutyrate (GABA) neosynthesized from [3H]glutamine was estimated in one substantia nigra and in the ipsilateral thalamus of halothane-anesthetized cats by perfusing a [3H]glutamine-enriched physiological medium through a push-pull cannula implanted in the two structures under investigation. After two hours of superfusion, muscimol (10(-6)M) was delivered through the nigral push-pull cannula for 50-60 min and local- and distal-evoked changes of [3H]GABA release were analyzed. In some experiments, changes of global neuronal activity induced by muscimol application were recorded in different thalamic nuclei, using a bipolar electrode. In a few of the above experiments, biochemical and electrophysiological determinations were simultaneously performed in the substantia nigra and the thalamus. The nigral application of muscimol (10(-6)M) induced locally an activation of the substantia nigra reticulata cells, as well as an increase in release of [3H]GABA. Distally, in the thalamus, two types of biochemical and electrophysiological responses were observed according to the localization of the tip of the push-pull cannula or the electrode. (1) An increased release of [3H]GABA and a depression of the global multi-unit cellular activity were obtained in the ventralis medialis-ventralis lateralis, the centralis lateralis and the paracentralis nuclei. These effects could reflect an activation of the GABAergic nigrothalamic neurons projecting to these different thalamic nuclei. (2) In contrast, in the medialis dorsalis paralamellar zone adjacent to the intralaminar nuclei of the thalamus, a decrease of [3H]GABA release and an activation of the multi-unit activity were obtained. These latter results may suggest either a polysynaptic response or the non-GABAergic nature of the nigrothalamic neurons afferent to the medialis dorsalis paralamellar zone.

Animals↗
PubMed1984

Feeding induced by injections of muscimol into the substantia nigra of rats: unaffected by haloperidol but abolished by large lesions of the superior colliculus.

Intense activation of central dopamine systems has been associated with oral stereotyped behaviour, whereas less intense stimulation of these systems can increase feeding in non-deprived animals. There are several lines of evidence which suggest that the gamma-aminobutyric acid-containing striatonigral and nigrotectal projections are essential pathways mediating dopamine-related oral stereotypy. The present series of experiments was conducted to examine whether the same output route also mediates dopamine-related feeding. In the first experiment it was shown that bilateral injections of a sub-stereotypic dose of muscimol (0.05 nM) into the substantia nigra increased feeding of non-deprived rats. In Experiment II the feeding response was further characterised by demonstrating that food intake was initially suppressed for 30 min after which it was potentiated for 90 min. In Experiment III it was shown that a single dose of haloperidol (0.4 mg/kg), which was adequate to suppress overall food intake, was ineffective in preventing the increase in feeding produced by intranigral muscimol (0.05 nM). In contrast, it was demonstrated in Experiment IV that large lesions of the superior colliculus completely abolished the muscimol-induced increase in feeding. These results suggest that the striatonigral and nigrotectal projections may be important efferent pathways for both the oral stereotypy and the feeding responses linked with central dopamine transmission.

Animals↗
PubMed1994

Kindling induces time-dependent and regional specific changes in the [3H]muscimol binding in the rat hippocampus: a quantitative autoradiographic study.

To investigate possible changes in the GABAA receptor agonist site in the CA1 area and fascia dentata of rats kindled by stimulation of Schaffer collaterals, a quantitative autoradiographic study of the [3H]muscimol binding was carried out. Two kindled groups were studied, at 24 h (fully kindled stage) and at 28 days (long-term stage) after the last class V seizure. Several concentrations of [3H]muscimol were tested in the range of the high/intermediate (5-40 nM) and low-affinity (60-100 nM) binding sites. In the fully kindled group, the binding over the complete range of tested [3H]muscimol concentrations was significantly increased by 30-50% in the fascia dentata, while the binding was significantly decreased by 10-25% in the CA1 area. The high/intermediate-affinity binding was still significantly increased by 20-30% in the fascia dentata 28 days after the last seizure. In this long-term group there was still a significant decrease of 10-18% of the low-affinity binding in the CA1 area. These results show that kindling epileptogenesis induces long-lasting changes in the GABAA receptor agonist binding sites that are region specific. We hypothesize that the changes encountered at the fully kindled stage, i.e. increased binding in the fascia dentata and decreased binding in the CA1 area, may underly the electrophysiologically observed increased paired-pulse depression of field potentials in the former and the decreased paired-pulse depression in the latter area [Kamphuis et al. (1992) Neurosci. Lett. 141, 101-105; Kamphuis et al. (1988) Brain Res. 440, 205-215; Zhao and Leung (1991) Brain Res. 564, 220-229; Zhao and Leung (1992) Brain Res. 582, 163-167]. We conclude that the observed changes may not only contribute to the induction of kindling epileptogenesis but may also play a role in the maintenance of the kindled state.

Allosteric Site↗
PubMed1996

Muscimol-induced long-term depression in the hippocampus: lack of dependence on extracellular calcium.

We have recently reported a new protocol for inducing long-term depression through activation of GABAA receptors in the hippocampal site. This long-term depression is reversed by bicuculline and potentiated by neurosteroids such as alphaxalone and 5 alpha-pregnan-3 alpha-ol-20-one. It was also shown that glutamate receptor activity is not involved in the induction of this type of long-term depression. The present study investigates the role of calcium in the induction of this novel form of long-term depression and attempts to determine the mechanism of reversal of muscimol-induced long-term depression. Extracellular recordings were made in the CA1 pyramidal cell layer of rat hippocampal slices following orthodromic stimulation of Schaffer collateral fibres in stratum radiatum (0.01 Hz). It was observed that the muscimol-induced long-term depression can be obtained in the absence of calcium in the bathing medium. In addition to this, the long-term depression was reversed by N-methyl-D-aspartate, kainic acid, high potassium medium, veratrine and the calcium ionophore A23187 but not high calcium (10 mM) medium. High potassium medium in the absence of calcium reversed the long-term depression induced by muscimol 10 microM. The results suggest that this type of glutamate-independent long-term depression can be induced in the absence of extracellular calcium. Extracellular calcium is not necessary for reversal of the long-term depression, although when intracellular calcium levels are raised, as by A23187, this is capable of inducing reversal.

Animals↗
PubMed1996

Importance of the ventrolateral region of the periaqueductal gray and adjacent tegmentum in the control of paradoxical sleep as studied by muscimol microinjections in the cat.

It has been demonstrated that coagulation in the area of the periaqueductal gray induces a marked increase in paradoxical sleep in the cat [Petitjean F. et al, (1975) brain Res. 88, 439-453]. This effect was obtained either by the destruction of ascending or descending fibres or by the lesion of a specific group of local neurons. To assess the role of these neurons, muscimol (0.5 microgram/0.5 microliter) was injected bilaterally in 31 cats in this area of the periaqueductal gray. Polygraphic recordings were performed before and after injections. Following muscimol (GABAA agonist) injection, there was a consistent increase in paradoxical sleep lasting 269 +/- 8 min (mean +/- S.E.M.), with a latency of 31 +/- 2 min. The increase varied from small (20-30%) to medium (30-50%) to large (50-100% of the recording time), depending on the injection site. The intensity of hypersomnia was correlated with the site of the injection. That is, the most profound hypersomnia was obtained when muscimol was injected in the vicinity of a target area which lies in the ventrolateral periaqueductal gray (at the level of the fourth nucleus) and in the reticular formation situated immediately below. Similar effects were also obtained in insomniac cats pretreated with p-chlorophenylalanine and in cats whose brainstem was transected 3 mm rostral to the injection site. Injections of baclofen, a GABAB agonist (0.25-5 micrograms), did not alter the quantity of paradoxical sleep, whereas injections of bicuculline, a GABAA antagonist, significantly decreased the quantity of paradoxical sleep at the doses of 0.2-2 micrograms. It was concluded that inactivation of ventrolateral periaqueductal gray neurons induces a very important increase in paradoxical sleep. The exact mechanisms of this effect remain to be investigated.

Animals↗
PubMed1995

Injection of muscimol in the posterior hypothalamus reduces the PGE1-hyperthermia in the rat.

The firing rate of the nerves innervating interscapular brown adipose tissue (IBAT), IBAT and colonic temperatures (TIBAT and Tc), heart rate, and oxygen (O2) consumption were monitored in urethane-anesthetized male Sprague-Dawley rats. These variables were measured for 40 min before (baseline values) and 40 min after a 56 ng muscimol injection in the posterior hypothalamus and an intracerebroventricular administration of 500 ng prostaglandin E1 (PGE1). The same variables were monitored in other rats with muscimol injection or PGE1 administration alone. No drug was injected in control rats. The results show that muscimol injection reduces the increases in firing rate, TIBAT, Tc, heart rate, O2 consumption induced by PGE1. These findings suggest that GABAergic tone in the posterior hypothalamus is important in the control of thermogenic changes induced by PGE1.

Adipose Tissue↗
PubMed1986

Postnatal development of transmitter systems: sexual differentiation of the GABAergic system and effects of muscimol.

The development and sex differences of the central nervous GABAergic system were examined by measuring GABA (gamma-aminobutyric acid) in discrete brain nuclei of the hypothalamus, as well as the nigrostriatal and the limbic systems of male and female rats on the day of birth and on days 5, 10, and 15. The highest concentrations were found in the hypothalamic and nigrostriatal nuclei; the lowest in the limbic system. Sex differences were observed only on day 10 in the medial preoptic area, with GABA being higher in males than in females; and also in the substantia nigra, where female GABA levels were higher than male. These results suggested an involvement of GABA in the sexual differentiation of the brain. As a control, concentrations of the GABA precursor glutamate were determined. No sex differences in glutamate concentrations were found in any brain region during the first 15 days postnatally. Since a GABA mimetic substance applied during the critical period of brain differentiation could disturb the development of the GABAergic system, the consequences of a perinatal treatment with the GABA agonist muscimol were investigated. Significant reduction of GABA concentrations by muscimol were observed in the hypothalamic and nigrostriatal systems at specific times postnatally. On day 5, GABA concentrations were diminished only in the medial preoptic area, then on day 10, in the anterior hypothalamus and the substantia nigra, and still later, on day 15, in the caudato putamen. In contrast, the effects of muscimol on glutamate concentrations could be observed over a longer postnatal period. Glutamate was already diminished on day 5 in 7 areas of the hypothalamic, nigrostriatal, and limbic systems.

Aging↗
PubMedDate not supplied

Effect of postnatal exposure to GABA agonist muscimol on age-related changes in hypothalamic noradrenaline concentration in rats.

Concentrations of cortical and hypothalamic monoamines and their metabolites after postnatal administration of the GABAA agonist muscimol or ethanol were studied in 37- and 120-day-old rats to clarify the role of GABAergic mechanisms in the development of central monoaminergic neurons. In control rats the hypothalamic noradrenaline (NA) concentration tended to be higher in 120-day-old rats when compared to 37-day-old controls, whereas in muscimol-treated rats the hypothalamic NA concentration was decreased as a function of age. Concentrations of dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) were increased in the hypothalamus as a function of age regardless of postnatal treatment. In the cerebral cortex there was an age-dependent increase in the concentrations of NA, serotonin (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA), as well as a decrease in the concentration of homovanillic acid (HVA) and 5-HIAA/5-HT and HVA/DA ratios in all rats. Thus, the drug treatments did not alter the course of development of cortical monoamine levels. These data suggest that postnatal exposure to the GABA agonist muscimol disturbs specifically the development of hypothalamic NA system in rats.

Aging↗
PubMedDate not supplied

3H-muscimol binding sites within the rat choroid plexus: pharmacological characterization and autoradiographic localization.

By using combined radioreceptor binding and autoradiographic techniques, we were able to localize the GABA 'A' receptor agonist 3H-muscimol in the rat choroid plexus. Within sections of rat choroid plexus, 3H-muscimol was bound specifically with a KD of 37 nM and a Bmax of 253 pmol/mg tissue. These values are consistent with the labelling of GABA 'A' receptor sites. The autoradiographic studies demonstrated that 3H-muscimol was attached to the epithelium of the choroid plexus. The blood vessels of the plexus did not exhibit specific labelling. Examination of these data suggests the existence of GABAergic mechanisms which control cerebrospinal fluid production or flow.

Animals↗
PubMed2004

Septal infusions of glucose or pyruvate with muscimol impair spontaneous alternation.

This experiment examined the effects of co-infusing the GABA agonist muscimol (0.5 nmol) with 33 nmol of glucose, pyruvate, fructose or sorbitol into the medial septum on spontaneous alternation. Only co-infusions of muscimol with glucose or pyruvate impaired spontaneous alternation performance; none of the other infusions had any significant effects. The findings suggest that glucose metabolism rather than hyperosmolarity is involved in the memory-impairing interaction between glucose and muscimol.

Animals↗
PubMed2004

Inactivation of the medial prefrontal cortex with the GABAA receptor agonist muscimol increases open-arm activity in the elevated plus-maze and attenuates shock-probe burying in rats.

This study examined the effects of infusions of a direct GABA(A) receptor agonist, muscimol, into the medial prefrontal cortex (MPFC), on fear behavior measured in the elevated plus-maze and shock-probe burying tests. Bilateral infusions of either a 0.175 or 4 nmol/0.5 microl dose of muscimol increased the percentage of entries and time spent in the open arms, and attenuated shock-probe burying. These findings indicate that intra-MPFC infusions of muscimol induce anxiolysis, and suggest that the direct stimulation of MPFC GABA(A) receptors attenuates fear-related behavior.

Animals↗
PubMed2005

Activation of feeding-related neural circuitry after unilateral injections of muscimol into the nucleus accumbens shell.

Chemical inhibition of neurons in the nucleus accumbens shell (AcbSh) elicits intense, behaviorally specific, feeding in satiated rats. We have demonstrated previously that this treatment activates a number of brain regions, most significantly the lateral hypothalamus (LH). This activation could be elicited through a direct neural connection with the AcbSh or secondarily through changes in autonomic activity, stress, or circulating levels of orexigenic or satiety factors. In the present study, we used the immunohistochemical localization of Fos protein to map neuronal activation after unilateral muscimol injections into the AcbSh to determine whether AcbSh-mediated Fos expression remains lateralized in the circuit and whether secondary systemic changes in the rat can be excluded as primary factors in the activation of downstream component nuclei. Rats receiving only saline injections exhibited very little Fos immunoreactivity. In contrast, unilateral injections of muscimol into the AcbSh consistently increased Fos expression in several brain regions. Three distinct patterns of expression were observed. Fos synthesis in the LH was increased only on the side of the brain ipsilateral to the muscimol injection. Fos expression remained primarily ipsilateral to the injection site in the septohypothalamic, paraventricular hypothalamic (PVN), paratenial thalamic, and lateral habenular nuclei, and medial substantia nigra, but was increased bilaterally in the piriform cortex, supraoptic nucleus, central nucleus of the amygdala, and nucleus of the solitary tract. Smaller numbers of Fos-immunoreactive cells were seen unilaterally in the bed nucleus of the stria terminalis, medial ventral pallidum, arcuate nucleus, and ventral tegmental area and bilaterally in the supraoptic and tuberomammillary nuclei. The labeling in the LH, PVN, and other unilaterally labeled structures provides evidence that these brain regions are components of an AcbSh-mediated neural circuit and suggests that they may be involved in the expression of AcbSh-mediated feeding behavior.

Analysis of Variance↗
PubMed2005

Hippocampal infusions of pyruvate reverse the memory-impairing effects of septal muscimol infusions.

Hippocampal infusions of glucose reverse memory deficits in spontaneous alternation and in a continuous multiple trial inhibitory avoidance task. The current experiments tested whether glucose metabolism may participate in these effects of glucose. Specifically, these experiments determined whether the glycolytic metabolite pyruvate would mimic these effects of glucose. Male Sprague-Dawley rats were given septal infusions of vehicle or the gamma-aminobutyric acid (GABA) receptor agonist muscimol (0.15 nmol for spontaneous alternation or 5 nmol for continuous multiple trial inhibitory avoidance) combined with hippocampal infusions of vehicle or pyruvate (200 nmol) 15 min prior to assessing spontaneous alternation or training in a continuous multiple trial inhibitory avoidance task. The infusions of muscimol decreased percent alternation scores and continuous multiple trial inhibitory avoidance retention latencies tested 48 h after training. More importantly, hippocampal infusions of pyruvate reversed the deficits produced by septal infusions of muscimol on both tasks. These findings show for the first time that hippocampal infusions of pyruvate influence memory and suggest that glucose may affect memory via glycolytic metabolism.

Animals↗
PubMed2005

Effects of injections of 8-hydroxy-2-(di-n-propylamino)tetralin or muscimol in the median raphe nucleus on c-fos mRNA in the rat brain.

Inhibition of the median raphe nucleus (MRN) by the local injection of 5-HT(1A) or GABA(A) receptor agonists produces strong activational effects on feeding, drinking and locomotor activity. Using an animal model of relapse, we have shown that intra-MRN injection of the 5-HT(1A) autoreceptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) reinstates alcohol seeking in rats. The circuitry underlying the behavioral effects of intra-MRN injection of these drugs is not known. In order to identify the brain areas that may be involved, we measured levels of mRNA of the immediate early gene c-fos in discrete nuclei of the rat brain following intra-MRN infusions of these drugs. Male Wistar rats received intra-MRN infusions of 8-OH-DPAT (1 mug), muscimol (25 ng) or saline vehicle immediately prior to placement in locomotor activity chambers. Thirty minutes later, they were decapitated, and their brains processed for in situ hybridization of c-fos mRNA. In agreement with previous reports, injections of 8-OH-DPAT or muscimol into the MRN resulted in large increases in locomotor activity. Intra-MRN injections of these drugs increased c-fos in a number of brain nuclei previously shown to be involved in the rewarding effects of drugs of abuse in a regionally specific manner. Both drugs significantly increased the expression of c-fos mRNA in the medial frontal cortex, nucleus accumbens, lateral septum, dorsal bed nucleus of the stria terminalis and ventral tegmental area. In the ventral hippocampus, only 8-OH-DPAT increased c-fos, while in the basolateral nucleus of the amygdala and locus coeruleus, it was increased only by muscimol. These results are discussed in terms of the projections of the MRN and the pathways involved in relapse to alcohol and drug seeking.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2005

The role of the GABA(A) agonist muscimol on memory performance: reward contingencies determine the nature of the deficit.

A matching-to-position (MTP) paradigm was altered to influence the type of associations a rat would use to solve the task. Our main behavioral manipulation was the application of the differential outcomes procedure (DOP). The DOP involves correlating each to-be-remembered event with a distinct reward condition. This procedure results in the development of unique reward expectancies that enhance and guide choice behavior. Such distinct reward expectancies are not formed when either a common or random assignment of reward is used (a non-differential outcomes procedure [NOP]). Intracerebroventricular infusions of the amnestic agent muscimol (GABA(A) agonist) or aCSF were delivered to male rats trained on a delayed MTP task that implemented either the DOP or the NOP. Muscimol impaired performance in a dose dependent fashion in both groups--but the nature of the deficit differed as a function of reinforcement contingencies. Rats trained with the DOP displayed a non-mnemonic delay-independent impairment: performance at all delay intervals was disrupted. In contrast, NOP-trained rats displayed a delay-dependent impairment demonstrating that muscimol can also have memory-disrupting effects. The difference in pattern of impairment appears to be a function of the associations formed during training and the type of cognitive strategies involved in maintaining behavior on a conditional delayed discrimination task when reinforcement contingencies are varied. Thus, these results demonstrate that increasing GABA(A) receptor activation impairs a range of associative and memory functions.

Animals↗
PubMed2005

Conditioned and unconditioned fear organized in the periaqueductal gray are differentially sensitive to injections of muscimol into amygdaloid nuclei.

The lateral and basolateral nuclei of the amygdala (LaA and BLA, respectively) serve as a filter for unconditioned and conditioned aversive information that ascends to higher structures from the brainstem, whereas the central nucleus of the amygdala (CeA) is considered to be the main output for the defense reaction. It has been shown that the dorsal periaqueductal gray (dPAG) is activated by threatening stimuli and has important functional links with the amygdala through two-way anatomical connections. In this work, we examined the influence of chemical inactivation of these nuclei of amygdala on the freezing and escape responses induced by electrical stimulation through electrodes implanted in the dPAG of Wistar rats. Each rat also bore a cannula implanted in the LaA, BLA or CeA for injections of muscimol (0.5 microg/0.5 microL) or its vehicle. The duration of freezing behavior that outlasts electrical stimulation of the dPAG was also measured. On the following day, these animals were submitted to a contextual fear-conditioning using foot shocks as unconditioned stimulus. Conditioned freezing to contextual cues previously associated with foot shocks was also inhibited by injections of muscimol into these amygdaloid nuclei. The contextual conditioned freezing behavior is generated in the neural circuits of conditioned fear in the amygdala. The data obtained also show that injections of muscimol into the three amygdaloid nuclei did not change the aversive threshold of freezing, but disrupted the dPAG post-stimulation freezing. Previous findings that the latter freezing results directly from dPAG stimulation and that it is not sensitive to a context shift suggest that it is unconditioned in nature. Thus, the amygdala can affect some, but not all, aspects of unconditioned freezing. Post-stimulation freezing may reflect the process of transferring aversive information from dPAG to higher brain structures.

Amygdala↗
PubMed2004

Modulation of the gait deficit in arthritic rats by infusions of muscimol and bicuculline.

Gait analysis in the adjuvant-induced arthritic rat model of chronic pain was used to examine the role of GABA(A) receptors in the development of pain. Drug solutions were administered continuously at 5+/-0.75 microl/h for 14 days via Alzet osmotic pumps (2ML2) placed under the skin of the back. The GABA(A) receptor agonist, muscimol, produces a dose-dependent reversal of the gait deficits seen in arthritic rats without reducing the tibiotarsal joints inflammatory edema or the histological picture of joint erosion and inflammation. The higher infusion rate for muscimol, 20 microg/h, caused the gait for the arthritic rats to be indistinguishable from that of normal non-arthritic rats. In normal, non-arthritic rats, muscimol did not show any effect on gait. The GABA(A) receptor antagonist bicuculline showed small but significant exacerbation of stride length (P < 0.05) single and double stance time (P < 0.05) and swing time deficits (P < 0.05) in the arthritic rats, but no changes in measures of gait in the normal control rat. The results suggest that the development of arthritic pain is increased in the absence of GABA(A) receptor tone and that increasing GABA(A) receptor tone can reduce arthritic pain but does not affect the disease process.

Animals↗
PubMed2001

Infusions of physostigmine into the hippocampus or the entorhinal cortex attenuate avoidance retention deficits produced by intra-septal infusions of the GABA agonist muscimol.

Septal gamma-aminobutyric acid (GABA) receptor activation is known to disrupt memory formation, although the mechanisms underlying this impairment remain unclear. The present study explored the possibility that high levels of septal GABA receptor activity might impair memory by down-regulating acetylcholine (ACh) function in archicortex and entorhinal cortex. To test this possibility, rats were trained on an avoidance task 15 min after receiving intra-septal infusions of vehicle or muscimol (5 nmol/0.5 microl) combined with unilateral intra-hippocampal (10 microl/1 microl) or intra-entorhinal cortex (1.875 microg/0.25 microl) infusions of vehicle or the acetylcholinesterase inhibitor physostigmine. We demonstrate that these infusions do not alter acquisition performance on a continuous multiple trial inhibitory avoidance task. However, intra-septal infusions of muscimol dramatically impair retention performance 48 h later. More importantly, infusions of physostigmine into the hippocampus or the entorhinal cortex, at doses that do not influence acquisition or retention performance when infused alone, attenuate the impairing effects of the muscimol infusions on retention. We suggest that high levels of septal GABA receptor activity might impair memory by down-regulating ACh levels in the hippocampal region, and that such memory impairments can be ameliorated by increasing ACh levels in the hippocampus or entorhinal cortex.

Animals↗