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PubMed1983

Diazepam stimulates the binding of GABA and muscimol but not THIP to rat brain membranes.

Diazepam (10-1000 nM) enhanced the binding of [3H]GABA and of the monocyclic GABA agonist [3H]muscimol, but failed to alter binding of the bicyclic GABA agonist [3H]THIP to fresh, well washed rat brain membranes incubated at 2 degrees C. Although stimulation of [3H]diazepam binding by THIP was observed at higher incubation temperatures and in the presence of chloride ions, these measures did not induce a corresponding enhancement of [3H]THIP binding by diazepam. These results extend earlier observations of the unusual behavior of THIP as a selective GABA agonist, and emphasize that enhancement of benzodiazepine binding by GABA agonists is not necessarily reflected in a complementary manner by any action of benzodiazepines on the binding of GABA agonists.

Analgesics↗
PubMed1986

The enhancement of diazepam and muscimol binding by pentobarbital and (+)-etomidate: size of the molecular arrangement estimated by electron irradiation inactivation of rat cortex.

Synaptosomal membranes were prepared from frozen rat cortices irradiated by 10 MeV electrons and the enhancement of [3H]diazepam and [3H]muscimol binding by pentobarbital (PB) and (+)-etomidate was studied. The target sizes of the corresponding parts of the receptor complex were estimated from the decrease in the enhancement as a function of irradiation dose. Different radiation inactivation constants suggest different regulatory units for the enhancement by PB and (+)-etomidate. Target sizes for PB and (+)-etomidate enhancement of [3H]diazepam binding were 127 +/- 14 and 360 + 124 kDa, respectively.

Animals↗
PubMed1989

Long-lasting insomnia induced by preoptic neuron lesions and its transient reversal by muscimol injection into the posterior hypothalamus in the cat.

In order to analyse the role of the anterior hypothalamus in the regulation of the sleep-waking cycle we made bilateral neuronal lesions at different levels of the anterior hypothalamus in cats, by means of microinjections of a cell-specific neurotoxin:ibotenic acid. These lesions resulted in severe insomnia in eight cats. This insomnia was characterized by a large decrease or even disappearance of paradoxical sleep and deep slow wave sleep and, to a lesser extent, by a decrease of light slow wave sleep, for 2-3 weeks. In the other five animals, we observed a large reduction of deep slow wave sleep (0-40% of control level), but a less intensive decrease of time spent in paradoxical sleep (50-75% of control level) and no marked effect on light slow wave sleep. During the first 3-6 postoperative days we also noticed hyperthermia in all cats; thereafter, the animals presented only a slight increase in brain temperature which did not appear to trigger the sleep impairment. Histological analysis of the different lesions revealed that the insomnia could be attributed to neuronal cell body destruction in the mediobasal part of the anterior hypothalamus covering; the medial preoptic area and a narrow portion of the lateral preoptic area as well as a restricted part of the anterior hypothalamic nucleus. In order to investigate the putative role of the posterior hypothalamic structures in the mechanism of insomnia after lesion of the mediobasal preoptic area neurons we injected an agonist of GABA into the ventrolateral part of the posterior hypothalamus to locally depress the neuronal activity. The bilateral intracerebral microinjection of muscimol (0.5-5 micrograms) induced a transient intensive hypersomnia (slow wave sleep and paradoxical sleep). These findings indicate that neuronal cell loss in the mediobasal preoptic area induced a long lasting insomnia. Thus, it may be hypothesized that the integrity of this structure is necessary for sleep appearance. Finally, our data are in keeping with an intrahypothalamic regulation of the sleep-waking cycle.

Animals↗
PubMed1984

Effects of intranigral injections of dopamine agonists and antagonists, glycine, muscimol and N-methyl-D,L-aspartate on locomotor activity.

Previously it has been shown that bilateral intranigral injections of dopamine into rats pretreated with a monoamine oxidase inhibitor induced prolonged stimulation of locomotor activity, while bilateral intranigral injections of haloperidol reduced the locomotor stimulation evoked by systemic amphetamine. In the present studies, the role of the substantia nigra in locomotor activity was further investigated using a variety of dopaminergic and other agonists and neuroleptics. Ergometrine, epinine, (+/-)-2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronapthalene hydrobromide (ADTN), 1,2,3,4-tetrahydro-6,7,-dihydroxyisoquinoline hydrochloride (THIQ), muscimol and glycine elicited locomotor activity when injected into the substantia nigra pars reticulata bilaterally. Additionally the non-dopaminergic agonists also elicited a degree of stereotyped behavior. Locomotor activity induced by intranigral ergometrine was blocked by systemic haloperidol but was not affected by intranigral haloperidol. Locomotor activity elicited by systemic amphetamine was blocked by bilateral intranigral alpha-flupenthixol, but that elicited by bilateral intra-accumbens ergometrine was not affected by alpha-flupenthixol or haloperidol injected into the substantia nigra pars reticulata bilaterally. The results provide further evidence that alterations of neurotransmission in the substantia nigra exert effects on locomotor activity.

Amphetamine↗
PubMed1989

MIF-1 and Tyr-MIF-1 augment muscimol-stimulated chloride uptake in cerebral cortex.

The peptides MIF-1 (Pro-Leu-Gly-NH2) and Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2) recently have been found to augment the effects of gamma-aminobutyric acid (GABA) on benzodiazepine receptor binding and chloride channel binding (Tyr-MIF-1) at the GABAA receptor complex. To determine whether these peptides affect the function of this complex in chloride transport, we evaluated chloride uptake stimulated by the GABA analog muscimol in synaptoneurosome preparations. In mice treated with either MIF-1 or Tyr-MIF-1 (1 mg/kg IP), maximal chloride uptake in cortex was increased compared with controls. The two peptides had similar effects in cortical preparations, but in cerebellum neither peptide altered chloride uptake. No differences from controls were observed in cortical synaptoneurosomes treated in vitro with either MIF-1 or Tyr-MIF-1. These results suggest that the brain peptides MIF-1 and Tyr-MIF-1 alter function at the GABAA receptor complex, perhaps by binding at a specific peptide receptor.

Animals↗
PubMed2004

Effects of rubral microinjections of muscimol and bicuculline in a genetic animal model of paroxysmal dystonia.

Previous studies suggested that GABAergic dysfunctions within the red nucleus are involved in stress-inducible paroxysmal dystonia of the dt(sz) mutant hamster. In the present study, rubral microinjections of the GABAA receptor agonist muscimol exerted only moderate antidystonic effects and the antagonist bicuculline failed to show significant effects on the severity of dystonia. These data indicate that disturbed rubral GABAergic inhibition is not important for the manifestation of dystonia in the dt(sz) mutant.

Animals↗
PubMed2005

Learning deficits induced by sleep deprivation and recovery are not associated with altered [(3)H]muscimol and [(3)H]flunitrazepam binding.

Several studies have shown that sleep deprivation produces deficits in learning tasks, but mechanisms underlying these effects remain unclear. Other lines of evidence indicate an involvement of brain GABA systems in cognitive processes. Here, we investigated the possibility that alterations in GABA(A) or benzodiazepine (BDZ) receptor binding might underlie avoidance deficits induced by sleep deprivation. Rats were deprived of sleep for 96 h using the platform method and then trained in a step-through inhibitory avoidance task, or allowed to recover sleep for 24 h before training (sleep rebound group). Thirty minutes after training, animals were given a retention test. Both sleep-deprived and sleep-recovered animals showed a significant impairment in avoidance responding compared to cage controls, and the sleep-deprived group performed significant worse than the sleep-recovered group. A separate group of animals was sacrificed either immediately after 96 h of sleep deprivation or after 96 h of sleep deprivation followed by 24 h of sleep recovery. [(3)H]muscimol and [(3)H]flunitrazepam binding were examined by quantitative autoradiography in 42 brain regions, including areas involved in cognitive processes. No significant differences among groups were found in any brain region, except for a reduction in [(3)H]flunitrazepam binding in the frontal cortex of sleep-recovered animals. These results confirm the deleterious effects of sleep loss on inhibitory avoidance learning, but suggest that such deficits cannot be attributed to altered GABA(A) or BDZ binding in brain.

Animals↗
PubMed2004

Behavioral effects of bicuculline microinjection in the dorsal versus ventral hippocampal formation of rats, and control of seizures by nigral muscimol.

This work aims to describe behavioral/electroencephalographic (EEG) seizures induced by bicuculline microinjection intracerebroventricularly (ICV) and in the dorsal hippocampal formation (DHF) or ventral hippocampal formation/amygdala area (VHF-AMY). We also test if GABAergic manipulation in the substantia nigra pars reticulata (SNPR) is capable of controlling those seizures. ICV injection of bicuculline induced a progressive sequence of convulsive responses, jumps and escapes from the open-field. This effect was partially reached by bicuculline injection in the DHF or VHF-AMY injection. Also: muscimol injection, but not GABA uptake blockers (nipecotic acid or a spider venom neurotoxin FrPbA2), into the SNPR abolished seizures induced by bicuculline injection in the DHF. It was concluded that different neuronal circuitry in the hippocampal formation are modulated, at least partially by nigral GABAergic mechanisms.

Animals↗
PubMed2005

Activation of GABA(A) receptors by taurine and muscimol blocks the neurotoxicity of beta-amyloid in rat hippocampal and cortical neurons.

The beta-amyloid peptide (Abeta) is centrally related to the pathogenesis of Alzheimer's disease (AD) and is potently neurotoxic to central nervous system neurons. The neurotoxicity of Abeta has been partially related to the over activation of glutamatergic transmission and excitotoxicity. Taurine is a naturally occurring beta-amino acid present in the mammalian brain. Due to its safety and tolerability, taurine has been clinically used in humans in the treatment of a number of non-neurological disorders. Here, we show that micromolar doses of taurine block the neurotoxicity of Abeta to rat hippocampal and cortical neurons in culture. Moreover, taurine also rescues central neurons from the excitotoxicity induced by high concentrations of extracellular glutamate. Neuroprotection by taurine is abrogated by picrotoxin, a GABA(A) receptor antagonist. GABA and muscimol, an agonist of the GABA(A) receptor, also block neuronal death induced by Abeta in rat hippocampal and cortical neurons. These results suggest that activation of GABA(A) receptors protects neurons against Abeta toxicity in AD-affected regions of the mammalian brain and that taurine should be investigated as a novel therapeutic tool in the treatment of AD and of other neurological disorders in which excitotoxicity plays a relevant role.

Amyloid beta-Peptides↗
PubMed1997

Infusion of quinpirole and muscimol into the ventral tegmental area inhibits fear-potentiated startle: implications for the role of dopamine in fear expression.

Dopamine (DA) D2 and gamma-aminobutyric acid (GABA)A somatodendritic receptors tonically inhibit mesolimbic projection neurons in the A10 DA cell grouping of the ventral tegmentum. In the present study we determined the contribution of the ventral tegmental area (VTA) to the expression of a classically conditioned fear-induced increase in the acoustic startle reflex. Saline applied to VTA neurons did not modify the capacity of a light previously associated with footshock to potentiate acoustic startle amplitudes; conversely, bilateral administration of the DA D2/3 agonist quinpirole or the GABAA receptor agonist muscimol into the ventral tegmentum blocked fear-potentiated startle without altering baseline acoustic startle responding. It was suggested that DA VTA neurons regulate the excitatory aspects of fear expression by gating levels of aversive emotional arousal within the amygdala-based fear system.

Analysis of Variance↗
PubMed2000

Effects of buspirone, diazepam, and zolpidem on open field behavior, and brain [3H]muscimol binding after buspirone pretreatment.

The effects of 5-HT(1A) receptor agonist buspirone, a nonselective (diazepam), and a selective (zolpidem) GABA(A) receptor agonist were compared in the open field test of neophobia. Unhabituated rats were pretreated with the drugs once, prior to a first exposure to the open field, and their behavior was recorded both during this test and during a second trial 24 h later. It has been hypothesized that the decrease in exploratory activity observed during the second test session may be considered an adaptive reaction to the first day aversive experience (neophobia). If so, a selective modulation of 5-HT and GABA systems activity during the test could bring about significant changes in animal behavior on the retest. Buspirone at the lowest dose of 0.3 mg/kg revealed anxiolytic-like properties on the first day, whereas the action of diazepam and zolpidem was modulated by the dose-related sedative effect. At the dose of 2.4 mg/kg buspirone elicited delayed in time anxiolytic-like action, i.e., produced the antithigmotactic effect during the retrial 24 h later. Diazepam and zolpidem failed to exhibit similar profile of action. Autoradiography of [3H]muscimol binding after pretreatment of rats with buspirone showed a significant increase in the selective radioligand binding within the frontal cortex and a similar, near-significant tendency in the dentate gyrus of the hippocampus. The behavioral data validate buspirone as important drug for the treatment of anxiety disorders, devoid of disruptive influence on motor and cognitive processes. The open field test, as modified by us, appeared sensitive in distinguishing the behavioral profiles of action of different anxiolytic compounds, including 5-HT(1A) receptor agonist. The present results support the assumption that reduced turnover of 5-HT due to stimulation of 5-HT(1A) autoreceptors, may bring about changes in GABA(A) receptor system activity, in some brain structures, leading to the anxiolytic effect.

Animals↗
PubMed2003

Rat behavior in two models of anxiety and brain [3H]muscimol binding: pharmacological, correlation, and multifactor analysis.

The contribution of GABAergic mechanisms to rat emotional behavior in two animal models of anxiety (open field test of neophobia and aversively conditioned freezing reaction), was confirmed by pharmacological analysis, using anxiolytic (midazolam) and anxiogenic (picrotoxin) compounds. Both substances are known to modulate GABA(A) receptors' activity in a positive or negative manner, respectively. It seemed, therefore, worthwhile to check whether the behavioral parameters measured in these animal models of anxiety correlate with [3H]muscimol binding (a highly selective GABA(A) receptor ligand) in different brain structures of nai;ve rats, with a view to establish the role of genetically determined expression of local GABA(A) receptors in the organization of rat emotional and motor behavior. Correlation analysis revealed no links between individually determined expression of GABA(A) receptors (quantitative receptor autoradiography) in the brain structures, and the emotional behavior of nai;ve, drug-free animals, in both tests. Factor analysis confirmed that animal behavior in both tests was under control of different central processes. Moreover, none of the behavioral and ligand binding parameters loaded on the same factor, confirming the negative results of the correlation study. The present results indicate that the origin of emotions is a complex phenomenon, probably involving the interaction between GABA-ergic innervation of many brain structures.

Analysis of Variance↗
PubMed1992

Failure of a chlordiazepoxide to reproduce the behavioral effects of muscimol administered into the basal forebrain.

Bilateral infusion of the GABAA-receptor agonist muscimol into the basal forebrain was previously found to impair visual conditional discrimination performance in rats. In order to examine whether the GABAergic input into the basal forebrain is active during performance of this task, the benzodiazepine receptor agonist chlordiazepoxide (15, 25, 40 micrograms/0.5 microliters/hemisphere) was bilaterally infused. Surprisingly, chlordiazepoxide did not affect performance. The impact of this result for the understanding of basal forebrain GABAergic functions is discussed.

Animals↗
PubMed2003

Vocalization after periaqueductal grey inactivation with the GABA agonist muscimol in the squirrel monkey.

In order to specify the role of the periaqueductal grey (PAG) in vocal production, we tested the effect of PAG inactivation on the electrical elicitability of vocalization from various brain structures in the squirrel monkey. For this purpose, we implanted stimulation electrodes at 64 vocalization-eliciting sites throughout the brain and compared the elicitability of vocalization before and after muscimol injection into the PAG. It turned out that only vocalization sites in the forebrain (cingulate cortex, hypothalamus) and rostralmost mesencephalic reticular formation could be blocked by PAG inactivation, whereas all vocalization sites in the caudal midbrain, pons and medulla remained unaffected. It is concluded that the PAG is not the site of vocal pattern generation, but rather serves gating functions.

Animals↗
PubMed1999

Unilateral muscimol inactivations of the interstitial nucleus of Cajal in the alert rhesus monkey do not elicit seesaw nystagmus.

Seesaw-nystagmus (SSN) is a unique form of nystagmus with disconjugate vertical and conjugate torsional eye movements. Although rare, this disorder serves as a model for neuronal binocular control of the alignment of vertical-torsional eye movements of both eyes. The pathomechanism of SSN, however, is unclear. Studies in patients have suggested that the jerk SSN is associated with a midbrain lesion, i.e. a lesion of the interstitial nucleus of Cajal (iC), a center of integration of vertical and torsional eye movements. To test this hypothesis, we examined three dimensional binocular eye movements after reversible local inactivations of the iC and its immediate vicinity in the midbrain of the alert monkey. Inactivations were induced by muscimol microinjections. Eye movements were recorded with binocular scleral search coils. Isolated inactivations of neither the iC nor its immediate vicinity in the midbrain (including the adjacent rostral interstitial nucleus of the medial longitudinal fascicle, riMLF) elicited a disconjugate vertical/torsional nystagmus (SSN). However, there was a direction-specific right/left asymmetry in which a larger vertical amplitude was associated with the contralesional eye and a larger torsional amplitude with the ipsilesional eye, indicating a vestibular imbalance. We conclude that, first, iC lesions do not elicit SSN and, second, that apart from the gaze holding deficit a vestibular imbalance contributes to the vertical/torsional nystagmus after iC lesions.

Animals↗
PubMed2000

GAD levels and muscimol binding in rat inferior colliculus following acoustic trauma.

Pharmacological studies of the inferior colliculus (IC) suggest that the inhibitory amino acid neurotransmitter gamma-aminobutyric acid (GABA) plays an important role in shaping responses to simple and complex acoustic stimuli. Several models of auditory dysfunction, including age-related hearing loss, tinnitus, and peripheral deafferentation, suggest an alteration of normal GABA neurotransmission in central auditory pathways. The present study attempts to further characterize noise-induced changes in GABA markers in the IC. Four groups (unexposed control, 0 h post-exposure, 42 h post-exposure, and 30 days post-exposure) of 3-month-old male Fischer 344 rats were exposed to a high intensity sound (12 kHz, 106 dB) for 10 h. Observed hair cell damage was primarily confined to the basal half of the cochlea. There was a significant decrease in glutamic acid decarboxylase (GAD(65)) immunoreactivity in the IC membrane fraction compared to controls (P<0.05) at 0 h (-41%) and 42 h (-28%) post-exposure, with complete recovery by 30 days post-exposure (P>0.98). Observed decreases in cytosolic levels of GAD(65) were not significant. Quantitative muscimol receptor binding revealed a significant increase (+20%) in IC 30 days after sound exposure (P<0.05). These data suggest that changes in GABA neurotransmission occur in the IC of animals exposed to intense sound. Additional studies are needed to determine whether these changes are a result of protective/compensatory mechanisms or merely peripheral differentiation, as well as whether these changes preserve or diminish central auditory system function.

Animals↗
PubMed2001

Injected muscimol in pedunculopontine tegmental nucleus alters ethanol self-administration.

The pedunculopontine tegmental nucleus (PPN) has been implicated in a variety of behavioral functions, including stimulus selection. Given the PPN interactions with the mesolimbic system, it was considered important to determine its involvement in ethanol self-administration. Long-Evans male rats were trained to self-administer 10% ethanol by using a sucrose-substitution procedure. After implantation of cannula guides, microinjections of 30, 100, and 300 ng of muscimol into the PPN before the self-administration session were performed. Ethanol self-administration was decreased at the 300-ng dose, in a manner similar to the actions of dopamine agonists microinjected in the nucleus accumbens. It is hypothesized that loss of PPN cholinergic input to the mesolimbic system affects the integrative activity of the nucleus accumbens and underlies the observed change in ethanol self-administration behavior.

Alcohol Drinking↗