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PubMed2000

Food intake after diazepam, morphine or muscimol: microinjections In the nucleus accumbens shell.

This study examined the effect on food intake of bilateral microinfusions of the benzodiazepine agents, diazepam and midazolam, the opioid agonist, morphine, and the GABA(A) agonist, muscimol into the shell of the nucleus accumbens in rats. Both muscimol (at 0.075 microg, combined bilateral dose) and morphine (1.0 microg) in the nucleus accumbens shell increased feeding as expected. However, it was clear that diazepam (2.5, 5.0, 25, 50 microg) and midazolam (7.5 microg) both failed to enhance feeding even at doses that are effective when microinjected in the brain stem. We conclude that opioid and GABA(A) agents promote feeding behavior by acting on receptors in the nucleus accumbens shell, but that benzodiazepines probably act elsewhere in the brain to increase food intake.

Animals↗
PubMed1999

The effects of neurosteroids on rat behavior and 3H-muscimol binding in the brain.

The effects of ICV administration of metabolites of progesterone and deoxycorticosterone [i.e., neurosteroids: AP (3alpha-hydroxy-5alpha-pregnan-20-one, allopregnanolone), 5alpha(-THDOC (3alphat-21-dihydroxy-5alpha-pregnan-20-one, 5alpha-tetrahydrodeoxycorticosterone), 5beta-THDOC (3alpha-21-dihydroxy-5beta-pregnan-20-one, 5beta-tetrahydrodeoxycorticosterone), and PS (3beta-hydroxy-5-pregnen-20-one sulfate, pregnenolone sulfate] were studied in the open-field test of neophobia and Vogel's test of conflict behavior in rats. The influence of in vivo administered 5beta-THDOC, a positive allosteric modulator of the GABA(A) receptor complex, on 3H-muscimol binding in different brain structures, was also studied with the help of quantitative autoradiography. The presented data did not reveal any anxioselective effects for a range of centrally active neurosteroids, in the ethologically orientated and conflict models of anxiety, after intracerebral drug administration. Their central effects appeared secondary to changes in rat gross behavior. It is possible that high local concentration of neurosteroids after ICV injection and production of a narrower range of behavioral effects than that of benzodiazepines, precluded manifestation of the antianxiety effects of AP, 5alpha-THDOC and 5beta-THDOC. Autoradiography did not reveal any significant changes in the specific binding of 3H-muscimol in brain structures after in vivo ICV administration of 5beta-THDOC at the behaviorally active dose. Thus, the possibility that neuroactive neurosteroids may provide a novel potential site for therapeutic interventions in anxiety disorders is not supported. The part of the experiment with 5beta-THDOC is interpreted as contributing to other results, suggesting the existence of a new category of neurosteroids acting as partial agonists of the GABA(A) receptor.

Animals↗
PubMed1989

Elicitation of feeding, drinking, and gnawing following microinjections of muscimol into the median raphe nucleus of rats.

Previous studies have demonstrated that injections of muscimol into the median raphe nucleus (MR) result in large increases in locomotor activity and food intake. The current experiment extends these results by showing that intra-MR muscimol injections in nondeprived rats also elicit nonprandial drinking and gnawing of wooden blocks. These findings indicate that stimulation of GABA receptors within the MR is able to energize a wide range of oral behaviors and is compatible with the view that the MR may be part of a "nonspecific" behavioral activation system.

Animals↗
PubMed2001

A change in the density of [(3)H]flumazenil, but not [(3)H]muscimol binding, in Brodmann's Area 9 from subjects with bipolar disorder.

BACKGROUND: This study examines the hypothesis that there are changes in cortical serotonergic, GABAergic and glutamatergic systems in bipolar disorder and schizophrenia. METHODS: In situ radioligand binding and autoradiography were used to measure neurochemical markers in Brodmann's Area (BA) 9 from control subjects and subjects with bipolar disorder or schizophrenia (n=8 per group). RESULTS: Compared to tissue from schizophrenic (mean+/-S.E.M, 385+/-44 fmol/mg ETE) and control (383+/-44 fmol/mg ETE) subjects, there was an increase in the density of [(3)H]flumazenil binding to the benzodiazepine binding site on the GABA(A) receptor in subjects with bipolar disorder (451+/-17 fmol/mg ETE; P<0.05). There was no difference in the density of [(3)H]muscimol binding to the GABA(A) receptor or in the density of the serotonin(1A) receptor, serotonin(2A) receptor, ionotropic glutamate receptors or the serotonin transporter between the three cohorts. There was an age-related decrease in NMDA receptor density in control subjects that was absent in schizophrenia and bipolar disorder. An age-related increase in [(3)H]flumazenil binding in schizophrenia was absent in control and bipolar disorder subjects. LIMITATIONS: This study involved a relatively small number of individuals. CONCLUSIONS: An increase in the gamma2-receptor sub-unit in the GABA(A) receptor has been shown to increase benzodiazepine but not [(3)H]muscimol binding, this is the mismatch in binding we have shown in BA 9 from subjects with bipolar disorder. Thus, a change in the assembly of receptor subunits into GABA(A) receptors may be involved in the neuropathology of bipolar disorder. There may also be differences in age-related changes in cortical receptor density between bipolar disorder and schizophrenia.

Adult↗
PubMed1998

Muscimol suppression of the dorsal cochlear nucleus impairs frequency discrimination in rats.

The cochlear nucleus is composed of three sub-nuclei: the dorsal (DCN), anteroventral (AVCN) and posteroventral cochlear nucleus (PVCN). In addition to connections between these sub-nuclei, each nucleus receives frequency specific tonotopically organised input from the cochlea. Evidence suggests that connections from the DCN to the AVCN are inhibitory and organised tonotopically but the functional significance of this pathway has yet to be elucidated. The possible role of this pathway in frequency discrimination using a T-maze behavioural paradigm and DCN suppression was examined. Five rats were trained on a two choice frequency discrimination task. Once frequency difference limens for 10-30% performance above chance were determined, rats had cannulae implanted bilaterally over the DCN. After recovery rats were tested on the behavioural task with nothing, saline and the GABA agonist muscimol injected into the DCN via the cannulae. Muscimol alone significantly reduced the rats ability to perform the task. This performance decrease was attributed to an inability to discriminate high frequency and not low frequency tones suggesting that place and not temporal coding of sound was compromised by DCN suppression. These results are consistent with the hypothesis that inhibitory drive from the DCN to AVCN may be crucial for the fine tuning of frequency information.

Acoustic Stimulation↗
PubMed2003

Exogenous brain-derived neurotrophic factor prevents postischemic downregulation of [3H]muscimol binding to GABA(A) receptors in the cortical penumbra.

We have previously shown that exogenous application of brain-derived neurotrophic factor (BDNF) reduces infarct volume in the cortical ischemic penumbra after experimental focal ischemia [Stroke 31 (2000) 2212-2217]. Since BDNF is known to modulate the expression and function of various neurotransmitter receptors, we addressed the question whether BDNF may act via modification of postischemic ligand binding to excitatory NMDA and AMPA and/or inhibitory GABA(A) receptors, respectively. Transient focal cerebral ischemia was induced in male Wistar rats for 2 h using the suture occlusion technique. A period of 30 min after occlusion of the middle cerebral artery, BDNF (300 microg/kg per hour in vehicle; n=5) or vehicle alone (n=5) was continuously infused intravenously for 3 h. Using quantitative receptor autoradiography, postischemic ligand binding of [(3)H]MK-801, [(3)H]AMPA and [(3)H]muscimol was analyzed in the ischemic core, the ischemic cortical penumbra and corresponding regions of the contralateral hemisphere. Transient focal ischemia caused a significant reduction of [(3)H]muscimol binding to GABA(A) receptors within the ischemic cortical penumbra of placebo-treated rats. This was largely prevented by exogenous application of BDNF. [(3)H]MK-801 and [(3)H]AMPA binding values were also reduced in the cortical penumbra and the corresponding area of the contralateral hemisphere. Our data suggest that the neuroprotective effect of BDNF against ischemic damage in the cortical penumbra may be mediated in part by maintained activity of the inhibitory GABAergic system which likely counteracts glutamate induced excitotoxicity.

Animals↗
PubMed2003

Muscimol prevents long-lasting potentiation of dorsal horn field potentials in rats with chronic constriction injury exhibiting decreased levels of the GABA transporter GAT-1.

The inhibitory activity of gamma-aminobutyric acid (GABA) is considered critical in setting the conditions for synaptic plasticity, and many studies support an important role of GABA in the suppression of nociceptive transmission in the dorsal horn. Consequently, any injury-induced modification of the GABA action has the potential to critically modify spinal synaptic plasticity. We have previously reported that chronic constriction injury of the sciatic nerve was accompanied by long-lasting potentiation of superficial spinal dorsal horn field potentials following high-frequency tetanus. In this study we examined whether the GABA-A receptor agonist muscimol would modify post-tetanic responses in rats with chronic constriction injury. In animals exhibiting maximal thermal hyperalgesia as one sign of neuropathic pain 7 days after loose ligation of the sciatic nerve, spinal application of muscimol (5, 10 or 20 microg) before the high-frequency (50 Hz) tetanus produced a long-lasting depression (rather than potentiation) of spinal dorsal horn field potentials. In separate but related Western immunoblot experiments, we also established that the chronic constriction injury was accompanied by significant decreases in the content of the GABA transporter GAT-1. These data demonstrated that GABA-A receptor agonists may effectively influence the expression of long-lasting synaptic plasticity in the spinal dorsal horn, and that an injury-induced loss in GABA transporter content may have contributed to a depletion of GABA from its terminals within the spinal dorsal horn. These data lent further support to the notion that the loss of GABA inhibition may have important consequences for the development of neuropathic pain.

Action Potentials↗
PubMed2002

Muscimol inhibition of medullary raphé neurons decreases the CO2 response and alters sleep in newborn piglets.

Medullary raphé neurons are chemosensitive in vitro (Wang et al., J. Physiol. Lond. 511 (1998)), are involved in the ventilatory response to CO(2) in vivo (Dreshaj et al., Respir. Physiol. 111 (1998); Nattie and Li, J. Appl. Physiol. 90 (2001)), and are abnormal in many Sudden Infant Death Syndrome (SIDS) victims (Panigrahy et al., J. Neuropathol. Exp. Neurol. 59 (2000)). In this study we determine whether the ventilatory response to CO(2) is altered when medullary raphé neuronal function is focally and reversibly inhibited in chronically instrumented newborn piglets. Ventilation was measured by whole body plethysmography in room air and in 5% CO(2) before and during microdialysis of muscimol, a gamma-amino butyric acid (GABA(A)) receptor agonist, into the medullary raphé. Muscimol (10 mM in the dialysate), had no effect on eupneic ventilation, but reduced significantly the CO(2) response by 17% during wakefulness. Sleep cycling was also disrupted, as characterized by a significant increase in the percentage of time spent awake and a significant decrease in the percentage of time spent in NREM sleep. Disturbances of medullary raphé function can alter central chemoreception and normal sleep architecture, which may contribute to the pathogenesis of SIDS.

Analysis of Variance↗
PubMedDate not supplied

The development of MK-801, kainate, AMPA, and muscimol binding sites in cat visual cortex.

Previous work using homogenate binding has shown that the development of (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10imin e maleate (MK-801) binding in cat visual cortex increases from 21 days to 42 days, the height of the plastic period, and decreases in adulthood. We have studied the generality of this finding by examining the development of NMDA binding sites in several brain regions and by examining the development of other binding sites in the visual cortex. After confirming the original finding, we extended it by showing that the sensitivity of MK-801 binding sites to glutamate and glycine decreases when the cat becomes an adult. We then examined the regional specificity of MK-801 binding. Retinal binding did not change significantly with age. Binding in both visual cortex and hippocampus increased significantly from 7 days to 42 days regardless of whether binding was measured per milligram wet weight or per milligram protein. The decline from 42 days to adulthood was less dramatic in the hippocampus than in the visual cortex and was statistically significant only when binding was measured per milligram protein. Saturation analyses also showed a difference in the two structures. Bmax in the visual cortex, but not in the hippocampus, decreased from 42 days to adulthood. To determine whether these developmental changes were specific to MK-801 binding sites, we compared the age-dependent binding of MK-801, kainate, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and muscimol. Like MK-801, kainate binding increased from 7 days to 42 days and decreased from 42 days to adulthood. AMPA and muscimol binding showed a similar increase in binding from 7 days to 42 days but did not decrease significantly from 42 days to adulthood. Displacement experiments suggest that AMPA and kainate bind to separate sites. The 42-day peak in NMDA and kainate binding suggests that their associated receptors may have a role in determining the plastic period of visual cortex.

Aging↗
PubMedDate not supplied

Muscimol and baclofen differentially suppress retinotopic and nonretinotopic responses in visual cortex.

This study relates to local field potentials and single-unit responses in cat visual cortex elicited by contrast reversal of bar gratings that were presented in single, double, or multiple discrete patch (es) of the visual field. Concurrent stimulation of many patches by means of the pseudorandom, binary m-sequence technique revealed interactions between their respective responses. An analysis identified two distinct components of local field potentials: a fast local component (FLC) and a slow distributed component (SDC). The FLC is thought to be a primarily postsynaptic response, as judged by its relatively short latency. It is directly generated by thalamocortical volleys following retinotopic stimulation of receptive fields of a small cluster of single cells, combined with responses to recurrent excitation and inhibition derived from the cells under study and immediately neighboring cells. In contrast, the SDC is thought to be an aggregate of dendritic potentials related to the long-range lateral connections (i.e. long-range coupling). We compared the suppressive effects of a GABA(A)-receptor agonist, muscimol, on the FLC and SDC with those of a GABA(B)-receptor agonist, baclofen, and found that muscimol more strongly suppressed the FLC than the SDC, and that the reverse was the case for baclofen. The differential suppression of the FLC and SDC found in the present study is consistent with the notion that intracortical electrical signals related to the FLC terminate on the somata and proximal/basal dendrites, while those related to the SDC terminate on distal dendrites.

Animals↗
PubMed1992

Condensation of muscimol or thiomuscimol with aminopyridazines yields GABA-A antagonists.

Ten analogs of muscimol and thiomuscimol in which the amino function was delocalized in an amidinic system were prepared by N2 alkylation of 6-aryl-3-aminopyridazines with (chloromethyl)isoxazole or (chloromethyl)isothiazole derivatives. These muscimol and thiomuscimol derivatives show potent binding properties for GABA-A receptors (they displace [3H]GABA and [3H]gabazine) and provoke convulsions after iv injections. They fit well with the model pharmacophore proposed by our group for the GABA-A antagonists and show similar structure-activity profiles to that of the pyridazinyl-GABAs.

Animals↗
PubMed1993

Nucleus basalis magnocellularis and attention: effects of muscimol infusions.

The basal forebrain is important in cognitive processing. Most studies have focused on the importance of this area in mnemonic processing. However, the nucleus basalis magnocellularis (NBM), which is a major component of the basal forebrain, may also be involved in attentional processes. Attention can influence the sensitivity of perceptual processes, as assessed by discriminability, or the selection of response strategies, as assessed by bias. This experiment examined whether temporary inactivation of the NBM, using the GABA agonist muscimol, would interfere with attention. Each rat was tested in a 2-choice reaction time (RT) task in which stimulus frequency was varied. RT and error rate increased, and discriminability decreased following muscimol infusions into the NBM. Bias was unchanged. The pattern of results provides evidence that the NBM is important in attention, and this influence of the NBM acts primarily on perceptual aspects of attention.

Animals↗
PubMed1994

Effects of muscimol applied to the basolateral amygdala on acquisition and expression of contextual fear conditioning in rats.

The amygdala is known to be important for normal aversive Pavlovian learning in the rat. The relative contribution of the amygdala to the learning vs. performance of conditional fear with the GABAa agonist muscimol was assessed. Rats were prepared with cannulas aimed at the basolateral amygdala and trained in a contextual fear conditioning paradigm in which each subject received a series of footshocks in a distinctive observation chamber. Conditional responses evoked after exposure to the observation chamber were assessed 24 hr later. Rats that were pretreated with muscimol before performance showed a significantly attenuated fear response, and injections made before acquisition resulted in a much smaller decrement in conditional fear measured 24 hr after training. These results indicate that acquisition-related processes that may be occurring within the amygdala are more difficult to disrupt than those associated with performance.

Amygdala↗
PubMed2004

Hippocampus and Pavlovian fear conditioning in rats: muscimol infusions into the ventral, but not dorsal, hippocampus impair the acquisition of conditional freezing to an auditory conditional stimulus.

The authors compared the effects of pharmacological inactivation of the dorsal hippocampus (DH) or ventral hippocampus (VH) on Pavlovian fear conditioning in rats. Freezing behavior served as the measure of fear. Pretraining infusions of muscimol, a GABAA receptor agonist, into the VH disrupted auditory, but not contextual, fear conditioning; DH infusions did not affect fear conditioning. Pretesting inactivation of the VH or DH did not affect the expression of conditional freezing. Pretraining electrolytic lesions of the VH reproduced the effects of muscimol infusions, whereas posttraining VH lesions disrupted both auditory and contextual freezing. Hence, neurons in the VH are importantly involved in the acquisition of auditory fear conditioning and the expression of auditory and contextual fear under some conditions.

Acoustic Stimulation↗
PubMed1989

The effects of the GABA agonist muscimol upon blood flow in different vascular territories of the rat cortex.

Local cerebral blood flow was measured in five regions of rat cortex immediately following intravenous administration of the gamma-aminobutyric acid (GABA) agonist muscimol. In contrast to recent observations, no increases in blood flow were found at either of the two time points analysed, and the data revealed that decreases in blood flow previously reported 30 min after muscimol treatment were in evidence as early as 30 s. These results are totally consistent with the conclusion that the overall effects of GABA agonists in the intact animal are to reduce blood flow in line with reduced metabolic demand in the neuropil. However, the heterogeneity of the reductions in cortical blood flow found here possibly suggests a biological role for vascular GABA systems in providing a mitigating influence on fluctuating tissue perfusion.

Animals↗
PubMed2003

Spatial learning deficits induced by muscimol and CL218,872: lack of effect of prenatal malnutrition.

The sensitivity of prenatal protein malnourished rats to the amnestic properties of the direct GABAA receptor agonist muscimol and the selective benzodiazepine (BZ) receptor agonist, CL218,872, was studied in the male offspring of rats provided with a protein deficient diet (6% casein) for 5 weeks prior to mating and throughout pregnancy. At postnatal day 90, rats were tested during acquisition of the submerged platform version of the Morris water maze task using four systemic doses of muscimol (0.1, 0.3, 1.0 and 1.8 mg/kg i.p.) or three systemic doses of CL218,872 (1.0, 3.2, and 5.6 mg/kg i.p.). In a dose dependent manner both drugs impaired acquisition of the task and impaired accuracy of the search pattern on the probe trial (platform removed). However, neither drug dissociated the performance of the two nutritional groups. These data are important in light of previous findings of differential behavioral effects of the non-specific BZ agonist, chlordiazepoxide (CDP), on spatial learning and on drug discrimination in prenatally malnourished rats and in the context of previous findings of reduced sensitivity to the anxiolytic effects of non-specific BZ receptor agonists across a wide variety of models of malnutrition. The present findings also support the concept that prenatal malnutrition does not affect the global functioning of the GABAA receptor, but fundamentally alters the way in which a subset of GABAA receptors (i.e. those containing the alpha2, alpha3 and/or the alpha5 but not the alpha1 subunit) is modulated by BZs.

Animals↗
PubMed2001

Lidocaine and muscimol microinjections in subthalamic nucleus reverse Parkinsonian symptoms.

Inactivation of neurones in the subthalamic nucleus (STN) of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treated monkey model of Parkinson's disease has been shown to relieve parkinsonian motor symptoms. In patients with Parkinson's disease, neurones in the STN display hyperactive firing rates and rhythmic discharge activity such as tremor-related oscillations (3-8 Hz) and synchronous high-frequency oscillations (15-30 Hz). In this study, microinjections of lidocaine (n = 4) and muscimol, a GABA(A) receptor agonist (n = 2), were performed in the STN of six patients with Parkinson's disease to determine whether the focal suppression of STN neuronal activity can lead to an improvement in tremor, bradykinesia and rigidity. We also report the first use of microelectrode recording of the effects of microinjections on neuronal activity in the human brain (n = 2). Microinjections of 10-23 microl of lidocaine produced striking improvements in bradykinesia, limb tremor and rigidity in three out of three patients. These improvements were correlated with good therapeutic effects of subsequent STN deep brain stimulation performed in the same microelectrode trajectories as these injections. The most dramatic observation following lidocaine injections was the appearance of dyskinetic limb movements. In one patient, simultaneous microelectrode recording during an injection of 3.5 microl of lidocaine demonstrated a suppression of neuronal activity at distances of < 0.9 mm from the injection site, but no suppression was observed at > or = 1.2 mm from the injection site. Microinjections of 5-10 microl of muscimol in a region with tremor-related activity resulted in suppression of limb tremor in two out of two patients. Interestingly, in one of these patients, 4 Hz oscillatory activity was diminished in a neurone recorded 1.3 mm from the injection site, but there was no reduction in the mean firing rate or 20 Hz oscillatory activity. These results demonstrate that inactivation of neuronal activity in the STN of patients with Parkinson's disease improves motor symptoms. These findings also suggest that a focal block of the STN might alter the oscillatory activity of neurones located beyond the inhibited region.

Aged↗
PubMed1992

Muscimol suppresses rCGU increase in the substantia nigra after destruction of the caudate nucleus.

Injection of ibotenic acid into the caudate nucleus caused an increase in the uptake of 2-deoxyglucose (2DG) in the ipsilateral substantia nigra pars reticulata (SNr). Increased 2DG uptake was completely suppressed by chronic infusion of muscimol, the gamma-aminobutyric acid (GABA) agonist. While delayed shorter infusion of muscimol from the 3rd to the 7th day, when 2DG accumulation was the most prominent, partially prevented this increase. These data suggest that GABA-mediated transneuronal processes play an important role in the delayed elevation in 2DG uptake in SNR but hyperexcitation due to disinhibition by the loss of GABAergic inputs may play only a partial role in this increase.

Animals↗