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PubMed1995

Zinc modulation of GABAA receptor-mediated chloride flux in rat hippocampal slices.

We studied the effect of ZnCl2 application on GABAA receptor-mediated 36CI- flux in microsacs prepared from whole rat hippocampus and in region-specific hippocampal slices. Slices were obtained from the dentate gyrus (DG), which contains the zinc-enriched hilar region, and from the CA1 region which contains lower levels of endogenous zinc. Muscimol (10 microM)-evoked 36Cl- flux was significantly reduced by ZnCl2 (100 microM) in hippocampal microsacs. In hippocampal slices, muscimol (50 microM)-evoked 36Cl- efflux was higher in CA1 (112.5 +/- 27.9% above basal efflux rate) than in DG slices (29.7 +/- 5.6%). In the presence of ZnCl2, the muscimol effect on efflux rate in CA1 and DG regions was decreased to 10.6 +/- 5.4% and 6.9 +/- 4.9%, respectively. Preincubation with the zinc chelator, tetrakis(2-pyridylmethyl)ethylenediamine (TPEN, 20 microM), caused a significant increase in muscimol-evoked 36Cl- efflux only in DG slices (57.2 +/- 7.0%), suggesting that GABAA receptors in the DG of rat hippocampus under physiological conditions may function under the inhibitory influence of endogenous chelatable zinc. In intracellular recordings, ZnCl2 (100 microM) application had no effect on the responses to GABA applied perisomatically or in the dendritic region of CA1 neurons. The lack of Zn2+ effect on the postsynaptic GABAA receptor-mediated responses suggests that the decreases of the 36Cl- efflux observed in the biochemical assays may be due to zinc action on neurons other than the principal pyramidal CA1 cells, and possibly the non-neuronal cell populations.

Animals↗
PubMed1995

GABAergic inhibitory inputs to subfornical organ neurons in rat slice preparations.

To investigate GABAergic inhibitory inputs to neurons of the subfornical organ (SFO), intracellular recordings were made in rat brain slice preparations. Inhibitory postsynaptic potentials, which occurred spontaneously or were evoked by focal electric stimulation, had reversal potentials of approximately -60 mV, and were almost totally abolished by the GABAA antagonists bicuculline at 3-100 microM or picrotoxin at 50 microM. Following the application of bicuculline or picrotoxin, the resting membrane potentials were decreased by 4-8 mV. GABA at 10-100 microM and the GABAA agonist muscimol at 1-100 microM decreased the membrane resistance and the firing rate in all neurons tested. The reversal potential of the response to muscimol was similar to that for inhibitory postsynaptic potentials. The actions of muscimol persisted in the presence of 1 microM tetrodotoxin, implying that muscimol must act directly on the recorded neurons. These results suggest that there is a tonic inhibitory GABAergic input to SFO neurons which are mainly mediated through GABAA receptors.

Animals↗
PubMed1984

The role of the colliculus superior in the expression of muscular rigidity.

Muscular rigidity, recorded as tonic activity in the electromyogram of the gastrocnemius-soleus muscle in the rat was produced by bilateral injections of muscimol (37.5-75 ng) into the intermediate or deep layers of the colliculus superior. This effect of muscimol was not only dose-dependent but also gamma-aminobutyric acid (GABA)-specific since it could be prevented by coadministration of the GABA antagonist bicuculline methiodide. Injections of muscimol into either the superficial layers of the colliculus superior or the underlying reticular formation were without effect in this respect. These results indicate that the region containing the terminals of the nigrocollicular pathway is involved in the expression of muscular rigidity (recorded as a tonic EMG activity). Muscimol injections into the colliculus superior did not lead to catalepsy thus providing additional evidence for the notion that muscular rigidity and catalepsy are two separate phenomena which are in part mediated by different neuronal pathways.

Animals↗
PubMed1984

Interactions of two phenylquinolines with picrotoxin and benzodiazepines in vivo and in vitro.

PK 8165 and PK 9084 are phenylquinolines with high affinity for the benzodiazepine binding site. Both phenylquinolines were proconvulsant in combination with subconvulsant doses of picrotoxin and pentylenetetrazole in mice. Both chlordiazepoxide (10 mg/kg) and the imidazodiazepine, RO 15-1788 (10 mg/kg) prevented these tonic-clonic convulsions. In vitro studies of rat cuneate nucleus indicated that the proconvulsant actions of PK 8165 and PK 9084 could be explained by their direct, albeit slightly different, interactions with the GABA-receptor complex. PK 8165 (100 microM) alone had no effect on responses to the GABA analogue muscimol, but enhanced the potency of picrotoxin as an antagonist of muscimol and reduced the potency of flurazepam as a potentiator of muscimol. PK 9084 (100 microM) alone caused a small antagonism of muscimol, but did not affect the potency of picrotoxin; flurazepam reversed the effect of PK 9084.

Animals↗
PubMed1986

Effect of GABAergic drugs in the behavioral 'despair' test in rats.

Aminooxyacetic acid (AOAA, 25 mg/kg i.p.), muscimol (2 mg/kg i.p.) and 4,5,6,7-tetrahydroisooxazol-[4,5-c]-pyridin-3-ol (THIP, 5 and 10 mg/kg s.c.), but not baclofen (10 mg/kg i.p.) administered three times (24, 5 and 1 h before the test) decreased the immobility time of rats in the behavioral 'despair' test. At these doses, AOAA, muscimol and THIP reduced motor activity. Muscimol (2 mg/kg) and THIP (5 and 10 mg/kg) exerted the antiimmobility effect even after single dosing 1 h before the test. Picrotoxin (1 and 2 mg/kg i.p.), but not bicuculline (2 mg/kg i.p.), prevented the effect of both muscimol and THIP in the behavioral 'despair' test.

Acetates↗
PubMed1988

Regulation of respiratory motor outflow to the larynx and diaphragm by GABA receptors.

Effects of intracisternal administration of the gamma-aminobutyric acid receptor agonist, muscimol, on recurrent laryngeal and phrenic nerve activities were assessed in the cat. Muscimol (0.1-2.4 micrograms) produced a dose-related inhibition of the respiratory activity in both of these nerves. The inhibition was seen as a decrease in the amplitude of nerve activity with no significant change in respiratory rate. The ED50 values for muscimol and its 95% confidence interval for inhibition of the inspiratory activity in the recurrent laryngeal and phrenic nerves were 0.22 micrograms (0.17-0.29) and 0.27 micrograms (0.19-0.38), respectively. The potency of muscimol for inhibition of these nerve activities was not significantly different. Expiratory activity in the recurrent laryngeal nerve was completely inhibited prior to either the inspiratory activity in this nerve or in the phrenic nerve. Intracisternal administration of the gamma-aminobutyric acid receptor antagonist, bicuculline, rapidly reversed the inhibition in both nerves. Reversal times for inhibition of the inspiratory activities in the recurrent laryngeal and phrenic nerves were not significantly different. Return of inspiratory activity in each nerve always preceded the return of expiratory activity in the recurrent laryngeal nerve. These results demonstrate that CNS gamma-aminobutyric acid receptors are involved in the regulation of respiratory motor outflow to the larynx as well as the diaphragm.

Animals↗
PubMed1986

Age-related substantia nigra-mediated seizure facilitation.

We investigated the role of the GABAergic system of the substantia nigra in seizures of rat pups. Rat pups had bilateral cannulae implanted chronically either in the substantia nigra or 1.5 mm dorsal to it. At age 16 to 17 days, seizures were induced in the cannulated rats and naive (intact) controls by exposure to flurothyl following pretreatment with the GABA agonist, muscimol, or vehicle. Naive rats were the most resistant to flurothyl seizures. Bilateral nigral infusions of muscimol markedly facilitated the development of flurothyl seizures in a dose-response manner and differed significantly from the vehicle controls or rats infused with muscimol dorsally to the substantia nigra. In contrast, bilateral nigral muscimol infusions protected adult rats against the development of flurothyl seizures. Our data indicate that the effects of nigral GABA agonist infusions on seizures are age-dependent; the altered responsivity of the GABAergic nigral system in immature rats may be responsible in part for the increased seizure susceptibility of the developing central nervous system.

Animals↗
PubMed1995

Drosophila GABA-gated chloride channel: modified [3H]EBOB binding site associated with Ala-->Ser or Gly mutants of Rdl subunit.

The non-competitive blocker site of the GABA-gated chloride ion channel in normal susceptible strains of Drosophila melanogaster and simulans binds 4-n-[3H]propyl-4'-ethynylbicycloorthobenzoate ([3H]EBOB) at specific sites with KdS of 1.6-1.9 nM and BmaxS of 171-181 fmol/mg protein. This specific binding of [3H]EBOB is strongly inhibited by: a large number and variety of insecticidal channel blockers at 20 nM (lindane, alpha-endosulfan, dieldrin, 12-ketoendrin, fipronil, and a representative bicycloorthobenzoate and dithiane) or 200 nM (picrotoxinin); the insecticidal channel activators avermectin and moxidectin at 20 nM; muscimol at 30 microM and GABA at 300 microM. Cyclodiene resistance in D. melanogaster has been attributed to a mutation resulting in an Ala302-->Ser replacement in the Rdl GABA receptor subunit and in D. simulans to an homologous Ala-->Ser or Gly replacement. These mutations are shown here to greatly reduce [3H]EBOB binding, i.e. lower affinity and apparent number of binding sites. The Ala-->Ser replacement with both melanogaster and simulans almost always reduces the potency in inhibiting [3H]EBOB binding of each of eight channel blockers and of muscimol and GABA. The Ala-->Gly replacement in D. simulans is generally less effective than the Ala-->Ser modification in reducing sensitivity to the channel blockers and to muscimol and GABA. The channel activators avermectin and moxidectin usually retain their inhibitory potency in the Rdl subunit mutants. Thus, it appears that replacement of Ala by Ser generally modifies the non-competitive blocker site and its coupling to the GABA-recognition site with less effect on the channel activator site. In contrast, the Ala-->Gly replacement has less impact in protecting the chloride channel from the action of insecticidal blockers. Each of the resistant strains has the same level of resistance to the lethal action of the five channel blockers examined but none to avermectins and muscimol.

Alanine↗
PubMed1988

The ontogeny of GABA receptors and glutamic acid decarboxylase in regions of the rat brain. Effect of prenatal exposure to diazepam.

The postnatal development of the binding of [3H]muscimol to both high-affinity and low-affinity GABA receptors and of the activity of glutamic acid decarboxylase has been studied in the frontal cortex, cerebellum, striatum and hypothalamus of the rat, after prenatal exposure to diazepam. The dams were injected subcutaneously with single daily doses of 1 mg diazepam/kg from day 7-20 of gestation. The developmental profiles of the binding of [3H]muscimol to high-affinity GABA receptors were very similar in both control and diazepam-treated offspring. Prenatal administration of drug revealed no significant alteration in the binding of [3H]muscimol. The results in controls supported the concept of a sequential development of this population of GABA receptors in relation to the different maturation of structures in the brain. For the study of low-affinity GABA receptors, the dams were treated in the same way and, additionally, 1 mg diazepam/kg/day was injected subcutaneously in the offspring from postnatal day 5-10. At postnatal days 21 and 90, no qualitative or quantitative differences in the binding of [3H]muscimol to low-affinity GABA receptors in control and diazepam-exposed groups of animals were observed. The developmental profiles of the activity of glutamic acid decarboxylase were qualitatively very similar in the four areas of the brain studied. Prenatal exposure to diazepam revealed a transient elevation of the activity of the enzyme up to 33% in the frontal cortex, the cerebellum and the hypothalamus in the first postnatal week. The possible functional significance of these alterations is discussed.

Animals↗
PubMed1996

Regional age-related alterations in cholinergic and GABAergic receptors in the rat brain.

The age-related changes of cholinergic and gamma-aminobutyric acid (GABA)ergic receptors were studied in 3-week- and 6-, 12-, 18- and 24-month-old Fisher 344 male rat brains using receptor autoradiography. [3H]Quinuclidinyl benzilate (QNB), [3H]hemicholinium-3 (HC) and [3H]muscimol were used to label acetylcholine receptors, acetylcholine reuptake sites and GABAA receptors, respectively. In immature rats (3-week-old), [3H]QNB and [3H]muscimol binding showed a significant increase in most brain areas, compared to adult young animals (6-month-old), whereas [3H]HC binding exhibited a significant increase only in the dentate gyrus, substantia nigra and cerebellum. In contrast, [3H]QNB and [3H]HC binding showed no significant changes in all brain areas during aging. On the other hands, [3H]muscimol binding showed a significant reduction in the substantia nigra and cerebellum of adult mature rats (12-month-old). Thereafter, the age-related reduction in [3H]muscimol binding was observed in all brain areas of aged rats (24-month-old). Our results demonstrate that the GABAergic system is susceptible to aging processes in the central nervous system, whereas the cholinergic system is unaltered by aging. Furthermore, our results suggest significant regional changes in both GABAergic and cholinergic systems in the brain even 3 weeks after birth. These findings suggest that the disturbance in GABAergic-cholinergic interactions may play a key role in age-related neurological deficits and cognitive dysfunction.

Aging↗
PubMed1983

Variations in response of the GABA-picrotoxin-benzodiazepine receptor complex to flurazepam.

Two effects of flurazepam have been studied on electrophysiological responses to muscimol in a slice preparation of rat cuneate nucleus. Flurazepam potentiated the responses to muscimol and also reduced the antagonism of these responses by picrotoxin. Repeated series of experiments over a 3 year period showed significant variations in the potentiation of muscimol by flurazepam which were negatively correlated with the apparent reduction in picrotoxin potency. A more reproducible reduction in picrotoxin potency by flurazepam was obtained when the data were re-calculated to take account of the possibility that picrotoxin might antagonize the potentiating effect of flurazepam as well as the direct response to muscimol. The simplest explanation of this relationship is that flurazepam and picrotoxin mutually antagonize each others effects on the GABA system. The underlying cause of the variation in flurazepam effect remains unknown.

Animals↗
PubMed1990

GABAergic mechanisms in the nucleus accumbens septi regulating rat motor activity: the effect of chronic treatment with desipramine.

The influence of chronic treatment with desipramine upon GABAergic mechanisms within the nucleus accumbens septi (NAS) affecting rat motor behavior was studied in the automatic open fields. It was shown that intra-accumbens injections of picrotoxin on one hand and muscimol and baclofen on the other, produced dose-dependent increase or decrease in rat motility, respectively. Locomotor stimulation usually observed after picrotoxin did not occur in rats given local injections of a solution containing both picrotoxin and GABA A receptor agonist muscimol. Muscimol (130 ng as a pure compound) blocked also hypermotility produced by intra-accumbens administration of dopamine releasing drug d-amphetamine (10 micrograms). This part of the experiment was summarized as indicating that both GABA A and GABA B receptor-related mechanisms, which are under negative control of dopaminergic neurons in the NAS, play an important role in regulating behavior in the rat. In the second part of the experiment it was observed that chronic treatment of rats with desipramine (DMI) (10 mg/kg, PO, twice daily for 21 days, rats were tested 24 hr after the last dose of the drug) significantly attenuated or blocked the inhibitory effect on locomotion of both baclofen and muscimol. The stimulatory influence of picrotoxin seemed also to be diminished, but it still attained the level of accepted statistical significance. On the basis of these and other data it is concluded that observed changes in the effects of GABAergic agonists in DMI-treated rats are probably due to an enhancement of local dopaminergic mechanisms, thus leading to the potentiation of a negative interaction between dopaminergic and GABAergic mechanisms within the NAS.(ABSTRACT TRUNCATED AT 250 WORDS)

Adaptation, Physiological↗
PubMed1992

Nonserotonergic control of nucleus accumbens dopamine metabolism by the median raphe nucleus.

Injections of the GABA agonist muscimol into the median raphe nucleus (MR) have been shown to result in an acceleration of dopamine metabolism within the nucleus accumbens. To examine whether serotonergic mechanisms play a role in this effect, muscimol or its vehicle was injected into the MR of either control subjects or of rats that had received prior injections of the serotonin-depleting agent p-chlorophenylalanine (PCPA). Although PCPA treatments produced massive depletions of forebrain serotonin, they failed to alter the effect of muscimol infusions on dopamine metabolism. This finding suggests that the effects of intra-MR injections of muscimol on accumbens dopamine turnover do not result entirely from an interaction between serotonergic and dopaminergic systems.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1986

Ontogeny of the GABA receptor complex in chick brain: studies in vivo and in vitro.

The ontogeny of the gamma-aminobutyric acid-A (GABAA) receptor complex in the chick brain was studied by specific binding of [3H]muscimol, [3H]flunitrazepam (Flu) and [35S]t-butylbicyclophosphorothionate (TBPS) to isolated membranes. During development in ovo, the specific binding of muscimol and flunitrazepam increased from day 8 and reached 50% of adult levels of day 20, while a comparable level of TBPS binding was achieved by day 17. The increases in TBPS and Flu binding were reflected in Bmax rather than Kd changes. In embryonic brain, only a low-affinity site for muscimol (Kd = 23 nM) was observed while an additional high-affinity site (Kd = 0.4 nM), as well as the low-affinity site, was found in adult tissue. Similar studies were carried out with cultures of cerebral neurons prepared from 8-day embryos. The level of specific binding of muscimol, Flu and TBPS increased in culture, achieved one half of the maximum level by days 4-5, maximal levels by day 10 and decreased slowly thereafter. The maximal levels in culture corresponded, respectively, to 27%, 67% and 57% of these found in the 18-day embryo. The binding of Flu to membranes from neurons, embryos and adults was enhanced by addition of GABA while TBPS binding was inhibited. The EC50 and IC50 values for these effects corresponded to those for gating of chloride channels. These findings indicate a coordinated expression of receptors for GABA, benzodiazepines and convulsant/TBPS during neuronal maturation both in vivo and in vitro. The schedule for this postsynaptic ontogeny is very similar to that for presynaptic markers of GABAergic neurons (see companion paper).

Animals↗
PubMed1991

Adult-like biphasic neurobehavioral changes induced by a GABA-A agonist in infant and weanling mice.

The neurobehavioral responsivity to peripherally injected muscimol, a gamma-aminobutyric acid-A (GABA-A) agonist, was assessed in infant (14-day-old), weanling (20-day-old) and young adult (53-day-old) outbred male mice. In the first experiment, relatively high doses of muscimol (ranging from 0.05 to 0.40 mg/kg in developing and from 0.50 to 3 mg/kg in adult animals) were found to dose-dependently induced solid catalepsy and ataxia, evaluated 5 times at 20-min intervals. In the second experiment, the GABA agonist was injected in dose ranges which include relatively small concentrations in order to assess its excitatory properties, observable in adults, on rearing and locomotion in developing mice. It appeared that levels of rearing and especially locomotion were enhanced at the low doses (0.025 and 0.050 mg/kg in developing, and 1.3 and 1.9 mg/kg in adult mice) and inhibited at the higher ones (0.150 mg/kg in developing and 1.9 and 2.5 mg/kg in adult mice). This adult-like biphasic action of muscimol in developing mice--excitation at low and depression/sedation at high doses--strongly suggests a full maturation of the GABA-A-related behavioral functions at a period of ontogeny where adult-like locomotion emerges. Given that previous studies have shown that muscimol can biphasically affect behavioral activity in newborn murines as well, it is suggested that GABA-related behavioral functions mature near-monotonically during ontogeny, unlike those related to other major neurotransmitter systems.

Aging↗
PubMed1982

Locomotor activity of rats in open field after microinjection of procaine into superior colliculus or underlying reticular formation.

Whereas large lesions of the superior colliculus in rats increase locomotor activity in the open field, bilateral collicular microinjections of muscimol (an agonist of the inhibitory neurotransmitter GABA) have been reported to reduce open-field activity. This difference might be due to muscimol's acting on a subpopulation of collicular neurones, or to some feature of the microinjection technique. The issue was investigated by observing open-field behavior after reversible lesions produced by bilateral microinjections of the local anaesthetic procaine (10-300 micrograms in 0.5 microliter) into midbrain sites. Injections of procaine into the superior colliculus produced effects similar to those reported after muscimol injections: both locomotor activity and other exploratory responses were suppressed, with the rats spending much of their time motionless in an alert posture. In contrast, animals with injections of procaine into the mesencephalic reticular formation (MRF) ventral to the superior colliculus resembled rats given large collicular lesions: they showed very striking increases in locomotor activity, while their rearing and exploratory head movements were reduced. It is suggested that in some experiments large collicular lesions may have increased locomotor activity in the open field because they invaded underlying MRF. However, it is also possible that in rodents the acute effects of collicular inactivation, as assessed by microinjection of muscimol or procaine, are different from the chronic effects that are observed in experiments with electrolytic or radiofrequency lesions.

Animals↗
PubMed1992

The interstitial nucleus of Cajal is involved in generating downward fast eye movement in alert cats.

We examined whether or not the interstitial nucleus of Cajal (INC) is involved in generating vertical fast eye movement. We used a gamma-aminobutyric acid (GABA) agonist (muscimol) to deactivate the INC cell bodies bilaterally in alert head-fixed cats. The INC was identified by recording vertical eye position-related burst-tonic neurons. Following muscimol infusion into the bilateral INC, the cats were unable to hold eccentric upward eye position after saccades, and the mean time constant of postsaccadic drift was 0.4 sec. In addition, downward saccades were virtually lost without clear impairment of horizontal saccades. Muscimol infusion into the Forel's field H resulted in loss of both upward and downward fast eye movement as reported previously. Bilateral electrolytic INC lesions produced results similar to those after muscimol infusion into the INC, suggesting that the cutting of passing fibers in the INC alone cannot explain the selective loss of downward fast eye movement. These results indicate that the INC itself is involved in generating downward fast eye movement. We propose that the loss of activity in possible downward burster-driving neurons in the INC can explain the selective loss of downward fast eye movement after bilateral INC lesions.

Animals↗
PubMed1990

Enkephalin biosynthesis and release in mouse striatum are inhibited by GABA receptor stimulation: compared changes in preproenkephalin mRNA and Tyr-Gly-Gly levels.

In order to assess changes in enkephalin release and biosynthesis, the levels of the tripeptide Tyr-Gly-Gly (YGG), a characteristic extracellular metabolite of enkephalins, and of the proenkephalin mRNA in mouse striatum were evaluated after a single administration of GABAergic agents. Significant and long-lasting decreases in steady state YGG levels were elicited by muscimol, a gamma-aminobutyric acid-A (GABAA) receptor agonist, diazepam, a benzodiazepine receptor agonist, or aminooxyacetic acid, a GABA-transaminase inhibitor. In addition, muscimol offset the elevation of striatal YGG elicited by bestatin, an aminopeptidase inhibitor, which entirely drives the released enkephalins into the metabolic pathway operated by enkephalinase (EC 3.4.24.11). Diazepam potentiated the effect of muscimol so that the YGG decrease induced by the combination of these two drugs was maximal after 30 min (-60%) and still significant (-40%) after 6 h, this potentiation being antagonized by pre-treatment with Ro 15-1788, a specific benzodiazepine receptor antagonist. By contrast [Met5]enkephalin steady-state levels were marginally affected by GABAergic agents, being only slightly reduced 6 h after the combination of muscimol and diazepam. After 3 h the same treatment also reduced by about 30% the level of proenkephalin mRNA, this change being maximal after 6 h (-45%) and still present after 24 h. These compared changes in various indexes of enkephalin neuron activity suggest that stimulation of GABAA receptors depresses enkephalin release immediately and for several hours, whereas preproenkephalin gene expression is decreased in a somewhat delayed and longer lasting manner. These patterns of temporal changes in biosynthesis and release of the neuropeptide presumably account for the limited changes in its steady state levels.

Aminooxyacetic Acid↗