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PubMed1989

Cerebellar GABAA receptor binding and function in vitro in two rat lines developed for high and low alcohol sensitivity.

The Bmax of the [3H]muscimol binding in the cerebellum of ethanol-naive alcohol-sensitive ANT (Alcohol Non-Tolerant) rats was only about 70% of that in the alcohol-insensitive AT (Alcohol Tolerant) rats. There were no line differences in the muscimol binding to cerebrocortical and hippocampal membranes. In the alcohol-sensitive rats, the cerebellar [3H]muscimol binding (5 nM) negatively correlated with the ethanol-induced motor-impairment measured in the tilting plane test. Muscimol stimulated the flux of 36Cl- in cerebellar synaptoneurosomes and non-filtered microsacs to the same extent in both rat lines. Ethanol produced only a small, although statistically significant, enhancement of the muscimol-stimulated chloride flux in both rat lines. The present data confirms our earlier finding of a low level of muscimol binding in the cerebellar membranes of alcohol-sensitive rats as compared to alcohol-insensitive rats. Further studies are needed to determine the relationship between the Cl- flux stimulation by muscimol and the differential muscimol binding in the cerebellum of these rat lines, and its importance for alcohol sensitivity.

Alcohol Drinking↗
PubMed1987

Movements of cats on a rotating cylinder: role of the substantia nigra pars reticulata and the deeper layers of the superior colliculus.

Recently it has been shown that the substantia nigra pars reticulata (SNR) is required for adjusting the body position. In this study the role of the SNR in the execution of movements was investigated. Therefore, the effects of bilateral SNR injections of picrotoxin (500 ng/0.5 microliter) and muscimol (200 ng/1 microliter) were investigated on movements of cats which were trained to cross a rotating cylinder. SNR injection of picrotoxin suppressed the movements that were executed by cats injected with distilled water (0.5 microliter), i.e. 'normal movements'. While crossing the rotating cylinder, picrotoxin-injected cats mainly executed movements that almost never occurred in distilled water treated cats. Picrotoxin-injected cats executed 'special movements', i.e. forward locomotion in which the hindlimbs were affected, and 'counter-movements'. While executing the latter movements no forward locomotion occurred at all; the cats solely executed lateral fore- and hindlimb movements opposite to the direction in which the cylinder rotated. SNR application of muscimol enhanced the execution of 'normal movements'. Since the SNR sends information to the deeper layers of the superior colliculus (dl-SC) via GABAergic fibers, it was also investigated whether pharmacological stimulation (muscimol) and inhibition (picrotoxin) of the GABAergic dl-SC activity affected these movements on the rotating cylinder: no changes were observed after injecting otherwise effective doses of muscimol (75 ng/1 microliter) and picrotoxin (100 ng/0.5 microliter). In order to compare the function of the SNR and dl-SC in programming a different type of movements, the effects of GABAergic agents in the dl-SC (picrotoxin 100 ng/0.5 microliter and muscimol 75 ng/1 microliter) and the SNR (picrotoxin 500 ng/0.5 microliter and muscimol 200 ng/1 microliter) were investigated on the feline ability to execute goal-directed movements in an experimental set-up that prevented the occurrence of targeting movements which were continuously guided by external, i.e. auditory, visual, tactile and olfactory stimuli. For that purpose cats were trained to step out of a startbox on a rotating cylinder, i.e. the target. Dl-SC injection of muscimol or SNR application of picrotoxin prevented the cats from stepping out of the startbox on the rotating cylinder. In contrast, cats injected with muscimol into the SNR or picrotoxin into the dl-SC stepped out of the startbox, although dl-SC application of picrotoxin elicited forelimb misplacements: frequently the cats placed their forelimbs alongside of, but not on the cylinder when trying to leave the startbox.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1983

Role of the ventromedial nucleus of the thalamus in motor behaviour--I. Effects of focal injections of drugs.

An assortment of drugs was injected into one or both ventromedial nuclei of the thalamus, to see how these influenced stereotypy, locomotion and posture in spontaneously behaving and actively rotating rats. Unilateral intrathalamic muscimol promoted weak ipsiversive circling, while bilateral treatment gave catalepsy. Similar injections of 4-amino-hex-5-enoic acid, which inhibits gamma-aminobutyrate metabolism, raised gamma-aminobutyrate levels in the ventromedial nuclei more than three-fold yet had none of these behavioural effects. The indirectly acting gamma-aminobutyrate agonists flurazepam and cis-1,3-aminocyclohexane carboxylic acid had little effect on posture and locomotion and, like muscimol and 4-amino-hex-5-enoic acid, elicited only very weak stereotypies. Procaine behaved like the gamma-aminobutyrate antagonist bicuculline, provoking vigorous locomotor hyperactivity and teeth chattering if given uni- or bilaterally. Pretreatment of one ventromedial nucleus with muscimol or 4-amino-hex-5-enoic acid, and to a lesser extent flurazepam or cis- 1,3-aminocyclohexane carboxylic acid, gave rise to pronounced ipsilateral asymmetries when combined with a large systemic dose of apomorphine. Contraversive rotations were initiated by unilateral stereotaxic injection of muscimol into the substantia nigra pars reticulata, or with apomorphine from the supersensitive striatum in unilaterally 6-hydroxydopamine lesioned rats. Drug treatments in the ipsilateral ventromedial nucleus showed a similar rank order of potency at inhibiting these circling behaviours, seemingly by reducing apomorphine-induced posture and muscimol-induced hypermotility. The suppression of circling by muscimol in these tests was highlighted by introducing the compound into the ventromedial nucleus at the height of circling activity. Both types of circling stimulus lost the capacity to increase locomotion, but still caused head turning and stereotypy in rats made cataleptic with bilateral ventromedial muscimol. Treating one ventromedial thalamus with muscimol greatly intensified any pre-existing posture directed towards that side, and vice versa. These data suggest that the ventromedial nucleus is not involved with the expression of stereotyped behaviours, but can profoundly influence posture and locomotion, especially in the presence of some other motor stimulus. The recovery of circus movements in rats with impaired ventromedial nucleus function implies this nucleus is not essential for the execution of circling in these models.

Amino Acids↗
PubMed1992

Effects of acute pentobarbital administration on GABAA receptor-regulated chloride uptake in rat brain synaptoneurosomes.

Effects of acute pentobarbital administration on GABAA receptor-regulated muscimol-stimulated, pentobarbital-stimulated, or flunitrazepam-enhanced, muscimol-stimulated chloride uptake were studied in the brains of Sprague-Dawley rats. Animals received sodium pentobarbital, 60 mg/kg IP, and cerebral cortical and cerebellar synaptoneurosomes were isolated at 10 min, 1 h, and when animals had awakened. The basal uptake of chloride was not changed in either cerebral cortex or cerebellum at different time periods after pentobarbital administration. Ten minutes after sodium pentobarbital administration, muscimol-stimulated chloride uptake was significantly reduced in cerebellum when the muscimol concentration was 2.5, 5, or 20 microM and in cerebral cortex when the concentration of muscimol was 5 or 10 microM (p less than 0.05, Duncan multiple-range test). One hour after pentobarbital administration or after animals had awakened, chloride uptake in brains from pentobarbital-treated animals was less at low concentration of muscimol (2.5 microM). No significant difference was found in either cerebral cortex or cerebellum in pentobarbital-(125-1,000 microM) stimulated or flunitrazepam-(2.5-20 microM) enhanced, muscimol-(3 microM) stimulated chloride uptake at different time periods after pentobarbital administration. Saline treatment had no effects on the basal or muscimol-stimulated chloride uptake in cerebellar synaptoneurosomes when compared with naive animals. The results demonstrate that GABAA receptor-regulated chloride uptake is decreased after acute pentobarbital administration, an effect that is reversible.

Animals↗
PubMed1999

Comparison of gamma-aminobutyric acid effects in different parts of the cat ileum.

The effects of gamma-aminobutyric acid (GABA) and those of a GABA(A) (muscimol) and a GABA(B) (baclofen) receptor agonists were determined on the spontaneous activity of longitudinally or circularly oriented preparations (segments) isolated from terminal, proximal and distal parts of the cat ileum. GABA applied at 1 microM to 2 mM caused dose-dependent biphasic changes (relaxation and contraction) in spontaneous activity of the longitudinal and circular layers in the terminal and distal parts of the cat ileum and monophasic changes (contraction) in the proximal part. The potency of GABA to elicit relaxant and/or contractile effects in different parts of the ileum showed a proximal-to-terminal increasing pattern. In the longitudinal layer of the distal and terminal ileum, muscimol (100 microM) mimicked the relaxation phase of the GABA effect, while baclofen (100 microM) simulated the contractile phase. Bicuculline, atropine and tetrodotoxin abolished GABA- and muscimol-induced relaxation and suppressed, but failed to prevent GABA- and baclofen-induced contractions. In addition, 2-hydroxysaclofen antagonized the baclofen-induced contractile effect, reduced the GABA-induced contractile phase but failed to prevent GABA- and muscimol-induced relaxation. In the circular layer of the same regions, muscimol mimicked the biphasic GABA effects, while baclofen was without effect. Bicuculline, atropine and tetrodotoxin completely prevented the GABA- and muscimol effects, while 2-hydroxysaclofen failed to antagonize them. In the longitudinal and circular layers of the proximal ileum, muscimol (100 microM) exerted a 'GABA-like' transient contractile effect, while baclofen (100 microM) did not elicit any response. Bicuculline, atropine and tetrodotoxin antagonized the GABA- and muscimol-induced contractile responses of longitudinal and circular layers, while 2-hydroxysaclofen was ineffective. The results suggested that the inhibitory and/or excitatory action of GABA on cholinergic transmission in different regions of cat ileum varies along an increasing gradient towards the terminal ileum and is mediated by GABA(A) and GABA(B) receptors in the terminal and distal ileum and by GABA(A) receptors in the proximal ileum.

Acetylcholinesterase↗
PubMed1986

The gamma-aminobutyrate/benzodiazepine receptor from pig brain. Enhancement of gamma-aminobutyrate-receptor binding by the anaesthetic propanidid.

The binding of [3H]muscimol, a gamma-aminobutyrate (GABA) receptor agonist, to a membrane preparation from pig cerebral cortex was enhanced by the anaesthetic propanidid in a concentration-dependent manner. At 0 degrees C, binding was stimulated to 220% of control values, with 50% stimulation at 60 microM-propanidid. At 37 degrees C, propanidid caused a more powerful stimulation of [3H]muscimol binding (340% of control values). Propanidid (1 mM) exerted little effect on the affinity of muscimol binding (KD approx. 10 nM), but increased the apparent number of high-affinity binding sites in the membrane by 2-fold. Enhancement of [3H]muscimol binding was observed only in the presence of Cl- ions, half-maximal activation being achieved at approx. 40 mM-Cl-. Picrotoxinin inhibited the stimulation of [3H]muscimol binding by propanidid with an IC50 (concentration causing 50% inhibition) value of approx. 25 microM. The enhancement of [3H]muscimol binding by propanidid was not additive with the enhancement produced by secobarbital. Phenobarbital inhibited the effect of propanidid and secobarbital. The GABA receptor was solubilized with Triton X-100 or with Chaps [3-[(3-cholamidopropyl)dimethylammonio]propanesulphonate]. Propanidid and secobarbital did not stimulate the binding of [3H]muscimol after solubilization with Triton X-100. However, the receptor could be solubilized by 5 mM-Chaps with retention of the stimulatory effects of propanidid and secobarbital. Unlike barbiturates, propanidid did not stimulate the binding of [3H]flunitrazepam to membranes. It is suggested that the ability to modulate the [3H]muscimol site of the GABA-receptor complex may be a common and perhaps functional characteristic of general anaesthetics.

Animals↗
PubMed2000

GABAA receptor mediated elevation of Ca2+ and modulation of gonadotrophin-releasing hormone action in alphaT3-1 gonadotropes.

gamma-amino butyric acid (GABA) is the major inhibitory neurotransmitter in the CNS, mediating fast inhibitory synaptic transmission, by activating GABAA receptors. However, these GABA-gated Cl- channels can also be excitatory, causing depolarization, and increasing Ca2+ entry via voltage-operated Ca2+ channels (VOCCs). Evidence exists for excitatory ionotropic GABA receptors in anterior pituitary cells, including gonadotropes, but these have not been directly characterized and their pharmacology remains controversial. Here we have measured the cytosolic Ca2+ concentration ([Ca2+]i) in alphaT3-1 gonadotropes, to test for expression of excitatory GABA receptors. The GABAA agonists, GABA and muscimol, both caused rapid, robust and dose-dependent increases in [Ca2+]i (EC50 values 2.7 and 1 microM), whereas the GABAB agonist, baclofen, did not. The GABAA antagonist, bicuculline, inhibited muscimol's effect, whereas the GABAB antagonist, phaclofen, did not. The neuroactive steroid 5alpha-pregnan-3alpha-ol-11,20-dione (an allosteric activator of GABAA receptors) increased [Ca2+]i, and this effect, like that of muscimol, was inhibited by picrotoxin. The muscimol effect on [Ca2+]i was blocked by the VOCC antagonist, nifedipine, or by Ca2+-free medium. When cells were pretreated with muscimol this increased the spike phase of the [Ca2+]i response to subsequent stimulation with gonadotropin-releasing hormone (GnRH). Similar amplification was seen in muscimol-pretreated cells stimulated with GnRH in Ca2+-free medium, but not when cells were pretreated with muscimol in Ca2+-free medium. The amplification was not, however, GnRH receptor-specific, because the spike response to ionomycin was also increased by muscimol pretreatment. These data provide the first direct evidence for expression of excitatory GABAA receptors, and the first demonstration of acute steroid effects, on GnRH-responsive pituitary cells. They also reveal a novel mechanism by which GABAA activation modulates GnRH action, raising the possibility that this may also influence gonadotrophin secretion from non-immortalized gonadotropes.

Anesthetics↗
PubMed1981

Distinction between the effects of barbiturates, benzodiazepines and phenytoin on responses to gamma-aminobutyric acid receptor activation and antagonism by bicuculline and picrotoxin.

1 Interactions of depressant and anticonvulsant drugs with the neuronal gamma-aminobutyric acid (GABA) receptor + effector system have been examined on afferent fibres to the rat cuneate nucleus in vitro. Three types of interaction have been measured: (a) potentiation of depolarizing responses to the GABA analogue, muscimol: (b) reduction in the potency of bicuculline as an antagonist of muscimol at the GABA receptor: (c) reduction in the potency of picrotoxin as an antagonist of muscimol acting on the effector mechanism. 2 Phenobarbitone reduced the potency of picrotoxin in doses which did not affect the potency of bicuculline and which caused only a small potentiation of muscimol. Pentobarbitone did not show such selectivity, a reduction in potency of picrotoxin always being accompanied by a reduction in potency of bicuculline and a substantial potentiation of muscimol. 3 Flurazepam and lorazepam both reduced the potency of picrotoxin without affecting that of bicuculline and with very little potentiation of muscimol. Phenytoin had no effect on the potency of picrotoxin whilst potentiating muscimol to the same extent as phenobarbitone. 4 The spectrum of drug activity in reducing the potency of picrotoxin correlates well with the reported anticonvulsant effects of these drugs against kindled amygdaloid seizures. Potentiation of muscimol and reduction of bicuculline potency appear more closely related to hypnotic properties.

Animals↗
PubMedDate not supplied

GABAmimetics diminish antinociception of meperidine under conditions which enhance other opioid mu-agonists.

This study investigated the effects of pretreatment with muscimol (GABA-agonist) or diazepam (indirect GABAmimetic) on i.v. meperidine, fentanyl, alphaprodine and morphine, using rabbit tooth pulp and mouse hot plate assays. A previous study reported that the ED50 values for fentanyl in rabbits were significantly lowered by 0.25 mg/kg of muscimol (13.8 to 1.8 micrograms/kg) and by 1.5 mg/kg of diazepam (13.1 to 1.1 micrograms/kg). ED50 values for meperidine in rabbits in this study were increased by muscimol (1.2 to 3.2 mg/kg) and diazepam (1.5 to 3.1 mg/kg). ED50 values for fentanyl in mice were significantly lowered by 0.25 mg/kg of muscimol (23.0 to 8.9 micrograms/kg) and 1.0 mg/kg of diazepam (23.3 to 12.8 micrograms/kg). ED50 values for meperidine in mice were significantly increased by muscimol (2.1 to 5.0 mg/kg) and diazepam (2.0 to 4.8 mg/kg). ED50 values for alphaprodine and morphine were significantly lowered by muscimol and diazepam in mice. A higher dose of muscimol (1.0 mg/kg) had no effect on the ED50 values of meperidine in mice. The antinociception of a submaximal dose of meperidine in rabbits was significantly reduced by a 10 min pretreatment with i.v. diazepam (1.5 mg/kg) at 15, 20, 30 and 45 min after i.v. meperidine. The antinociception of a submaximal dose of fentanyl in rabbits was significantly increased by a 10 min pretreatment with i.v. diazepam (1.5 mg/kg) at 5, 10, 15 and 20 min after i.v. fentanyl. Pretreatment with 0.1 mg/kg of scopolamine enhanced the antinociceptive effect of a submaximal dose of fentanyl in both animal models. Diazepam reduced the antinociception produced by the combination scopolamine-fentanyl to that of fentanyl-vehicle control in both animal models. Pretreatment with 0.1 mg/kg of scopolamine did not change the magnitude of antinociception of a submaximal dose of meperidine in rabbits. Since meperidine possesses inherent anticholinergic activity, it is suggested that this anticholinergic activity may be involved in the reduction effects by muscimol and diazepam.

Alphaprodine↗
PubMed1986

gamma-Aminobutyric acid (GABA)- and barbiturate-mediated 36Cl- uptake in rat brain synaptoneurosomes: evidence for rapid desensitization of the GABA receptor-coupled chloride ion channel.

"Desensitization" of the gamma-aminobutyric acid (GABA) receptor-coupled chloride ion channel was studied using an in vitro method for measuring chloride (Cl-) permeability in brain vesicles (synaptoneurosomes). Muscimol, a GABA agonist, stimulated 36Cl- uptake in rat cerebral cortical synaptoneurosomes in a concentration-dependent manner (EC50 7.3 +/- 0.5 microM), whereas pentobarbital stimulated 36Cl- uptake in a biphasic manner, indicated by a bell-shaped concentration-response relationship, with a maximal response at 500 microM (EC50 271 +/- 17 microM). Higher concentrations of pentobarbital led to progressively smaller stimulation of 36Cl- uptake and blocked muscimol-stimulated 36Cl- uptake. Lower concentrations of pentobarbital (100-200 microM), when added with muscimol, produced an additive effect in stimulating 36Cl- uptake, whereas even lower (subthreshold) concentrations of pentobarbital (50 microM) potentiated muscimol-stimulated 36Cl- uptake. Following continuous exposure of synaptoneurosomes (up to 20 min) to muscimol (50 microM) or pentobarbital (500 microM), the 36Cl- uptake response diminished to a new steady state level with a t1/2 of approximately 6 sec and 30 sec, respectively. The decrement in response to these agonists was dependent on both concentration and length of exposure. No decrement was observed in the ability of subthreshold concentrations of pentobarbital to enhance muscimol-stimulated 36Cl- uptake following prolonged (20 min) incubation. "Heterologous desensitization" between muscimol and pentobarbital was observed in experiments where either muscimol or pentobarbital was added to the vesicles following pretreatment with the other. These findings suggest that "desensitization" of the GABA receptor/Cl- ion channel may involve both the GABA and barbiturate recognition sites or a common effector component such as the ionophore itself.

Animals↗
PubMed1989

GABA[A] receptor level changes in female hamster forebrain following in vivo estrogen progesterone and benzodiazepine treatment: a quantitative autoradiography analysis.

The levels of gamma amino butyric acid (GABAA) receptors (i.e. 3H-Muscimol binding sites) were determined by quantitative neurotransmitter receptors autoradiography in ovariectomized (OVX), OVX-estradiolo (E), OVX-progesterone (P), OVX-E + P, diazepam (DZ) and DZ + Ro15-1788 treated female hamsters. The various hormonal treatments altered 3H muscimol binding in many brain areas, whereas DZ and DZ + Ro15-1788 had little influence on GABAA receptor levels at the onset of the blocked aggressive behavioral activity. For example, E, P and E + P all significantly increased 3H muscimol binding in medial preoptic area, ventromedial hypothalamic nuclei, and vertical diagonal bandmedial septal nucleus, whereas P treatment increased binding in the caudate-putamen and decreased it in reuniens nucleus of the thalamus. E and E + P treatments increased 3H muscimol binding in the corticomedial amygdala nucleus and hippocampus. Diazepam treatment decreased the GABAA receptor binding in the caudate-putamen and basolateral amygdala, while having no effect in the other brain regions where hormone treatment was effective. In vitro incubation of brain sections with micromolar concentrations of E or P did not change muscimol binding. These results suggest that ovarian steroids, and benzodiazepines to a lesser extent, modulate 3H muscimol binding but do so in different brain regions. The hormone effects on 3H muscimol binding in the critical reproductive centres at a time period that coincides with the onset of its behavioral effect is consistent with a genomic controlled activity.

Animals↗
PubMed1979

GABAergic and glycinergic mechanisms within the substantia nigra: pharmacological specificity of dopamine-independent contralateral turning behavior and interactions with other neurotransmitters.

The pharmacological specificity of the GABA agonist muscimol-induced contralateral turning behavior after unilateral injection into substantia nigra pars reticulata (SNR) has been studied. Muscimol-induced turning was antagonized by intranigral bicuculline methochloride (BMC) and picrotoxin, whereas antagonists of glycine, morphine, dopamine, noradrenaline, and serotonin were ineffective. Glycine induced a qualitatively similar turning behavior which was strychnine-sensitive but relatively BMC and picrotoxin-insensitive. Other drugs, including substance P, kainic acid, clonidine, oxymetazoline, serotonin, and carbachol, induced turning that could be dissociated from the effect of muscimol. Muscimol-induced turning was dopamine-independent, indicated by resistance to haloperidol (1 mg/kg), to pretreatment with reserpine (7.5 mg/kg) plus alpha-methyl-p-tyrosine (200 mg/kg), to haloperidol injections into the SNR, striatum and nucleus accumbens, and finally to kainic acid lesions of the striatum. 6-Hydroxydopamine lesions increased the efficacy of intranigral muscimol, while kainic acid lesions of the SNR antagonized muscimol. Muscimol-induced turning was inhibited by oxotremorine (0.25 mg/kg), by intranigral carbachol, and by apomorphine (0.1--0.5 mg/kg), but only moderately by intranigrally injected apomorphine. These data suggest specificity of GABA-agonist-induced contralateral turning and indicate an interaction between nigral GABA and other neurotransmitters, particularly dopamine and acetylcholine.

Animals↗
PubMed2005

Regulation of native GABAA receptors by PKC and protein phosphatase activity.

RATIONALE AND OBJECTIVE: Protein kinase C (PKC) modulation of ionotropic receptors is a common mechanism for regulation of channel function. The effects of PKC and phosphatase activation on native gamma-aminobutyric acid (GABA(A)) receptors in adult brain are unknown. Previous studies of recombinant GABA(A) receptors have provided evidence that PKC activation inhibits receptor function, whereas other studies suggest that PKC either increases or does not alter GABA(A) receptor function. The present study explored (a) the effects of PKC and phosphatase activity on GABA-mediated (36)Cl(-) uptake in cerebral cortical synaptoneurosomes and (b) the effect of PKC activity on muscimol-induced loss of righting reflex (LORR) in adult rats. METHODS: GABA(A) receptor function in vitro was measured by muscimol-induced (36)Cl(-) uptake into cerebral cortical synaptoneurosomes. The in vivo effect of PKC on GABA(A)-mediated function was measured by intracerebroventricular (i.c.v.) injection of 4-beta-phorbol-12,13-dibutyrate (PDBu) or calphostin C followed by determination of muscimol-induced LORR. RESULTS: Adenosine triphosphate (ATP) and PDBu produced a concentration-dependent and specific reduction in muscimol-stimulated (36)Cl(-) uptake that was blocked by the PKC inhibitor calphostin C. Both adenosine diphosphate and 4alphaPDBu were ineffective. Phosphatase inhibition produced similar inhibition of muscimol responses. Furthermore, i.c.v. administration of PDBu and calphostin C produced opposing effects on both the onset and the duration of muscimol-induced LORR in rats. CONCLUSIONS: The present study provides evidence that PKC activation reduces GABA(A) receptor function in native receptors both in vitro and in vivo. Phosphatase inhibitors decrease muscimol-mediated Cl(-) uptake in GABA(A) receptors demonstrating coordinated regulation of native receptors by PKC and phosphatases.

Adenosine Diphosphate↗
PubMed1979

Amphetamine-induced circling behavior in rats: effects of unilateral microinjections of GABA and GABA-related drugs into substantia nigra.

In these experiments, the GABA control upon dopaminergic nigrostriatal neurons has been investigated using circling behavior in the rat. Chronically cannulated rats were given D-amphetamine (2 mg/kg i.p.) 45 min before unilateral microinjection (0.2 microliter/2 min) into the substantia nigra (SN) of GABA, muscimol, chlordiazepoxide (CDP) or bicuculline. Circling behavior was continuously recorded for 165 min using an automated rotometer. (1) Non-microinjected control rats exhibit a 'spontaneous' circling behavior after amphetamine. (2) When applied to the SN contralateral to the preferential side of the 'spontaneous' rotations, saline enhances contraversive circling; GABA (5 X 10(-5)M), CDP (5 X 10(-5)M) and muscimol (5 x 10(-7)M, 5 X 10(-8)M) counteract this effect and induce (except CDP) light ipsiversive rotations; GABA (10(-2)M) and muscimol (5 x 10(-5)M) further enhance contraversive turning. (3) When applied to the SN ipsilateral to the preferential side of the 'spontaneous' rotations, saline has no marked effect on the ipsiversive circling behavior but induces weak contraversive turning; GABA (5 X 10(-5)M), CDP (5 X 10(-5)M) and muscimol (5 x 10(-8)M) enhance the ipsiversive rotations; GABA (10(-2)M) and muscimol (5 x 10(-5)M) transiently decrease the ipsiversive circling; bicuculline (5 x 10(-5)M) induces a vigorous contraversive turning associated with a transient inhibition of the ipsiversive rotations. These results suggest that the activity of the nigral neurons is presumably stimulated by the microinjection itself, by bicuculline and, to a lesser extent, by high concentrations of GABA and muscimol, and inhibited by low concentrations of GABA, muscimol and CDP. These findings could further support the hypotheses of a GABAergic inhibitory control upon DA nigrostriatal pathways and of a GABA-like activity of CDP.

Animals↗
PubMed1988

Genetic selection for benzodiazepine ataxia produces functional changes in the gamma-aminobutyric acid receptor chloride channel complex.

The gamma-aminobutyric acid (GABA) receptor-operated chloride channel complex was evaluated in mice selected for differential sensitivity to the ataxic effects of diazepam (diazepam-sensitive (DS) and diazepam-resistant (DR) lines). The ataxic effects of several drugs purported to produce some of their actions through the benzodiazepine-GABA receptor complex were examined using the rotarod test. The duration of impairment produced by diazepam, ethanol, 4,5,6,7-tetrahydroisoxazol[5,4-C]pyridine-3-ol (THIP) and phenobarbital was greater in the diazepam-sensitive than in the diazepam-resistant mice. In contrast, pentobarbital produced an equivalent duration of ataxia in the two lines. Muscimol-stimulated 36Cl- influx and the binding of [35S]t-butylbicyclophosphorothionate (TBPS) and [3H]flunitrazepam were measured using isolated brain membrane vesicles (microsacs). Depolarization-dependent 45Ca2+ uptake was measured in whole brain synaptosomes. Muscimol was a more potent stimulator of 36Cl- flux in the DS compared to the DR mice, although no difference between the lines was found in muscimol-stimulation of [3H]flunitrazepam binding. Flunitrazepam augmented the muscimol-stimulated 36Cl- uptake in the DS but not in the DR mice. However, no differences between the lines of mice were found in either density or affinity of [3H]flunitrazepam binding sites. Similarly, no differences in either the density or affinity of [35S]TBPS binding sites was found. Ethanol (10-45 mM) potentiated the muscimol-stimulation of 36Cl- in DS, with no effect in DR mice. However, ethanol inhibition of [35S]TBPS binding was equivalent in the two lines of mice. Pentobarbital produced an equal potentiation of the muscimol-stimulated 36Cl- flux in the two lines, but phenobarbital potentiated the muscimol-induced 36Cl- influx slightly more in DS mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Pharmacological characteristics of two different types of inhibitory GABA receptors on Achatina fulica neurones.

GABA (gamma-aminobutyric acid) receptors of Achatina fulica neurones have been classified into two types associated with neuronal inhibition and one type with excitation. The pharmacological features of muscimol I and baclofen types associated with inhibition were investigated in this study. Activation of muscimol I type receptors on TAN (tonically autoactive neurone) by GABA, muscimol and trans-4-aminocrotonic acid (TACA) produced a transient outward current (Iout) with an increase in membrane conductance (g). Their relative potencies at GABA ED50 (approximately 10(-4) M) were: GABA: muscimol: TACA = 1:0.6:0.3. The relation between Iout and g increase (delta g) induced by various concentrations of these compounds was linear. The Hill coefficients for GABA were close to 1.0. The GABA effects were potentiated by pentobarbitone, antagonized competitively by pitrazepin and non-competitively by picrotoxin and diazepam, and unaffected by bicuculline. The reversal potentials of the effects of GABA, muscimol and TACA on TAN changed under various [Cl-]0 according to the Nernst equation for Ec1, but not under various [K+]0 and [Na+]0. Activation of baclofen type GABA receptors on RPeNLN (right pedal nerve large neurone) by GABA and (+/-)-baclofen produced a slow Iout with an increase in g. The two compounds were almost equipotent (ED50: approximately 3 x 10(-4) M). The relation between Iout and delta g produced by various concentrations was linear. The Hill coefficients for GABA were also close to 1.0. The reversal potentials of GABA and (+/-)-baclofen on RPeNLN changed under various [K+]0 according to the Nernst equation for EK, but not under various [Cl-]0 and [Na+]0. The two compounds hardly affected the voltage-gated and slowly inactivating calcium current. The Iout produced by GABA and (+/-)-baclofen was reduced by tetraethylammonium chloride, but was unaffected by 4-aminopyridine, bicuculline, pitrazepin and picrotoxin. In conclusion, the pharmacological features of muscimol I type GABA receptors are partly comparable to those of mammalian GABAA receptors, except for the influences of bicuculline and diazepam: the features of the baclofen type GABA receptor, which did not occur with muscimol I type receptors in the same neurone, were similar to those of GABAB.

Animals↗
PubMed1993

Excitatory and inhibitory responses mediated by GABAA and GABAB receptors in guinea pig distal colon.

The actions of gamma-aminobutyric acid (GABA) and the receptor selective agonists, muscimol (GABAA) and baclofen (GABAB), on motor activity of the longitudinal muscle-myenteric plexus of guinea-pig distal colon were studied in vitro. Preparations exhibited spontaneous contractions that were blocked by scopolamine (1 microM) or tetrodotoxin (1 microM). GABA (3-100 microM) inhibited these contractions; the EC50 was 8 microM. GABA-induced relaxations were not blocked by picrotoxin (30 microM). The GABAA receptor antagonist, bicuculline (3-30 microM), increased the amplitude of spontaneous contractions; this response was not blocked by tetrodotoxin. Baclofen (3-100 microM; EC50 = 14 microM) mimicked the GABA-induced relaxation. Baclofen-induced relaxations were not blocked by the GABAB antagonist, phaclofen (30-100 microM). Muscimol (10-100 microM) induced a contraction followed by a relaxation; both responses faded in the presence of muscimol. The muscimol EC50's for contraction and relaxation were 12.5 and 11 microM, respectively. The muscimol contraction was blocked by tetrodotoxin, scopolamine and picrotoxin and was reduced by hexamethonium (30 microM). Muscimol relaxations were blocked by tetrodotoxin, picrotoxin and apamin (0.1 microM). Muscimol responses were not altered after preincubation of the tissues with cortisol (10 pM-1 microM). These data indicate that GABA can act at presynaptic GABAB receptors to inhibit acetylcholine release from enteric neurons and reduce spontaneous contractions. There are also GABAA receptors on excitatory and inhibitory neurons and agonist action at these receptors results in contraction and relaxation.

Animals↗
PubMed1985

Modulation of acetylcholine release from rat striatal slices by the GABA/benzodiazepine receptor complex.

GABA, THIP and muscimol enhance spontaneous and inhibit electrically induced release of tritium labelled compounds from rat striatal slices which have been pre-labelled with 3H-choline. Baclofen is inactive in this model. Muscimol can inhibit electrically induced release of tritiated material by approximately 75% with half maximal effects at 2 microM. The response to muscimol can be blocked by the GABA antagonists bicuculline methobromide, picrotoxin, anisatin, R 5135 and CPTBO (cyclopentylbicyclophosphate). Drugs which act on the benzodiazepine receptor (BR) require the presence of muscimol to be effective and they modulate the effects of muscimol in a bidirectional manner. Thus BR agonists enhance and inverse BR agonists attenuate the inhibitory effects of muscimol on electrically induced release. Ro15-1788, a BR antagonist, does not modulate the inhibitory effects of muscimol but antagonizes the actions of clonazepam, a BR agonist, and of DMCM, an inverse BR agonist. These results demonstrate that a GABA/benzodiazepine receptor complex can modulate acetylcholine release from rat striatal slices in vitro.

Acetylcholine↗