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At least 19 recordsLinked to original sources
PubMed1977

Rotational behavior induced in rats by intranigral application of GABA-related drugs and GABA antagonists.

GABA and GABA-related drugs such as muscimol, gamma-hydroxybutyric acid and baclofen injected unilaterally into the substantia nigra of rats elicited contraversive turning. Unilateral injections of picrotoxin and bicuculline produced either ipsi- or contraversive turning depending on the volume of vehicle. I.p. applied haloperidol did not abolish the muscimol-induced turning. This and the direction of rotational behavior suggests that the turning behavior elicited by GABA-related drugs is not mediated by the nigrostriatal dopaminergic tract.

Aminobutyrates↗
PubMed1986

Anisotropic inhibition in the receptive field surround of the frog retinal ganglion cells, evidenced by bicuculline and SR 95103, a new GABA antagonist.

When GABA antagonists (picrotoxin, bicuculline methiodide and SR 95103) were intravitreally injected in the frog, they increased the number of spikes of transient retinal ganglion cells, as well as the duration of the response. Thus, the transient pattern of the response became more sustained. GABA antagonists also provoked a marked increase in the size of the receptive field, which might be due to the abolition of the inhibition exerted by the surround upon the centre of the field. In fact, a stimulus applied to the surround of the field simultaneously with one applied to the centre no longer provoked the reduction of the field area nor that of the number of spikes. These are effects which were always observed before drug injection. After picrotoxin injection, the enlarged field was concentric with the initial one, both angular diameters doubled, whereas after bicuculline or SR 95103, the enlarged field was not concentric with the initial one and only one diameter increased. Thus, GABA inhibition appears to be distributed according to an anisotropic spatial pattern. Whether this anisotropy might be an input for direction selectivity in the frog visual system is a topic of discussion. With respect to SR 95103, this compound proved to act like a selective GABA antagonist with long lasting effects.

Animals↗
PubMed1990

Effects of GABA antagonists and structural GABA analogues on baclofen stimulated gastric acid secretion in the rat.

The effects of GABA receptor antagonists (bicuculline and phaclofen) and structural GABA-analogues on baclofen stimulated gastric acid secretion were studied in standardized perfused rat stomach preparations. Pretreatment with bicuculline, a GABAA-receptor antagonist, in the doses of 1 and 3 mg/kg, subcutaneously, had no influence on the gastric acid response to baclofen. In addition, phaclofen, a GABAB antagonist, in the doses of 3 to 30 mg/kg, intravenously, was found to have no significant effect on the acid response to baclofen. However, GABA-analogues (MOPS and ABA; 10-30 mg/kg, i.v.) and lipophilic GABA derivatives structurally related to beta-amino acids (APPA and APHA; 30 mg/kg, i.v.) significantly counteracted the secretagogue action of baclofen. Further experiments on APPA action showed that the antisecretory effect of APPA could be overcome by higher doses of baclofen. APPA did not affect bethanechol stimulated acid secretion. These results suggest that the secretagogue action of baclofen is independent to GABAA- and GABAB-receptors and that APPA may interact with baclofen in regulation mechanisms of acid secretion, although further investigations are necessary to define the mode of action of APPA on the GABA-ergic system.

Amino Acids↗
PubMed1986

Biphasic effects of systemically administered GABA antagonists on cardiac vagal activity.

Systemic administration of the GABA antagonist picrotoxin 6.0 mg/kg i.v. elicited hypertension and a fall in sinus rate with a return to baseline levels in intact rats. Antagonists of GABA act in the supraspinal CNS to augment sympathetic outflow to the heart and vasculature. Therefore, in this study the spinal cord was transected prior to drug administration in order to eliminate sympathetically mediated effects. In spinal rats, picrotoxin 6.0 mg/kg evoked a biphasic sinus rate response characterized by an initial decrease followed by an increase above baseline sinus rate. Bilateral vagotomy or atropine pretreatment blocked sinus rate changes elicited by picrotoxin, demonstrating that these effects were vagally mediated. Midcollicular decerebration altered the biphasic sinus rate response by preventing the late rise but not the initial decrease in sinus rate. Infusion of another GABA antagonist, bicuculline, elicited a similar biphasic sinus rate response, although the time-course was shorter. Unexpectedly, picrotoxin or bicuculline administration in spinal rats caused an increase in mean blood pressure which was prevented by decerebration and different from that observed in intact rats with respect to time course. In spinal rats pretreatment with a vasopressin antagonist, D(CH2)5Tyr(Me)AVP, blocked the pressor response induced by picrotoxin infusion without altering the biphasic changes in sinus rate. These results suggest that, in the rat: (1) two GABAergic inhibitory mechanisms at different levels of the neuraxis exert opposite effects on cardiac vagal activity; and (2) GABA antagonists may elevate arterial pressure by a mechanism distinct from their previously described sympathoexcitatory effects.

Animals↗
PubMed1985

On GABAergic mechanisms in the optokinetic nystagmus of the frog: effects of bicuculline, allylglycine and SR 95103, a new GABA antagonist.

In a monocular situation, an intravitreal injection of the GABA antagonists, bicuculline or SR 95103 provoked both the suppression of the optokinetic nystagmus (OKN) related to the injected eye and the appearance of a Nasal-Temporal (N-T) component in the OKN triggered by the contralateral non-injected eye (this N-T component being absent in control OKN). These two effects were added in a binocular condition. Similar results were obtained with L-C allylglycine which reduces the endogenous GABA level, but these effects were delayed when compared to those of GABA antagonists. All these data are roughly analogous to those previously obtained with picrotoxin (a non-competitive GABA antagonist) and thus confirm that GABA mechanisms are involved in the control of the frog OKN. Furthermore, SR 95103 acted in this model as a potent selective GABA antagonist, as has been demonstrated in another system.

Allylglycine↗
PubMed1989

Inhibitory effect of intravenous GABA antagonists on gastric acid secretion stimulated by secretagogues in rats.

Effect of intravenous administration of GABA antagonists on gastric acid secretion in perfused stomachs was studied in rats anesthetized with urethane. Bethanechol (BeCh)-stimulated acid secretion was definitely inhibited by bicuculline, a GABA antagonist, and strychnine, a glycine antagonist, but not by picrotoxin and pentylenetetrazol, GABA antagonists. The inhibitory effect of bicuculline and strychnine was accompanied by vigorous convulsions. Only the bicuculline-induced inhibition was still seen in d-tubocurarine paralyzed rats, and it was abolished in spinal rats. 2-Deoxy-D-glucose (2-DG)-stimulated acid secretion was apparently depressed by all the GABA antagonists of bicuculline, picrotoxin and pentylenetetrazol. The inhibitory effect of picrotoxin, but not bicuculline, on the 2-DG stimulation was still elicited in spinal rats. Inhibition of acid secretion stimulated by pentobarbital, a centrally acting secretagogue, was produced by picrotoxin and pentylenetetrazol in spinal rats. These findings suggest that bicuculline acts centrally to inhibit acid secretion stimulated both peripherally by BeCh and centrally by 2-DG, besides nonspecific mechanisms due to convulsions, and the action would be directed to centers which are implicated in stimulation of the sympatho-adrenomedullary system; picrotoxin and pentylenetetrazol also act centrally to inhibit 2-DG- or pentobarbital-stimulated acid secretion through depression of the central vagal tone which leads to inhibition of gastric acid secretion.

Animals↗
PubMed1990

Suppression of spontaneous generalized non-convulsive seizures in the rat by microinjection of GABA antagonists into the superior colliculus.

Intranigral injections of GABA agonists suppress spontaneous and chemically induced generalized non-convulsive seizures in the rat. In order to examine whether the GABAergic nigrotectal pathway could be involved in this suppression, bilateral injections of GABA antagonists were performed in the superior colliculus of rats with spontaneous generalized non-convulsive seizures. Bilateral microinjections into this structure of the GABA antagonists picrotoxin (20 and 40 ng/side) and bicuculline methiodide (5 ng/side) suppressed spike-and-wave discharges for 40 min and 20 min post injection, respectively. Unilateral injections of picrotoxin (40 ng) into the superior colliculus as well as bilateral injections of a GABA agonist (muscimol; 80 ng) did not induce significant modifications. These results show that blockade of the GABAergic transmission at the level of the superior colliculus results in a suppression of generalized non-convulsive seizures. These data support the hypothesis that the suppressive effect of intranigral injections of GABA agonists over generalized non-convulsive seizures involves, at least in part, the nigrotectal GABAergic pathway.

Animals↗
PubMed1986

Iontophoretic studies on rat hippocampus with some novel GABA antagonists.

Twelve substances which appear to be GABA antagonists, judging by their ability to reverse the inhibitory effect of GABA on 35S-TBPS binding to rat brain membranes, were tested iontophoretically on population spikes in the rat hippocampus. Eight of them, including seven which completely reversed the inhibitory action of GABA on 35S-TBPS binding, caused a marked enhancement of population spikes, with slow onset and long duration and they antagonized the inhibition of population spikes by GABA. These effects were similar to those produced by bicuculline. Electrophysiologically, the most potent of the "complete reversers" were bathophenanthroline disulfonate and brucine. In vitro, amoxapine and brucine most effectively reversed the inhibitory action of GABA on 35S-TBPS binding. Of the five substances which only partly reversed the inhibitory effect of GABA on 35S-TBPS binding, four depressed the population spikes and potentiated the inhibitory action of GABA. The fifth "partial reverser", pipazethate, potently increased the population spikes, like the "complete reversers". Although other interpretations are possible the results are consistent with the existence of several GABA-A receptor types in brain, only some of which are blocked by certain partial reversers.

Action Potentials↗
PubMed1988

GABA antagonists potentiate the cardioinhibitory reflex induced by capsaicin in the cat.

The GABA antagonists picrotoxin (PX) and bicuculline (BIC) were given intravenously (i.v.) or applied topically to the region of the nucleus of the solitary tract (NTS) in intact or in precollicularly decerebrate cats under chloralose-urethane anaesthesia, and their effects on capsaicin (CAP)-induced reflex bradycardia were studied. The administration of PX or BIC was found to result in a decrease of the resting heart rate and a significant increase of the cardioinhibitory reflex evoked by CAP. The maximum effects of these GABA antagonists developed within 3-10 min and lasted for about 40-60 min. Neither the resting heart rate nor the response to CAP was affected by strychnine. It is concluded that the CAP-sensitive unmyelinated barosensory afferents and/or the interneurons in the NTS are under a tonically active GABA-ergic inhibitory control originating in the brain stem.

Animals↗
PubMed1987

GABA-antagonist inverts movement and object detection in flies.

Movement detection is one of the most elementary visual computations performed by vertebrates as well as invertebrates. However, comparatively little is known about the biophysical mechanisms underlying this computation. It has been proposed on both physiological and theoretical grounds that inhibition plays a crucial role in the directional selectivity of elementary movement detectors (EMDs). For the first time, we have studied electrophysiological and behavioral changes induced in flies after application of picrotoxinin, an antagonist of GABA. The results show that inhibitory interactions play an important role in movement detection in flies. Furthermore, our behavioral results suggest that the computation of object position is based primarily on movement detection.

Action Potentials↗
PubMed1986

Antagonism of acute feeding response to 2-deoxyglucose and 5-thioglucose by GABA antagonists: the relative role of ventromedial and lateral hypothalamus.

The effect of GABA antagonists picrotoxin and bicuculline was studied on hyperphagia caused by 2-DG and 5-TG. The GABA antagonists were administered either SC or into the VMH or LH through stereotaxically implanted chronic cannulae. The peripheral as well as VMH injection antagonised the hyperphagia significantly. In contrast, injection of these agents into the LH failed to produce any effect. These findings show that in a glucoprivic state there might be an increased GABAergic activity in the VMH.

Animals↗
PubMed1993

Effects of GABA antagonists on inhibitory avoidance.

Experimental data indicate that GABA is involved in memory processes. However there are marked inconsistencies in the reported effects of interference with GABA synaptic activity on memory consolidation of aversively-motivated tasks. Both amnesia and improvement of performance have been reported after treatment with GABA antagonists. These contradictory effects could be explained by procedural differences in training. To test for this possibility rats were trained in passive avoidance using two levels of footshock and injected with a wide range of doses of picrotoxin and bicuculline. Picrotoxin did not modify the conditioned response while bicuculline induced amnesia only with the lower doses at both low and high footshock intensities. It was concluded that GABA is involved in memory consolidation, and that the conflicting results in the literature are indeed due, in part, to procedural differences, and also to the mode of action of these drugs.

Animals↗
PubMed1981

GABA-antagonists and spatial summation in Y-type cat retinal ganglion cells.

1. The effect of GABA-antagonists on centre size of Y-type retinal ganglion cells was measured under conditions which ensured that cells were rod driven. 2. Both bicuculline and picrotoxin, administered intravenously, led to reliable and reversible changes in centre size as determined by area-sensitivity measurements. 3. The administration of GABA-antagonists produced opposite results in on- and off-centre cells; the centre summing area decreased in on-centre cells and increased in off-centre cells.

Animals↗
PubMed1982

Classification of some GABA antagonists with regard to site of action and potency in slices of rat cuneate nucleus.

Compounds reported to be GABA antagonists have been studied quantitatively on dorsal funiculus fibres and terminals in the rat cuneate nucleus in vitro. The potencies of the antagonists against the GABA analogue muscimol were determined as pA2 values. Distinction was made between three different sites of antagonist action within the GABA receptor and ionophore complex. Competitive antagonists, presumed to act at the GABA receptor, and their pA2 values were bicuculline (5.98), bicuculline methochloride (5.88), strychnine (5.29) and tubocurarine (4.95). Antagonists which were not competitive and acted predominantly at the 'picrotoxin site' on the ionophore were picrotoxin (6.19), picrotoxinin (6.03), isopropylbicyclophosphate (5.82) and leptazol (2.89). A third type of antagonism was shown by frusemide. Attention is drawn to the picrotoxin site and its likely importance in the regulation of GABA-mediated inhibition by drugs.

Animals↗
PubMed1991

Effects of GABA antagonists and habituation to novelty on ethanol-induced locomotor activity in mice.

The effects of the gamma-aminobutyric acid (GABA) antagonists picrotoxin and bicuculline on ethanol-induced motor excitation were assessed on habituated and non-habituated mice. Habituated mice were exposed to the testing apparatus for 30 min on 4 consecutive days before testing. Mice were treated with several doses of ethanol (0.8, 1.2 and 1.6 g/kg, intraperitoneally) and at each dose were pretreated with picrotoxin (0.25, 0.5 and 1.0 mg/kg, i.p.) or bicuculline (0.5, 1.0 and 2.0 mg/kg, i.p.). Habituated animals had consistently lower scores than non-habituated animals throughout the experiment. Ethanol alone produced a significant increase in motor activity. Picrotoxin and bicuculline alone decreased motor activity only at the two higher doses in both habituated and non-habituated mice. For the non-habituated mice, picrotoxin and bicuculline at the lowest doses decreased ethanol induced motor activity at the 0.8 and 1.2 g/kg ethanol doses, whereas in habituated mice, only bicuculline attenuated activity. At the highest dose of ethanol, picrotoxin increased ethanol-induced excitation for both non-habituated and habituated animals, whereas bicuculline only augmented the activity of the non-habituated animals at this ethanol dose. Neither antagonist affected blood-ethanol levels. These results suggest that habituation affects not only motor activity per se but also changes in activity due to the combination of GABA antagonists and ethanol.

Animals↗
PubMedDate not supplied

[New GABA-A receptor blockers: attempts to find more powerful clozapine-like selective GABA antagonists].

Because clozapine and a number of other antipsychotic, as well as antidepressant drugs selectively block subsets of GABAA receptors, we have routinely screened 1100 compounds since 1983 for GABA antagonistic effects on 35S-TBPS binding, with a view to finding more potent clozapine-like selective GABAA receptor blockers. About 225 GABA antagonists were identified. Among compounds not previously published, four groups of tricyclic compounds (phenothiazines, phenoxazines, acridines and phenazines) contained GABAA receptor blockers, with acridines and oxidized phenothiazines in general being the most potent. Other active groups include cocaine derivatives, xanthines, indoles and phenethylamine derivatives. A large group of miscellaneous structures includes all known GABAA receptor blockers, as well as some antihistamines, antitussives, antimalarial/antiprotozoals, potential antidepressant, and a large non-therapeutic category consisting of diverse chemical structures. The amino steroid R5135 remains the most potent GABAA receptor blocker by far (EC50 = 5.7 nM, delta Bopt = 130%), and is non-aromatic. Pitrazepin, the next-most potent GABAA receptor blocker (EC50 = 360 nM), also fully reverses the inhibitory effect of 1 microM GABA on 35S-TBPS binding, but is 63-fold less potent than R5135. Appropriately positioned amidino groups, ring (aromatic) nitrogen, ether and keto groups can contribute to the potency of GABAA receptor blockade. Clozapine-like selective GABAA receptor blockers with EC50 values in the low nanomolar range remain to be identified. Such compounds may have potent antipsychotic effects.

Antipsychotic Agents↗
PubMed1985

Facilitation of hippocampal long-lasting potentiation by GABA antagonists.

Long-lasting potentiation (LLP) of synaptic transmission in the CAI region of the hippocampal slice preparation has been examined. The effects of reduced postsynaptic inhibition given by application of gamma-aminobutyric acid (GABA) antagonists (mainly picrotoxin) on the generation of LLP were investigated. It was first demonstrated that picrotoxin had little effect on excitatory synaptic transmission itself as judged by the rising phase of the field EPSP. Moreover, there were largely no actions on short-lasting synaptic effects such as paired pulse facilitation and frequency potentiation. On the other hand, following drug application, much fewer afferent volleys were needed to generate a given amount of LLP. Long-lasting potentiation could be produced by trains containing as few as 2-5 impulses, trains that normally give rise to only short-lasting effects. There was no apparent difference in the maximal amount of LLP that could be produced for a given input, suggesting that the GABA antagonists do not operate by enhancing the capacity for LLP production but by facilitating its induction. As in normal solution, the LLP in the presence of the drugs was confined to the tetanized pathway. Tetanization in the treated slices was associated with enhanced somatic firing as well as an increase of the negative extracellular potential recorded in the dendritic layer. It is proposed that part of this increased negativity represents current through synaptically opened N-methyl-D-aspartate (NMDA) receptor channels. Furthermore, it is suggested that the facilitated induction of LLP in the presence of GABA antagonists is related to a facilitated activation of these NMDA receptor channels which is secondary to the higher levels of dendritic depolarization attained during tetanization under conditions of reduced postsynaptic inhibition.

Afferent Pathways↗