-
Brain Research Jul 1982The neutral amino acid gamma-aminobutyric acid (GABA) produced membrane hyperpolarization and increased membrane chloride ion conductance of spinal cord (SC) and...
The neutral amino acid gamma-aminobutyric acid (GABA) produced membrane hyperpolarization and increased membrane chloride ion conductance of spinal cord (SC) and cortical (CTX) neurons in cell culture. GABA dose-response curves were obtained for SC neurons by pressure applying known concentrations of GABA from micropipettes with large tips (miniperfusion pipettes). GABA response threshold was about 2 micrometers and large responses were elicited at GABA concentrations greater than 10 micrometers. Bicuculline (BICUC) (0.1-10 micrometers) reversibly antagonized GABA responses on both SC and CTX neurons with a half maximal inhibitory concentration of about 1 micrometer. BICUC antagonism of GABA responses was competitive (Lineweaver-Burke analysis). These results are compared with data on GABA and BICUC displacement of [3H]GABA binding to membranes of SC and CTX neurons in cell culture. It is suggested that high affinity GABA receptors are likely to be relevant for postsynaptic GABA responses while low affinity GABA receptors may be presynaptic.
Topics: Animals; Bicuculline; Cells, Cultured; Cerebral Cortex; Dose-Response Relationship, Drug; GABA Antagonists; Membrane Potentials; Mice; Neurons; Receptors, Cell Surface; Receptors, GABA-A; Spinal Cord; gamma-Aminobutyric Acid
PubMed: 6288177
DOI: 10.1016/0006-8993(82)90913-1 -
Journal of Neurophysiology Jan 2013GABAergic and glycinergic inhibition play key roles in the function of spinal motor pathways. However, there is little direct information on the extent to which...
GABAergic and glycinergic inhibition play key roles in the function of spinal motor pathways. However, there is little direct information on the extent to which inhibition controls the activity of spinal neurons during behavior or the relative effectiveness of GABA and glycine on cell activity under normal conditions. These issues were investigated in three macaque monkeys trained to perform voluntary ramp-and-hold wrist movements and grip. Pipettes with an extracellular recording electrode and iontophoresis barrels were used to eject GABA, glycine, and/or their respective antagonists, bicuculline and strychnine, as the activity of single neurons was recorded in the C6-T1 spinal segments during hand movements. The firing rate of the vast majority of neurons decreased when an inhibitory neurotransmitter was ejected from the electrode, suggesting that most movement-related spinal neurons are sensitive to both GABA and glycine. Most movement-related neurons exhibited increased activity during iontophoresis of an antagonist, suggesting that both GABAergic and glycinergic inhibition actively regulate the majority of spinal neurons during movement. These conclusions were supported by the responses of neurons tested with both agonists or both antagonists. Bicuculline and strychnine produced the largest increases in firing rate during dynamic movements (ramp phase), smaller increases during maintained torque/force (hold phase), and the smallest increase during the rest period. Since excitatory inputs also tend to increase progressively from rest to static to dynamic muscle contractions, this result is consistent with coupled excitatory and inhibitory inputs to spinal neurons during movement.
Topics: Action Potentials; Animals; Behavior, Animal; Bicuculline; GABA-A Receptor Antagonists; Glycine; Glycine Agents; Macaca nemestrina; Male; Movement; Neural Inhibition; Neurons; Spinal Cord; Strychnine; gamma-Aminobutyric Acid
PubMed: 23076104
DOI: 10.1152/jn.01081.2011 -
The Journal of General Physiology Jul 1979The effect of intravenous strychnine and the GABA antagonists picrotoxin and bicuculline upon the discharge pattern of center-surround-organized cat retinal ganglion...
The effect of intravenous strychnine and the GABA antagonists picrotoxin and bicuculline upon the discharge pattern of center-surround-organized cat retinal ganglion cells of X and Y type were studied. Stimuli (mostly scotopic, and some photopic) were selected such that responses from both on and off-center cells were either due to the center, due to the surround, or clearly mixed. Pre-drug control responses were obtained, and their behavior following administration of the antagonists was observed for periods up to several hours. X-cell responses were affected in a consistent manner by strychnine while being unaffected by GABA antagonists. All observed changes following strychnine were consistent with a shift in center-surround balance of X cells in favor of the center. For Y-cell responses to flashing annuli following strychnine, there was either no shift or a relatively small shift in center-surround balance. Compared to X-cell responses to flashing lights, those of Y cells were very little affected by strychnine and in most cases were unaffected. It thus appears that glycine plays a similar role in receptive field organization of X cells as does GABA in Y cells (Kirby and Enroth-Cugell, 1976. J. Gen. Physiol. 68:465-484).
Topics: Action Potentials; Animals; Bicuculline; Cats; Light; Picrotoxin; Retina; Strychnine
PubMed: 479822
DOI: 10.1085/jgp.74.1.71 -
Neuropsychopharmacology : Official... Feb 2015The rostromedial tegmental nucleus (RMTg) is a strong inhibitor of dopamine neurons in the ventral tegmental area (VTA) reported to influence neurobiological and...
The rostromedial tegmental nucleus (RMTg) is a strong inhibitor of dopamine neurons in the ventral tegmental area (VTA) reported to influence neurobiological and behavioral responses to reward omission, aversive and fear-eliciting stimuli, and certain drugs of abuse. Insofar as previous studies implicate ventral mesencephalic dopamine neurons as an essential component of locomotor activation, we hypothesized that the RMTg also should modulate locomotion activation. We observed that bilateral infusions into the RMTg of the gamma-aminobutyric acid A (GABAA) agonist, muscimol, indeed activate locomotion. Alternatively, bilateral RMTg infusions of the GABAA receptor antagonist, bicuculline, suppress robust activations of locomotion elicited in two distinct ways: (1) by disinhibitory stimulation of neurons in the lateral preoptic area and (2) by return of rats to an environment previously paired with amphetamine administration. The possibility that suppressive locomotor effects of RMTg bicuculline infusions were due to unintended spread of drug to the nearby VTA was falsified by a control experiment showing that bilateral infusions of bicuculline into the VTA produce activation rather than suppression of locomotion. These results objectively implicate the RMTg in the regulation of locomotor activation. The effect is important because much evidence reported in the literature suggests that locomotor activation can be an involuntary behavioral expression of expectation and/or want without which the willingness to execute adaptive behaviors is impaired.
Topics: Amphetamine; Animals; Bicuculline; Conditioning, Psychological; Locomotion; Male; Microinjections; Muscimol; Pedunculopontine Tegmental Nucleus; Preoptic Area; Rats; Ventral Tegmental Area
PubMed: 25164249
DOI: 10.1038/npp.2014.223 -
The Journal of Neuroscience : the... Jan 1995Studies of patients with temporal lobe epilepsy and of experimental models of this disorder suggest that the hippocampal dentate gyrus may be a common site of seizure...
Studies of patients with temporal lobe epilepsy and of experimental models of this disorder suggest that the hippocampal dentate gyrus may be a common site of seizure onset and propagation. However, the nature of the dentate "network defect" that could give rise to spontaneous, intermittent, and synchronous population discharges is poorly understood. We have hypothesized that large expanses of the dentate granule cell layer have an underlying tendency to discharge synchronously in response to afferent excitation, but do not do so normally because vulnerable dentate hilar neurons establish lateral inhibition in the granule cell layer and thereby prevent focal discharges from spreading to surrounding segments. To address this hypothesis, we (1) identified functionally independent segments of the granule cell layer; (2) determined whether discharges in one segment evoke lateral inhibition in surrounding segments; and, (3) determined if disinhibition induces normally independent segments of the granule cell layer to discharge synchronously. Simultaneous extracellular recordings were made from two locations along the longitudinal or transverse axes of the granule cell layer using saline- and bicuculline-filled electrodes that were glued together. Leakage of 10 mM bicuculline from the electrode tip produced no detectable spontaneous activity. However, single perforant path stimuli evoked multiple population spikes at the bicuculline electrode and simultaneous normal responses at the nearby saline electrode. The multiple spikes evoked at the bicuculline electrode did not propagate to, and were not detected by, the adjacent saline electrode, indicating functional separation between neighboring subgroups of granule cells. Paired-pulse stimulation revealed that multiple discharges were not only restricted to one segment of the granule cell layer, but strongly inhibited surrounding segments. This lateral inhibition in surrounding segments often lasted longer than 150 msec. Finally, we evaluated granule cell activity at two normally independent sites within the granule cell layer both before and after disinhibition was induced by high frequency stimulus trains or bicuculline injection. Following a 10 sec, 20 Hz perforant path stimulus train, 2 Hz stimulation evoked virtually identical synchronized epileptiform discharges from normally separated sites. Similarly, intrahippocampal or intravenous bicuculline injection produced spontaneous synchronous epileptiform discharges throughout the granule cell layer. These results indicate that lateral or "surround" inhibition is an operant physiological mechanism in the normal dentate gyrus and suggest that afferent stimuli to a disinhibited dentate network evoke highly synchronized discharges from large expanses of the granule cell layer that are normally kept functionally separated by GABA-mediated inhibition.
Topics: Animals; Bicuculline; Electric Stimulation; Electrodes; Functional Laterality; Granulocytes; Hippocampus; Male; Neural Inhibition; Neurons; Rats; Rats, Sprague-Dawley; Reference Values; Time Factors
PubMed: 7823182
DOI: 10.1523/JNEUROSCI.15-01-00811.1995 -
Anesthesiology Jul 1985The effects of enflurane on three epilepsy models were studied in cats. The models used were seizures in amygdaloid kindled cats and those induced by bicuculline and...
The effects of enflurane on three epilepsy models were studied in cats. The models used were seizures in amygdaloid kindled cats and those induced by bicuculline and penicillin. The authors found that not only a subconvulsive (1.5%) but a convulsive (3.5%) dose of enflurane suppressed the seizures in all models. There was no sign of activation by enflurane of the epileptic focal activities in the dose range studied: the penicillin-induced cortical seizure was suppressed completely, and the threshold dose of bicuculline required to induce seizure in normal cats and the threshold current required to induce seizure in amygdaloid-kindled cats were both increased by both the subconvulsive and convulsive dose of enflurane. The pattern of suppression was, however, dissimilar in each model. It was dose dependent in the case of penicillin-induced seizure, while it was biphasic in several aspects in the seizures of bicuculline-induced and amygdaloid kindled models. For the subconvulsive dose the degrees of increase in the thresholds required to induce seizure in bicuculline-induced and amygdaloid-kindled models were both greater than those for the convulsive dose of enflurane. In spite of such a definite suppression of the excitability of focus, the propagation of amygdaloid after-discharge was facilitated by the convulsive dose. The intensity of convulsion induced by suprathreshold dose of bicuculline was depressed in a dose-related manner. The intensity of the convulsion in the amygdaloid-kindled model was also suppressed when it was estimated by visual inspection of behavior and the degree of activation of the brain electrical activities. The authors conclude that there is little, if any, exacerbation by enflurane of preexisting epileptic foci, the only exception possibly being the case of certain myoclonic type epilepsies such as progressive myoclonic epilepsy and photosensitive epilepsy. This anesthetic probably can be used with a considerable degree of safety for epileptic patients.
Topics: Amygdala; Animals; Anticonvulsants; Bicuculline; Cats; Disease Models, Animal; Dose-Response Relationship, Drug; Electrodes, Implanted; Electroencephalography; Enflurane; Epilepsy; Female; Kindling, Neurologic; Male; Penicillin G; Seizures
PubMed: 4014769
DOI: 10.1097/00000542-198507000-00005 -
The Journal of Physiology Mar 19811. The effects of i.v. administration of the glycine-antagonist strychnine nitrate and the GABA-antagonists bicuculline hydrochloride and picrotoxin on the recurrent...
1. The effects of i.v. administration of the glycine-antagonist strychnine nitrate and the GABA-antagonists bicuculline hydrochloride and picrotoxin on the recurrent inhibition of lumbosacral alpha-motoneurones were studied in cats anaesthetized with pentobarbitone sodium. 2. As revealed from both monosynaptic reflex experiments and intracellular recordings, each of the drugs generally reduced, but rarely abolished, the recurrent inhibition. The amount of reduction was more or less identical for bicuculline and picrotoxin. 3. By applying de- and hyperpolarizing currents intracellularly it could be shown that both the strychnine-resistant and bicuculline/picrotoxin-resistant recurrent inhibitory potentials were genuinely post-synaptic in nature. 4. The strychnine-resistant part of the recurrent inhibition had a later maximum and a longer duration than the part which was resistant to bicuculline/picrotoxin. 5. The time course of the strychnine-resistant recurrent inhibition was more or less identical to that of the bicuculline/picrotoxin-sensitive recurrent inhibition. 6. The bicuculline/picrotoxin-resistant recurrent inhibition was blocked by strychnine and, vice versa, the strychnine-resistant recurrent inhibition was blocked by bicuculline/picrotoxin. The combined administration of strychnine and bicuculline/picrotoxin always resulted in a virtual abolition of the recurrent inhibitory effects. 7. The values for central delay suggested that both the strychnine-resistant and bicuculline/picrotoxin-resistant inhibitions were mediated via disynaptic pathways. 8. The results suggest that both glycine and GABA act as transmitter substances of Renshaw cells in mediating recurrent inhibition to alpha-motoneurones. 9. No organizational pattern of the two types of recurrent inhibition based on motor pool category or motor unit type could be detected.
Topics: Animals; Bicuculline; Cats; Evoked Potentials; GABA Antagonists; Motor Neurons; Neural Inhibition; Picrotoxin; Spinal Nerve Roots; Strychnine
PubMed: 7264991
DOI: 10.1113/jphysiol.1981.sp013624 -
Journal of Pharmacological Sciences Aug 2016In the present study, we investigated the effect of kamishoyosan (KSS) on conditioned fear-induced freezing in ovariectomized (OVX) rats. Socially isolated OVX rats...
In the present study, we investigated the effect of kamishoyosan (KSS) on conditioned fear-induced freezing in ovariectomized (OVX) rats. Socially isolated OVX rats showed the longest freezing time among the following four groups: group-housed sham-operated (Sham), isolated Sham, group-housed OVX, and isolated OVX rats. Repeated oral administration of KSS (30-300 mg/kg) reduced conditioned fear-induced freezing in socially isolated OVX rats. The reduction of freezing by KSS was reversed by flumazenil (3 mg/kg) and bicuculline (3 mg/kg). These findings suggest that the GABAA-benzodiazepine receptor complex is involved in the anxiolytic effect of KSS in socially isolated OVX rats.
Topics: Animals; Bicuculline; Conditioning, Psychological; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Fear; Female; Flumazenil; Herb-Drug Interactions; Immobility Response, Tonic; Ovariectomy; Rats; Social Isolation
PubMed: 27558587
DOI: 10.1016/j.jphs.2016.07.007 -
Molecular Pharmacology Jun 2019GABA receptors (GABARs) are targets for important classes of clinical agents (e.g., anxiolytics, anticonvulsants, and general anesthetics) that act as positive...
GABA receptors (GABARs) are targets for important classes of clinical agents (e.g., anxiolytics, anticonvulsants, and general anesthetics) that act as positive allosteric modulators (PAMs). Previously, using photoreactive analogs of etomidate ([H]azietomidate) and mephobarbital [[H]1-methyl-5-allyl-5-(-trifluoromethyl-diazirynylphenyl)barbituric acid ([H]-TFD-MPAB)], we identified two homologous but pharmacologically distinct classes of general anesthetic binding sites in the 132 GABAR transmembrane domain at - ( sites) and - / - ( sites) subunit interfaces. We now use competition photolabeling with [H]azietomidate and [H]TFD-MPAB to identify -substituted propofol analogs and other drugs that bind selectively to intersubunit anesthetic sites. Propofol and 4-chloro-propofol bind with 5-fold selectivity to , while derivatives with bulkier lipophilic substitutions [4-(-butyl)-propofol and 4-(hydroxyl(phenyl)methyl)-propofol] bind with ∼10-fold higher affinity to sites. Similar to TFD-MPAB and propofol, these drugs bind in the presence of GABA with similar affinity to the - and - sites. However, we discovered four compounds that bind with different affinities to the two interface sites. Two of these bind with higher affinity to one of the sites than to the sites. We deduce that 4-benzoyl-propofol binds with >100-fold higher affinity to the - site than to the - or - sites, whereas loreclezole, an anticonvulsant, binds with 5- and 100-fold higher affinity to the - site than to the and - sites. These studies provide a first identification of PAMs that bind selectively to a single intersubunit site in the GABAR transmembrane domain, a property that may facilitate the development of subtype selective GABAR PAMs.
Topics: Allosteric Regulation; Anesthetics; Bicuculline; Binding Sites; Etomidate; HEK293 Cells; Humans; Propofol; Protein Domains; Protein Subunits; Receptors, GABA-A; Triazoles
PubMed: 30952799
DOI: 10.1124/mol.118.114975 -
The Journal of Neuroscience : the... Mar 1991The barn owl uses interaural time differences (ITDs) to localize the azimuthal position of sound. ITDs are processed by an anatomically distinct pathway in the...
The barn owl uses interaural time differences (ITDs) to localize the azimuthal position of sound. ITDs are processed by an anatomically distinct pathway in the brainstem. Neuronal selectivity for ITD is generated in the nucleus laminaris (NL) and conveyed to both the anterior portion of the ventral nucleus of the lateral lemniscus (VLVa) and the central (ICc) and external (ICx) nuclei of the inferior colliculus. With tonal stimuli, neurons in all regions are found to respond maximally not only to the real ITD, but also to ITDs that differ by integer multiples of the tonal period. This phenomenon, phase ambiguity, does not occur when ICx neurons are stimulated with noise. The main aim of this study was to determine the role of GABAergic inhibition in the processing of ITDs. Selectivity for ITD is similar in the NL and VLVa and improves in the ICc and ICx. Iontophoresis of bicuculline methiodide (BMI), a selective GABAA antagonist, decreased the ITD selectivity of ICc and ICx neurons, but did not affect that of VLVa neurons. Responses of VLVa and ICc neurons to unfavorable ITDs were below the monaural response levels. BMI raised both binaural responses to unfavorable ITDs and monaural responses, though the former remained smaller than the latter. During BMI application, ICx neurons showed phase ambiguity to noise stimuli and no longer responded to a unique ITD. BMI increased the response magnitude and changed the temporal discharge patterns in the VLVa, ICc, and ICx. Iontophoretically applied GABA exerted effects opposite to those of BMI, and the effects could be antagonized with simultaneous application of BMI. These results suggest that GABAergic inhibition (1) sharpens ITD selectivity in the ICc and ICx, (2) contributes to the elimination of phase ambiguity in the ICx, and (3) controls response magnitude and temporal characteristics in the VLVa, ICc, and ICx. Through these actions, GABAergic inhibition shapes the horizontal dimension of the auditory receptive fields.
Topics: Acoustic Stimulation; Animals; Auditory Pathways; Bicuculline; Birds; Brain; Brain Stem; Female; GABA Antagonists; Inferior Colliculi; Male; Models, Neurological; Neurons; Time Factors; gamma-Aminobutyric Acid
PubMed: 2002359
DOI: 10.1523/JNEUROSCI.11-03-00722.1991