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British Journal of Pharmacology Jul 19811 Interactions of depressant and anticonvulsant drugs with the neuronal gamma-aminobutyric acid (GABA) receptor + effector system have been examined on afferent fibres...
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.
Topics: Animals; Barbiturates; Benzodiazepines; Bicuculline; Dose-Response Relationship, Drug; Drug Interactions; Muscimol; Phenytoin; Picrotoxin; Rats; Receptors, Cell Surface; Receptors, GABA-A
PubMed: 6265019
DOI: 10.1111/j.1476-5381.1981.tb16810.x -
Experimental Neurology Feb 2021The hippocampus is vulnerable to traumatic brain injury (TBI), and hippocampal damage is associated with cognitive deficits that are often the hallmark of TBI. Recent...
The hippocampus is vulnerable to traumatic brain injury (TBI), and hippocampal damage is associated with cognitive deficits that are often the hallmark of TBI. Recent studies have found that TBI induces enhanced neurogenesis in the dentate gyrus (DG) of the hippocampus, and this cellular response is related to innate cognitive recovery. However, cellular mechanisms of the role of DG neurogenesis in post-TBI recovery remain unclear. This study investigated changes in long-term potentiation (LTP) within the DG in relation to TBI-induced neurogenesis. Adult male rats received a moderate TBI or sham injury and were sacrificed for brain slice recordings at 30 or 60 days post-injury. Recordings were taken from the medial perforant path input to DG granule cells in the presence or absence of the GABAergic antagonist picrotoxin, reflecting activity of either all DG granule cells or predominately newborn granule cells, respectively. Measurements of LTP observed in the total granule cell population (with picrotoxin) showed a prolonged impairment which worsened between 30 and 60 days post-TBI. Under conditions which predominantly reflected the LTP elicited in newly born granule cells (no picrotoxin), a strikingly different pattern of post-TBI changes was observed, with a time-dependent cycle of functional impairment and recovery. At 30 days after injury this cell population showed little or no LTP, but by 60 days the capacity for LTP of the newly born granule cells was no different from that of sham controls. The time-frame of LTP improvements in the newborn cell population, comparable to that of behavioral recovery reported previously, suggests the unique functional properties of newborn granule cells enable them to contribute to restorative change following brain injury.
Topics: Animals; Atrophy; Behavior, Animal; Brain Injuries, Traumatic; Cytoplasmic Granules; Electrophysiological Phenomena; GABA Antagonists; Hippocampus; Long-Term Potentiation; Male; Neuronal Plasticity; Picrotoxin; Rats; Rats, Sprague-Dawley; Recovery of Function; Synapses
PubMed: 33188818
DOI: 10.1016/j.expneurol.2020.113527 -
Vision Research Dec 1996The inhibitory actions of picrotoxin (PTX) and zinc on the GABAC receptor in acutely isolated catfish cone horizontal cells were studied and compared using the...
The inhibitory actions of picrotoxin (PTX) and zinc on the GABAC receptor in acutely isolated catfish cone horizontal cells were studied and compared using the whole-cell patch clamp technique. PTX blocked the GABAC current elicited by 30 microM GABA with IC50 = 0.64 microM. Over a PTX concentration range of 1-100 microM, simultaneous application of PTX with GABA (30 microM) produced current transients at both the onset and offset of the drug pulse. When the PTX concentration was maintained before, during, and after GABA application, the current transients at the onset and offset of GABA application disappeared. Thus, these transients seem to reflect a slower initial action of PTX at, and faster washout of PTX from, the GABAC receptor than GABA when they were co-applied. The full recovery from PTX inhibition required a second GABA application. Recovery could not be achieved by a prolonged wash in the absence of GABA. These results suggest that PTX effect is use-dependent. Zinc also potently blocked the GABAC current elicited by 30 microM GABA with an IC50 about an order of magnitude higher than that of PTX (IC50 = 8.2 microM). However, only the onset, but not the offset current transient was observed when zinc was simultaneously applied with GABA. The full recovery of the GABAC current from zinc inhibition was obtained after washing for 20 sec and did not require a subsequent GABA application. This indicates that the zinc effect is use-independent. Our findings suggest that: (1) the zinc binding site is on the surface of the GABAC receptor molecule; (2) there is a PTX binding site that is probably inside the receptor and its access requires GABA binding to the receptor.
Topics: Animals; Cell Culture Techniques; Dose-Response Relationship, Drug; Electric Conductivity; Electrophysiology; Ictaluridae; Patch-Clamp Techniques; Picrotoxin; Receptors, GABA; Retina; Zinc
PubMed: 9068852
DOI: 10.1016/s0042-6989(96)00141-1 -
Neurobiology of Learning and Memory Sep 2014The neural circuitry mediating fear extinction has been increasingly well studied and delineated. The rodent infralimbic subregion (IL) of the ventromedial prefrontal...
The neural circuitry mediating fear extinction has been increasingly well studied and delineated. The rodent infralimbic subregion (IL) of the ventromedial prefrontal cortex (vmPFC) has been found to promote extinction, whereas the prelimbic cortex (PL) demonstrates an opposing, pro-fear, function. Studies employing in vivo electrophysiological recordings have observed that while increased IL single-unit firing and bursting predicts robust extinction retrieval, increased PL firing can correlate with sustained fear and poor extinction. These relationships between single-unit firing and extinction do not hold under all experimental conditions, however. In the current study, we further investigated the relationship between vmPFC and PL single-unit firing and extinction using inbred mouse models of intact (C57BL/6J, B6) and deficient (129S1/SvImJ, S1) extinction strains. Simultaneous single-unit recordings were made in the PL and vmPFC (encompassing IL) as B6 and S1 mice performed extinction training and retrieval. Impaired extinction retrieval in S1 mice was associated with elevated PL single-unit firing, as compared to firing in extinguishing B6 mice, consistent with the hypothesized pro-fear contribution of PL. Analysis of local field potentials also revealed significantly higher gamma power in the PL of S1 than B6 mice during extinction training and retrieval. In the vmPFC, impaired extinction in S1 mice was also associated with exaggerated single-unit firing, relative to B6 mice. This is in apparent contradiction to evidence that IL activity promotes extinction, but could reflect a (failed) compensatory effort by the vmPFC to mitigate fear-promoting activity in other regions, such as the PL or amygdala. In support of this hypothesis, augmenting IL activity via direct infusion of the GABAA receptor antagonist picrotoxin rescued impaired extinction retrieval in S1 mice. Chronic fluoxetine treatment produced modest reductions in fear during extinction retrieval and increased the number of Zif268-labeled cells in layer II of IL, but failed to increase vmPFC single-unit firing. Collectively, these findings further support the important contribution these cortical regions play in determining the balance between robust extinction on the one hand, and sustained fear on the other. Elucidating the precise nature of these roles could help inform understanding of the pathophysiology of fear-related anxiety disorders.
Topics: Animals; Early Growth Response Protein 1; Extinction, Psychological; Fear; Fluoxetine; GABA Antagonists; Male; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Patch-Clamp Techniques; Picrotoxin; Prefrontal Cortex; Selective Serotonin Reuptake Inhibitors
PubMed: 24231425
DOI: 10.1016/j.nlm.2013.11.002 -
Journal of Neurophysiology Sep 1999The role of gamma-aminobutyric acid-A (GABAA) and GABAC receptors in the GABA-induced biphasic response in neurons of the rat major pelvic ganglia (MPG) were examined in...
The role of gamma-aminobutyric acid-A (GABAA) and GABAC receptors in the GABA-induced biphasic response in neurons of the rat major pelvic ganglia (MPG) were examined in vitro. Application of GABA (100 microM) to MPG neurons produced a biphasic response, an initial depolarization (GABAd) followed by a hyperpolarization (GABAh). The input resistance of the MPG neurons was decreased during the GABAd, whereas it was increased during the GABAh. The GABAd could be further separated into the early component (early GABAd) with a duration of 27 +/- 5 s (mean +/- SE; n = 11) and the late component (late GABAd) with a duration of 109 +/- 11 s (n = 11). The duration of the GABAh was 516 +/- 64 s (n = 11). The effects of GABA (5-500 microM) in producing the depolarization and the hyperpolarization were concentration-dependent. GABA (5-30 microM) induced only late depolarizations. The early component of the depolarization appeared when the concentration of GABA was >50 microM. Muscimol produced only early depolarizing responses. Baclofen (100 microM) had no effect on the membrane potential and input resistance of MPG neurons. Bicuculline (60 microM) blocked the early GABAd but not the late GABAd and the GABAh. Application of picrotoxin (100 microM) with bicuculline (60 microM) blocked both the late GABAd and the GABAh. CGP55845A (3 microM), a selective GABAB receptor antagonist, did not affect the GABA-induced responses. cis-4-Aminocrotonic acid (CACA, 1 mM) and trans-4-aminocrotonic acid (TACA, 1 mM), selective GABAC receptor agonists, produced late biphasic responses in the MPG neurons. The duration of the CACA responses was almost the same as those of the late GABAd and GABAh obtained in the presence of bicuculline. Imidazole-4-acetic acid (I4AA, 100 microM), a GABAC receptor antagonist, depressed the late GABAd and the GABAh but not the early GABAd. I4AA (100 microM) and picrotoxin (100 microM) also suppressed the biphasic response to CACA. The early GABAd and the late GABAd were reversed in polarity at -32 +/- 3 mV (n = 7) and -38 +/- 2 mV (n = 4), respectively, in the Krebs solution. The reversal potential of the GABAh was -34 +/- 2 mV (n = 4) in the Krebs solution. The reversal potentials of the late GABAd and the GABAh shifted to -20 +/- 3 mV (n = 5) and -22 +/- 3 mV (n = 5), respectively, in 85 mM Cl- solution. These results indicate that the late GABA(d) and the GABAh are mediated predominantly by bicuculline-insensitive, picrotoxin-sensitive GABA receptors, GABAC (or GABAAOr) receptors, in neurons of the rat MPG.
Topics: Animals; Bicuculline; Drug Resistance; GABA Agonists; GABA Antagonists; GABA-A Receptor Agonists; GABA-A Receptor Antagonists; Ganglia, Parasympathetic; Male; Membrane Potentials; Neurons; Pelvis; Picrotoxin; Rats; Rats, Wistar; Receptors, GABA; Receptors, GABA-A; gamma-Aminobutyric Acid
PubMed: 10482764
DOI: 10.1152/jn.1999.82.3.1489 -
The Journal of Physiology Mar 19751. In the isolated frog spinal cord picrotoxin, bicuculline, and strychnine were evaluated for their effects on synaptically induced root potentials recorded by the...
1. In the isolated frog spinal cord picrotoxin, bicuculline, and strychnine were evaluated for their effects on synaptically induced root potentials recorded by the sucrose gap technique. 2. Picrotoxin (greater than 10- minus 4 M) completely blocked the dorsal root potential (DRP) elicited by stimulating the ventral root of the same segment (VR-DRP). Although picrotoxin antagonized the DRP elicited by stimulation of either an adjacent dorsal root (DR-DRP) or the lateral column (LC-DRP), a slower component to these potentials appeared and increased in size as the concentration of picrotoxin was increased. Thus picrotoxin brings out a later, picrotoxin resistant component to the DR-DRP and LC-DRP. 3. Strychnine (10- minus 8-10- minus 5 M) reduced and abolished the VR-DRP without prolongation and progressively increased and prolonged the DR-DRP (and LC-DRP) and the DR-VRP. Strychnine in higher concentrations (greater than 10- minus 4 M) also reduced the amplitude and prolonged the duration of the compound action potential of afferent fibres. 4. These results combined with those presented in the preceding paper (Barker, Nicoll & Padjen, 1975) suggest that (1) a GABA-like transmitter mediates the final step in the DR-DRP and LC-DRP pathways and that (2) either taurine or beta-alanine may mediate the last step in the VR-DRP pathway.
Topics: Action Potentials; Alanine; Animals; Bicuculline; Convulsants; Electric Stimulation; In Vitro Techniques; Neurons, Afferent; Perfusion; Picrotoxin; Rana pipiens; Spinal Nerve Roots; Strychnine; Synapses; Synaptic Transmission; Taurine; gamma-Aminobutyric Acid
PubMed: 167156
DOI: 10.1113/jphysiol.1975.sp010860 -
Scientific Reports Jun 2018Superficial laminae of the spinal cord possess a considerable number of neurons with spontaneous activity as reported in vivo and in vitro preparations of several...
Superficial laminae of the spinal cord possess a considerable number of neurons with spontaneous activity as reported in vivo and in vitro preparations of several species. Such neurons may play a role in the development of the nociceptive system and/or in the spinal coding of somatosensory signals. We have used electrophysiological techniques in a horizontal spinal cord slice preparation from adult mice to investigate how this activity is generated and what are the main patterns of activity that can be found. The results show the existence of neurons that fire regularly and irregularly. Within each of these main types, it was possible to distinguish patterns of spontaneous activity formed by single action potentials and different types of bursts according to intra-burst firing frequency. Activity in neurons with irregular patterns was blocked by a mixture of antagonists of the main neurotransmitter receptors present in the cord. Approximately 82% of neurons with a regular firing pattern were insensitive to synaptic antagonists but their activity was inhibited by specific ion channel blockers. It is suggested that these neurons generate endogenous activity due to the functional expression of hyperpolarisation-activated and persistent sodium currents driving the activity of irregular neurons.
Topics: Action Potentials; Animals; Chromosome Pairing; Membrane Potentials; Mice; Neurons; Picrotoxin; Posterior Horn Cells; Quinoxalines; Riluzole; Sodium; Strychnine; Tetrodotoxin
PubMed: 29950700
DOI: 10.1038/s41598-018-27993-y -
Japanese Journal of Pharmacology Jun 1980Two types of conditioned behaviors were investigated for the purpose of evaluating anxiolytic drugs. A conditioning procedure used was an active avoidance in...
Two types of conditioned behaviors were investigated for the purpose of evaluating anxiolytic drugs. A conditioning procedure used was an active avoidance in poorly-performing mice. Chlordiazepoxide, diazepam, chlorazepate and meprobamate increased the avoidance rate, while chlorpromazine, haloperidol and nortriptyline did not produce such an effect. The effect of diazepam was potentiated by gamma-aminobutyric acid (GABA) and aminoxyacetic acid (AOAA) and antagonized by picrotoxin and thiosemicarbazide, but was influenced little by spiroperidol, alpha-methyltyrosine, phenoxybenzamine and levallorphan. In addition, the effect of other anxiolytics was potentiated by AOAA and antagonized by picrotoxin. Biperiden, methamphetamine, caffeine and morphine also induced an avoidance enhancement, which was not influenced by AOAA. A drug discrimination experiment was also performed using a milk-reinforced two-lever operant method. In the rats trained to discriminate phenobarbital from saline, diazepam produced a dose-related phenobarbital-lever selection, which was potentiated by AOAA and antagonized by picrotoxin. Chlordiazepoxide, chlorazepate and meprobamate also elicited responses on the phenobarbital-lever. On the other hand, haloperidol, nortriptyline, biperiden, methamphetamine, caffeine and morphine produced a saline-lever selection, at the doses tested. These results suggest that, among several drugs tested, the avoidance enhancement and discriminative response control by anxiolytics may be closely linked with the GABA system.
Topics: Aminooxyacetic Acid; Animals; Anti-Anxiety Agents; Avoidance Learning; Discrimination Learning; Drug Synergism; Male; Methyltyrosines; Mice; Picrotoxin; Rats; Semicarbazides; Spiperone; gamma-Aminobutyric Acid
PubMed: 6109035
DOI: 10.1254/jjp.30.325 -
British Journal of Pharmacology Jun 19951. We examined how gamma-aminobutyric acid (GABA) influences interaction of picrotoxin and tert-butylbicyclophosphorothionate (TBPS) with recombinant rat alpha 1 beta 2...
1. We examined how gamma-aminobutyric acid (GABA) influences interaction of picrotoxin and tert-butylbicyclophosphorothionate (TBPS) with recombinant rat alpha 1 beta 2 gamma 2 GABAA receptors stably expressed in human embryonic kidney cells (HEK293), as monitored with changes in Cl- currents measured by the whole-cell patch clamp technique. 2. During application of GABA (5 microM) for 15 s, picrotoxin and TBPS dose-dependently accelerated the decay of inward GABA-induced currents (a holding potential of -60 mV under a symmetrical Cl- gradient). The drugs, upon preincubation with the receptors, also reduced the initial current amplitude in a preincubation time and concentration-dependent manner. This indicates their interaction with both GABA-bound and resting receptors. 3. The half maximal inhibitory concentration for picrotoxin and TBPS at the beginning of a 15 s GABA (5 microM) pulse was several times greater than that obtained at the end of the pulse. GABA thus appears to enhance picrotoxin and TBPS potency, but only at concentrations leading to occupancy of both high and low affinity GABA sites, i.e., 5 microM. Preincubation of the receptors with the drugs in the presence of GABA at 200 nM, which leads to occupancy of only high affinity GABA sites in the alpha 1 beta 2 gamma 2 subtype, produced no appreciable change in potency of picrotoxin or TBPS. This indicates that they preferentially interact with multiliganded, but not monoliganded receptors, unlike U-93631, a novel ligand to the picrotoxin site, which has higher affinity to both mono- and multiliganded receptors than resting receptors. 4. The time-dependent decay and preincubation time-dependent reduction of initial amplitude of GABA-induced Cl- currents followed monoexponential time courses, and time constants thus obtained displayed a linear relationship with drug concentration. Analysis of the data using a kinetic model with a single drug site showed that GABA (5 microM) enhanced the association rate for picrotoxin and TBPS nearly 100 fold, but their dissociation rate only 10 fold. The dissociation rate obtained from current recovery from picrotoxin or TBPS block yielded nearly identical values to the above analysis.5. We conclude that picrotoxin and TBPS interact with both resting and GABA-bound receptors, but their affinity for the latter is about 10 times greater than that for the former, largely due to a markedly increased association rate to the multiliganded receptors (but not monoliganded ones). This and our earlier study with U-93631 improves our understanding of functional coupling between GABA and picrotoxin sites, which appears to be useful in characterizing the mode of interaction for various picrotoxin site ligands.
Topics: Animals; Binding, Competitive; Bridged Bicyclo Compounds, Heterocyclic; Cell Line; Chlorides; Cloning, Molecular; Dose-Response Relationship, Drug; Drug Interactions; GABA Antagonists; Humans; Ion Channels; Kidney; Kinetics; Patch-Clamp Techniques; Picrotoxin; Rats; Receptors, GABA-A; gamma-Aminobutyric Acid
PubMed: 7582470
DOI: 10.1111/j.1476-5381.1995.tb16368.x -
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