Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Bicuculline”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources
PubMed2000

Regional brain activation by bicuculline visualized by functional magnetic resonance imaging. Time-resolved assessment of bicuculline-induced changes in local cerebral blood volume using an intravascular contrast agent.

Functional magnetic resonance imaging (fMRI) has been applied to study rat focal brain activation induced by intravenous administration of the GABA(A) antagonist bicuculline. Using magnetite nanoparticles as a blood pool contrast agent, local changes in cerebral blood volume (CBV) were assessed with high temporal (10 s) and spatial (0.35 x 0.6 mm(2)) resolutions. Upon infusion of the bicuculline region-specific increases in CBV have been observed, suggesting CBV to reflect brain activity. During the first 2 min, the signal increases were predominant in the cortex, followed by increases in other brain areas, such as the caudate putamen, thalamus and cerebellum. Ten minutes after the start of infusion, a dominant response was observed in the thalamus, while in the caudate putamen a biphasic response pattern was seen. The magnitude of the signal responses in all brain regions was dependent on the dose of bicuculline and, in general, matched the known distribution of GABA(A) binding sites. This study suggests that pharmacological fMRI, displaying brain function at the highly specific level of drug-receptor interaction, should foster our understanding of normal and pathological brain function.

Animals↗
PubMed2001

Inhibition of nicotinic acetylcholine receptors by bicuculline.

A study was made on the effects of bicuculline, the classical gamma-aminobutyric acid-A receptor antagonist, on heteromeric mouse muscle alphabetagammadelta, heteromeric neuronal rat alpha2beta4 and alpha4beta2 and homomeric human alpha7 nicotinic acetylcholine receptors (nAChRs), expressed in Xenopus oocytes. Bicuculline reduced the ACh-induced currents in a rapid and reversible way, with IC50 values of 34+/-1.5 microM for mouse muscle alphabetagammadelta and 12.4+/-0.7 and 18+/-1 microM for rat neuronal alpha2beta4 and alpha4beta2 nAChRs, respectively. Therefore, the three types of heteromeric receptors are inhibited by bicuculline but the neuronal alpha2beta4 and alpha4beta2 receptors were more sensitive than the muscle alphabetagammadelta receptor. The Hill coefficients for ACh-current inhibition were close to one for all types of receptors, suggesting a single site of action for bicuculline inhibition of nAChRs. Bicuculline shifted the ACh-dose-current response curve to the right and the maximal current was reduced, a reduction that for the heteromeric receptors was not overcome by high concentrations of ACh. The effect of bicuculline was examined at different membrane potentials, and the ACh-current-membrane potential relationships obtained indicate that the inhibition by bicuculline is voltage-dependent for muscle alphabetagammadelta and neuronal alpha2beta4 and alpha4beta2 nAChRs. All these results are consistent with the notion that bicuculline blocks the heteromeric muscle and neuronal nAChRs in a non-competitive way. Studies were also made on the wild type (wt alpha7) and mutant leu-to-threo (L248T) homomeric human neuronal alpha7-nAChRs. In sharp contrast to the heteromeric ACh receptors examined, bicuculline blocked in a competitive way the homomeric wt alpha7-nAChRs, as evidenced by a parallel shift of the bicuculline dose-ACh-current inhibition on raising the ACh concentration. Moreover, similar to the effects of serotonin on wt and mutant alpha7 ACh receptors, the mutation converted bicuculline from an antagonist into a competitive agonist. All this suggests that bicuculline may serve as a lead molecule to design new anticholinergic substances.

Animals↗
PubMed1998

Influence of orchidectomy and ovariectomy on the blood-brain barrier permeability during bicuculline-induced seizures.

The changes in the permeability of the blood-brain barrier (BBB) during bicuculline-induced seizures were investigated in ovariectomized female and orchidectomized male rats. The rats were anesthetized with diethyl ether. Evans blue, which was used as a BBB tracer, was injected into femoral vein 5 min before administering bicuculline to induce grandmal seizures. Ten groups of rats were studied: Group I: control female; Group II: control male; Group IIl: intact female + bicuculline; Group IV: intact male + bicuculline; Group V: ovariectomized female; Group VI: orchidectomized male; Group VII: ovariectomized female + bicuculline; Group VIII: orchidectomized male + bicuculline (1.2 mg/kg, i.v.); Group IX: ovariectomized female + estrogen + bicuculline; Group X: orchidectomized male + estrogen + bicuculline. Adult male and female rats were orchidectomized and ovariectomized 3 weeks before the experiments, or sham operated under general anesthesia. During bicucculline-induced seizures, the mean arterial blood pressure increased significantly in both intact and ovariectomized and orchidectomized rats. BBB lesions were present in 80 percent of intact female rats and 50 percent of ovariectomized rats after bicuculline-induced seizures. This difference between intact and ovariectomized rats was found to be significant (p < 0.01). There was no statistically significant change in the BBB permeability between intact and orchidectomized rats after convulsion. Generating seizures in both ovariectomized and orchidectomised rats, after administrating of estrogen, did not lead to any significant alteration in BBB permeability. Our results suggest that the extravasation of Evans blue albumin was most pronounced in the brain of intact female rats when compared to ovariectomized rats after bicuculline-induced seizures. After administrating estrogen, the decreased BBB permeability values of ovariectomised rats could not reach the values in intact rats.

Animals↗
PubMed1996

Zinc modulation of bicuculline-sensitive and -insensitive GABA receptors in the developing rat hippocampus.

Intracellular recordings were used to study the effects of zinc on the bicuculline-sensitive and -insensitive responses evoked by GABA in CA3 rat hippocampal neurons in slices obtained from postnatal day (P) 0 to P8. In the absence of bicuculline, zinc inhibited GABA-induced responses in a concentration-dependent manner. This effect was developmentally regulated, being maximal (50%) between P0 and P5 and then declining to 30% after P5. In the presence of bicuculline, GABA-resistant responses were potentiated in 49% of cases, depressed in 38% and not affected in 13%. The period of maximum potentiation between P0 and P2 coincided with that of maximum expression of the bicuculline-resistant receptors. The effects of zinc were also studied using the whole-cell and outside-out configuration of the patch-clamp technique on bicuculline-sensitive and -insensitive GABA-induced currents elicited in isolated cells acutely dissociated from the same slices as those used for intracellular recordings. At a holding potential of -50 mV in symmetrical chloride solutions, GABA (50 and 100 microM) activated whole-cell inward currents which were reversibly blocked by zinc. The EC50 values for the blocking effect of zinc on currents evoked by 50 and 100 microM GABA were 6.6 nM and 5.8 microM respectively. In the presence of bicuculline (100 microM), zinc potentiated the residual responses to GABA; the response curve was bell-shaped with a peak at 1 microM. When the response to GABA was completely abolished by bicuculline, zinc (1 microM) was often able to restore it. In the presence of bicuculline, however, zinc was not able to restore the response to isoguvacine. In two excised outside-out patches, zinc (1 microM) increased the activity of opening of bicuculline-resistant GABA-evoked single channel currents (Np) from 1 to 1.87 and from 0.25 to 0.42 respectively, without changing single-channel conductance. These data suggest that down- or up-regulation of bicuculline-sensitive or -insensitive GABA receptors may be functionally important in regulating synaptic activity during development.

Animals↗
PubMed1999

Bicuculline block of small-conductance calcium-activated potassium channels.

Small-conductance calcium-activated potassium channels (SK channels) are gated solely by intracellular calcium ions and their activity is responsible for the slow afterhyperpolarization (AHP) that follows an action potential in many excitable cells. Brain slice studies commonly employ a methyl derivative of bicuculline (bicuculline-m), a GABAA (gamma-aminobutyric acid) receptor antagonist, to diminish the tonic inhibitory influences of GABAergic synapses, or to investigate the role of these synapses in specialized neural networks. However, recent evidence suggests that bicuculline-m may not be specific for GABAA receptors and may also block the slow AHP. Therefore, the effects of bicuculline-m on cloned apamin-sensitive SK2 and apamin-insensitive SK1 channels were examined following expression in Xenopus oocytes. The results show that at concentrations employed for slice recordings, bicuculline-m potently blocks both apamin-sensitive SK2 currents and apamin-insensitive SK1 currents when applied to outside-out patches. Apamin-insensitive SK1 currents run down in excised patches. The potency of bicuculline-m block also decreases with time after patch excision. Site-directed mutagenesis that changes two residues in the outer vestibule of the SK1 pore that confers apamin sensitivity also reduces run down of the current in patches, and endows stable sensitivity to bicuculline-m indistinguishable from SK2. Therefore, the use of bicuculline-m in slice recordings may mask apamin-sensitive slow AHPs that are important determinants of neuronal excitability. In addition, bicuculline-m-insensitive slow AHPs may indicate that the underlying channels have run down.

Animals↗
PubMed1981

A re-examination of the GABA-inhibitory action of bicuculline on lobster muscle.

The GABA-inhibitory action of bicuculline on lobster muscle was critically re-examined. Bicuculline (20-100 micrometers) depressed the GABA-evoked conductance increase in a reversible manner, the double reciprocal transformation of the GABA dose/conductance curves remaining linear. If bicuculline was assumed to be a pure non-competitive antagonist, then the observed depression of the GABA curves at high GABA concentrations was underestimated. Also, the action of bicuculline was not in accordance with a dualistic antagonism (competitive and pure non-competitive type). Regarding bicuculline as a "mixed" non-competitive antagonist however, gave a better overall fit to the experimental data. Combinations of bicuculline and picrotoxinin also depressed the GABA response in a manner expected from the combination of two "mixed" non-competitive antagonists. It was concluded that bicuculline (like picrotoxinin and picrotoxin) behaves as a "mixed" non-competitive rather than a pure non-competitive antagonist of GABA on lobster muscle. However bicuculline methochloride proved inactive on the lobster. Moreover, bicuculline itself became less effective in a more acidic solution (pH 5.6, where more of the protonated form would exist). An intracellular or intramembrane site of action of this antagonist was therefore postulated.

Animals↗
PubMed1993

Attenuation of anticonvulsant effects of diazepam after chronic treatment with bicuculline.

Changes in the GABAergic system after chronic treatment with bicuculline were examined in two strains of inbred rats, Fischer 344 (F344) and Lewis (LEW). Rats received an IP injection of either bicuculline (2 mg/kg) or vehicle once a day for 12 days. After this chronic treatment, the effects of diazepam (1 mg/kg, IP) and pentobarbital (20 mg/kg, IP) on bicuculline-induced convulsions were measured. Bicuculline was acutely infused into a tail vein at 0.0415 mg/min, and the infusion was terminated when rats showed seizure. Following the chronic bicuculline treatment, the anticonvulsant effect of diazepam, but not of pentobarbital, was significantly reduced as compared to its effect following chronic vehicle treatment in both strains. Both diazepam and pentobarbital showed a significant difference in anticonvulsant effects between strains (F344 > LEW). The hypnotic effects of muscimol, barbital, pentobarbital, and ethanol following chronic bicuculline treatment were examined. There was no significant difference in sleep time induced by these drugs between bicuculline- and vehicle-treated rats. These results suggest that the attenuation of diazepam's anticonvulsant effect after chronic bicuculline treatment may result from functional changes in benzodiazepine receptors and that the anticonvulsant effects of diazepam and pentobarbital may be influenced by genetic factors. Moreover, the hypnotic effects of several drugs tested are apparently not affected by chronic bicuculline treatment.

Animals↗
PubMed1988

Bicuculline up-regulation of GABAA receptors in rat brain.

Effects of acute and subacute administration of bicuculline on [3H]muscimol, [3H]flunitrazepam, and t-[35S]butylbicyclophosphorothionate ([35S]TBPS) binding to various brain regions were studied in Sprague-Dawley rats. Acute administration of bicuculline affected neither the KD nor the Bmax of the three receptor sites. In rats treated subacutely with bicuculline (2 mg/kg, i.p., daily for 10 days), [3H]muscimol binding was increased in the frontal cortex, cerebellum, striatum, and substantia nigra. Scatchard analysis revealed that subacute treatment of rats with bicuculline resulted in a significantly lower KD of high-affinity sites in the striatum and in a significantly lower KD of high- and low-affinity sites in the frontal cortex. In the cerebellum, two binding sites were apparent in controls and acutely treated animals; however, only the high-affinity site was defined in subacutely treated animals, with an increase in the Bmax value. Triton X-100 treatment of frontal cortical membranes eliminated the difference in [3H]muscimol binding between control and subacute bicuculline treatments. On the other hand, [3H]muscimol binding was significantly increased in the cerebellum from bicuculline-treated animals even after Triton X-100 treatment. The apparent Ki of bicuculline for the GABAA receptor was also decreased in the frontal cortex and the striatum following the treatment. However, subacute administration of bicuculline affected neither the KD nor the Bmax of [3H]flunitrazepam and [35S]TBPS binding in the frontal cortex and the cerebellum. These results suggest that GABAA receptors are up-regulated after subacute administration of bicuculline, with no change in benzodiazepine and picrotoxin binding sites.

Animals↗
PubMed1983

Bicuculline insensitive effects of baclofen.

The action of bicuculline on the effect of baclofen and muscimol were investigated in behavioural, biochemical and binding studies in rats. Both (+/-)-baclofen (5 mg kg-1 i.p.) and muscimol (1.4 mg kg-1 i.p.) decreased motor activity and aggressiveness. In investigated doses the drugs mentioned raised DOPAC concentration in the rat striatum. (+)-Bicuculline (1.25 mg kg-1 s.c.) potentiated the behavioural effects of baclofen but failed to alter significantly those of muscimol. The DOPAC rise caused by baclofen and muscimol was not substantially affected by bicuculline. 3H-GABA binding to bicuculline insensitive GABA sites was determined in the rat striatal tissue. (+)-Bicuculline was used to suppress bicuculline sensitive GABA binding. Two GABA binding sites were revealed in the presence of calcium ions of which the low affinity site (KD = 447 nM, B max = 109 pmol g-1 protein) was affected by bicuculline whereas the high affinity site (KD = 8 nM, B max = 24 pmol g-1 protein) was not. Muscimol, GABA and (+/-)-baclofen bound in vitro to these GABA sites with IC50, 44, 49 and 431 nM respectively. The involvement of bicuculline insensitive GABA sites in the effects of (+/-)-baclofen on behaviour and dopamine metabolism is suggested.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1992

Effects of bicuculline on [3H]SR 95531 binding in discrete regions of rat brains.

Effects of bicuculline in vitro, and acute and chronic treatment of a subconvulsive dose of bicuculline on [3H]SR 95531 binding to discrete regions of rat brains were studied in Sprague-Dawley rats. Scatchard analysis of the binding isotherms exhibited two populations of binding sites for [3H]SR 95531 in frontal cortex, cerebellum, striatum and substantia nigra. The apparent KD for high-affinity sites was significantly increased in the frontal cortex and cerebellum in the presence of bicuculline (1 microM) with no change in Bmax. In contrast, the apparent affinity for low-affinity sites was not altered in the presence of bicuculline in these regions, whereas the Bmax was significantly decreased in the cerebellum. Following acute (2 mg/kg, i.p.) or chronic (2 mg/kg, i.p. for 10 days) bicuculline treatment, [3H]SR 95531 binding was also investigated in various regions of brains. The acute bicuculline treatment did not affect the [3H]SR 95531 binding in any of the regions studied. In contrast, apparent affinity for [3H]SR 95531 was significantly decreased in low-affinity sites of all regions studied in rats treated chronically with bicuculline. The Bmax values of high and low-affinity sites were significantly increased in the cerebellum with no change in the frontal cortex, striatum and substantia nigra. The present study demonstrates that chronic bicuculline treatment decreases apparent affinity of [3H]SR 95531 binding whereas the treatment increases apparent affinity of [3H]muscimol binding (1) in various brain regions. The results indicate that significant increase in Bmax of [3H]SR 95531 and [3H]muscimol binding in the cerebellum may be due to true up-regulation of GABA binding sites, involving increased de novo synthesis of receptor protein.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

ucb L059, a novel anticonvulsant, reduces bicuculline-induced hyperexcitability in rat hippocampal CA3 in vivo.

Local diffusion of bicuculline from a bicuculline-containing recording micropipette increased the orthodromic field population spike (PS2), elicited upon commissural stimulation in the hippocampal CA3 region of anaesthetized rats. This increase in PS2 was consistently reduced by 5.4 mg/kg of the novel anticonvulsant drug ucb L059 ((S)-alpha-ethyl-2-oxo-pyrrolidine acetamide), when injected i.v. 10 min prior to lowering in place the bicuculline-containing micropipette. ucb L059 had no effect on PS2 in the absence of bicuculline. Paired-pulse stimulation produced marked inhibition of the second PS2 at low interstimulus interval, an effect which was significantly reduced by bicuculline. Although ucb L059 reduced the effect of bicuculline on both PS2S elicited by paired stimulations, the drug did not alter the reduction by bicuculline of paired-pulse inhibition at low interstimulus interval. These results suggest that ucb L059 prevents increases in CA3 neuronal excitability by bicuculline through a non gamma-aminobutyric acid-ergic mechanism.

Animals↗
PubMed1990

Bicuculline actions on isolated rat atria, mouse vas-deferens and guinea-pig ileum are unrelated to GABA A receptor blockade.

1. Some new pharmacological activities of bicuculline were found in isolated rat atria, mouse vas deferens and guinea-pig ileum. 2. In isolated rat atria bicuculline (10-300 microM) induced potent positive inotropic and negative chronotropic effects which were not antagonized by propranolol (1 microM), 6-hydroxydopamine pretreatment (50 mg/kg i.v. twice), ranitidine (3 microM) or atropine (1 microM). Bicuculline (10-300 microM) potentiated electrically evoked contractions in mouse vas deferens and inhibited them (30-500 microM) in guinea-pig ileum. It was inactive on unstimulated mouse vas deferens. 3. The above effects were completely reproduced by the bicuculline related-substance, beta-hydrastine, but not by the bicuculline N-methyl derivative, bicuculline methiodide (BMI), on the isolated rat atria. BMI inhibited instead of potentiating the mouse vas deferens twitches and potentiated instead of inhibiting the guinea-pig ileum twitches. 4. Picrotoxin, the other classic non-competitive GABA A antagonist, was completely devoid of the effects reported for bicuculline. 5. We concluded that, on the three preparations studied, bicuculline possesses some effects which are unrelated to its GABA A receptor blocking activity.

Animals↗
PubMed1997

Influence of gender and gonadectomy on bicuculline-induced convulsions and on GABAA receptors.

The response to IV administration of GABAA receptor antagonist bicuculline was studied in young (30 days) and in adult gonad-intact or gonadectomized male and female rats. The properties of GABAA receptors, obtained from cortex and cerebellum 30 days following gonadectomy, and the affinity of muscimol and bicuculline for cortical and cerebellar GABA binding sites were also studied. While young rats failed to show sex differences, the threshold doses of bicuculline producing the first myoclonic twitch and running/bouncing clonus (RB clonus) were lower in adult male than female rats. Fifteen days after gonadectomy or sham operation male rats needed less bicuculline to the onset of myoclonic twitch and RB clonus than identically treated females, while orchidectomized rats needed more bicuculline to the onset of tonic hindlimb extension than all other groups examined. All sex differences disappeared 30 days following gonadectomy. At the same time, in males gonadectomy decreased the affinity and enhanced the density of cortical 3H-muscimol binding sites. In female rats, gonadectomy only decreased the affinity of cortical GABAA receptors. Only regional but not sex differences were observed in the affinity of muscimol and bicuculline for GABAA receptors. Sex differences in the threshold doses of bicuculline-producing convulsions do not correlate either with the properties of cortical and cerebellar GABAA receptors or with the affinity of bicuculline for the same binding sites.

Animals↗
PubMed1996

Involvement of glutamate receptors in strychnine- and bicuculline-induced allodynia in conscious mice.

BACKGROUND: Glycine and gamma-aminobutyric acid (GABA) are inhibitory neurotransmitters that appear to be important in sensory processing in the spinal dorsal horn. Intrathecal administration of strychnine (strychnine-sensitive glycine receptor antagonist) or bicuculline (GABAA antagonist) was reported to induce allodynia. Although the strychnine-induced allodynia was shown to be mediated through the N-methyl-D-aspartate (NMDA)-type glutamate receptor, it is not clear whether the bicuculline-evoked-allodynia is mediated through the glutamate receptor system or how different the allodynia induced by strychnine and bicuculline are. METHODS: Male ddY mice weighing 20 +/- 2 g were used in this study. A 27-G stainless-steel needle attached to a microsyringe was inserted between the L5 and L6 vertebrae by a slight modification of the method of Hylden and Wilcox. Drugs in vehicle were injected slowly into the subarachnoid space to conscious mice at 22 +/- 2 degrees C. The volume of the intrathecal injection was 5 microliters. Studies on allodynia were carried out essentially according to the method of Yaksh and Harty. RESULTS: The intrathecal administration of strychnine or bicuculline in conscious mice resulted in allodynia elicited by nonnoxious brushing of the flanks. The maximum allodynia induced by strychnine was observed 5 min after intrathecal injection, but that induced by bicuculline was observed 10 min after intrathecal injection. Both responses gradually decreased over the experimental period of 50 min. The allodynia induced by strychnine was dose-dependently relieved by NMDA receptor antagonists (D-AP5, ketamine, and 7-C1-KYNA) and non-NMDA receptor antagonists (GAMS and CNQX) but not by metabotropic receptor antagonists (L-AP3 and L-AP4). On the other hand, allodynia induced by bicuculline was dose-dependently relieved by GAMS, L-AP3, and L-AP4, but not by D-AP5, ketamine, 7-C1-KYNA, and CNQX. Whereas the strychnine-evoked allodynia was dose-dependently relieved by the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) and the soluble guanylate cyclase inhibitor methylene blue, the bicuculline-induced one was dose-dependently relieved by methylene blue but not by L-NAME. CONCLUSIONS: These results demonstrate that both strychnine- and bicuculline-evoked allodynia were mediated through pathways that include the glutamate receptor and nitric oxide systems but in a different manner. the current study suggests that GABA and glycine may modulate responses to an innocuous tactile stimulus as inhibitory neurotransmitters at presynaptic and postsynaptic sites in the spinal cord, respectively.

Animals↗