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At least 991 records · Page 55Linked to original sources
PubMed1984

Evidence for association of a high affinity avermectin binding site with the benzodiazepine receptor.

Avermectin B1a concentrations corresponding to the KD value of a specific high affinity binding site for [3H]avermectin B1a are sufficient to stimulate the specific high affinity binding of [3H]flunitrazepam to its receptors. This stimulation of [3H]flunitrazepam binding by low concentrations of avermectin B1a was enhanced by chloride ions and picrotoxinin and reduced by the GABA agonists THIP and PSA. The similar modulation by chloride ions, GABA agonists and picrotoxinin and the resistance against washing of membranes of avermectin B1a bound to its specific high affinity binding site or to the site modulating [3H]flunitrazepam binding indicate a close association of the specific high affinity binding site for [3H]avermectin B1a with the GABA-benzodiazepine receptor complex.

Animals↗
PubMed1987

Benzodiazepine receptors are involved in tabernanthine-induced tremor: in vitro and in vivo evidence.

Tabernanthine, an indol alkaloid, is structurally related to carbolines (harmane, harmaline) which, in vitro, displace specific flunitrazepam binding to brain benzodiazepine receptors. In vivo, both tabernanthine and carbolines cause a fine general tremor, suggesting that a possible interaction with benzodiazepine receptors could be involved in the activity of tabernanthine. This hypothesis was validated by the in vitro and in vivo antagonism of benzodiazepine by tabernanthine. In vitro, tabernanthine inhibited specific flunitrazepam binding in a competitive manner with an affinity (IC50 150 microM) in the same range as harmane. Tabernanthine appeared as a benzodiazepine receptor inverse agonist in a discriminant in vitro binding assay. In vivo, the time course of tremorigenic activity was related to the tabernanthine concentration in brain (half-life = 2 h). Moreover, tabernanthine-induced tremor was inhibited reversibly by flunitrazepam or by Ro-15 1788 (an antagonist of benzodiazepine-receptors). These results suggest that part of the action of tabernanthine may be mediated by an interaction at the benzodiazepine receptor level.

Alkaloids↗
PubMed1987

GABA induces down-regulation of the benzodiazepine-GABA receptor complex in the rat cultured neurons.

Cultured neurons from embryonic rat brain display central type benzodiazepine receptors characterized by high-affinity binding of [3H]flunitrazepam which is allosterically enhanced in the presence of gamma-aminobutyric acid (GABA). A 48 h treatment of the cultured neurons with 1 microM diazepam, 0.1 microM clonazepam or 0.1 microM beta-carboline ester derivatives did not change either Bmax or KD values of the [3H]flunitrazepam specific binding. A 48 h incubation in the presence of GABA (1 mM) or muscimol (0.1 mM) induced a 30% decrease of the Bmax value of [3H]flunitrazepam specific binding without change of the KD value. The down-regulation was dependent on GABA concentrations and temperature, and was partially inhibited by bicuculline but not by the benzodiazepine antagonist Ro 15-1788. The other subunits of the benzodiazepine-GABA-chloride channel receptor complex also seemed to be down-regulated by GABA since there was a decrease of the specific binding of [3H]muscimol and [35S]t-butylbicyclophosphorothionate (TBPS) to the GABAA and chloride channel sites respectively. The GABA-induced down-regulation of the GABA-benzodiazepine receptor seems to be selective since the specific binding of ligands to other receptors was not affected. Our results suggests that activation of the low-affinity GABA subunit which is involved in cellular electrophysiological responses, induced the receptor down-regulation.

Animals↗
PubMed1989

Chronic diazepam treatment produces regionally specific changes in GABA-stimulated chloride influx.

GABA-stimulated 36Cl- influx was used to investigate regional differences in response to chronic diazepam treatment by comparing cortical and cerebellar tissue from rats chronically treated with diazepam for 3 weeks. Using a treatment protocol which has previously been shown to produce behavioral tolerance and physical dependence, cortical membrane preparations from chronic diazepam-treated rats were found to exhibit a decreased responsiveness to the stimulation of 36Cl- influx by GABA and a corresponding decrease in the ability of flunitrazepam to enhance GABA-stimulated 36Cl-influx. This decrease in sensitivity to flunitrazepam, however, appears to reflect the underlying decrease in sensitivity to GABA. In contrast, in membrane vesicles prepared from cerebella of chronic diazepam-treated rats, there was no measurable effect on GABA-stimulated 36Cl--influx or on the enhancement of GABA-stimulated 36Cl- influx by flunitrazepam. These results support the suggestion that there is a regionally specific reduction in GABA/benzodiazepine receptor function following chronic benzodiazepine treatment.

Animals↗
PubMed1996

N3-phenacyluridine, a novel hypnotic compound, interacts with the benzodiazepine receptor.

N3-Phenacyluridine (3-phenacyl-1-beta-D-ribofuranosyluracil) has potent sedative and hypnotic activities following intracerebroventricular injection in mice. To study the mechanism of action of N3-phenacyluridine, the interaction of this compound with the benzodiazepine receptor has been investigated. Results obtained showed that this compound inhibited specific binding of [3H]flunitrazepam to synaptic membranes of bovine cortex in a concentration-dependent fashion (IC50 = 129 microM). Scatchard analysis of [3H]flunitrazepam binding revealed that N3-phenacyluridine interacted with the ligand at the benzodiazepine receptor binding site in a competitive manner. Ro15-1788 (8-fluoro-3-carboethoxy-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5a ]1, 4-benzodiazepine), a benzodiazepine receptor antagonist, also inhibited the specific binding of [3H]flunitrazepam in the presence of the compound. The results suggest that the pharmacological activity of N3-phenacyluridine may be partially mediated through the benzodiazepine receptor.

Analysis of Variance↗
PubMed1987

Coexistence of central and peripheral benzodiazepine binding sites in the human pineal gland.

The pineal gland and particularly its major hormone, melatonin, may participate in several physiological functions, including sleep promotion, anticonvulsant activity and the modulation of biological rhythms and affective disorders. These effects may be related to an interaction with benzodiazepine receptors, which have been demonstrated to be present in the pineal gland of several species including man. The present study examined the characteristics of benzodiazepine binding site subtypes in the human pineal gland, using [3H]flunitrazepam and [3H]PK 11195 as specific ligands for central and peripheral type benzodiazepine binding sites respectively. Scatchard analysis of [3H]flunitrazepam binding to pineal membrane preparations was linear, indicating the presence of a single population of sites. Clonazepam and RO 15-1788, which have a high affinity for central benzodiazepine binding sites, were potent competitors for [3H]flunitrazepam binding in the human pineal, whereas RO 5-4864 had a low affinity for these sites. Analyses of [3H]PK 11195 binding to pineal membranes also revealed the presence of a single population of sites. RO 5-4864, a specific ligand for peripheral benzodiazepine binding sites was the most potent of the drugs tested in displacing [3H]PK 11195, whereas clonazepam and RO 15-1788 were weak inhibitors of [3H]PK 11195 binding to pineal membranes. Overall, these results demonstrate, for the first time, the coexistence of peripheral and central benzodiazepine binding sites in the human pineal gland.

Aged↗
PubMed1982

Effect of ethanol administration and withdrawal on benzodiazepine receptor binding in the rat brain.

Administration of single doses of ethanol or presence of ethanol in the incubation medium does not change 3H-flunitrazepam binding in rat cerebral cortex, hippocampus and cerebellum. In rats made dependent on ethanol by three daily ethanol administrations for six days and sacrifices 1 hr after the last ethanol dose 3H-flunitrazepam binding is decreased in the cerebral cortex and cerebellum. This decrease is present only in membranes preincubated with Triton X-100 and is due to decreased number of binding sites. In rats sacrificed 16 hours after the last chronic ethanol dose the 3H-flunitrazepam binding returns to control levels.

Animals↗
PubMed1983

Novel non-benzodiazepine anxiolytics.

Several new non-benzodiazepine anxiolytics are reported. These include tracazolate, zopiclone, CL218,872, CGS9896, buspirone, MK-801 and fenobam. A comparison of anticonflict effects and propensity to cause sedation and potentiate the actions of ethanol is given as well as their effects upon the binding of [3H]flunitrazepam in vitro. Their anxiolytic properties after treatment with the benzodiazepine antagonist, RO15-1788, are reported also. Tracazolate shows a wide separation between anxiolytic activity and ability to cause sedation and to potentiate alcohol. It enhanced binding of [3H]-flunitrazepam in contrast to benzodiazepines which displace it. Buspirone was without anticonflict activity and had no effect on benzodiazepine binding while fenobam and MK-801, also without effect on binding, showed large and small differences on causing sedation and potentiating alcohol respectively. Among the displacers of [3H]flunitrazepam zopiclone showed diminished sedation liability, compared to diazepam, as did CL218,872 and CGS9896. Zopiclone caused potentiation of ethanol however, at doses close to anxiolytic doses, while CL218,872 and CGS9896 showed a wider safety margin for potentiation of ethanol compared to anxiolytic doses. The drug RO15-1788 antagonised the anticonflict effects of benzodiazepine displacers and had no effects upon the other agents studied.

Animals↗
PubMed1985

Trazodone and m-chlorophenylpiperazine. Concentration in brain and receptor activity in regions in the brain associated with anxiety.

Trazodone, its active metabolite 1-(m-chlorophenyl)piperazine (mCPP) and two isomers of mCPP were tested for affinity to the binding sites for [3H]flunitrazepam ([3H]FLU) and [3H]p-aminoclonidine ([3H]pAC) in the frontal cortex, amygdala and hippocampus of the rat. When tested at the binding site for [3H]flunitrazepam, trazodone showed an average IC50 of 1.7 mM in all three regions of the brain while mCPP yielded an average IC50 of 0.36 mM. These same two compounds, when tested at the binding site for [3H]p-aminoclonidine, resulted in an average IC50 of 4.5 microM for trazodone and 0.6 microM for mCPP. When plasma values of trazodone and mCPP in the rat were similar to those obtained in patients given therapeutic doses, the concentrations of trazodone were found to be between 6 and 7 microM and between 2 and 3 microM for mCPP in the same brain regions of the brain used in the binding assays. Thus, a sufficient concentration of trazodone and mCPP can accumulate in brain tissue to displace approx. 50% of the [3H]p-aminoclonidine from its binding site but very little [3H]flunitrazepam from its binding site. These results, combined with the reported anxiolytic effects of the alpha-2 agonist, clonidine and the noradrenergic hyperactivity theory of anxiety, indicate that the mechanism of the anxiolytic activity of trazodone, may be a direct action on the central alpha-2 binding site.

Animals↗
PubMed1986

Effect of chronic treatment of ethanol on benzodiazepine and picrotoxin sites on the GABA receptor complex in regions of the brain of the rat.

Ethanol has been shown to enhance gamma-aminobutyric acid (GABA)ergic transmission. In this study an examination was made of the effect of chronic treatment with ethanol and its withdrawal at 24 h on the binding of [3H]flunitrazepam and [35S]t-butylbicyclophosphorothionate (TBPS) to brain regions in rat. Rats were rendered tolerant to, and dependent on, ethanol by an intragastric intubation method. The affinity (KD) or the binding capacity (Bmax) of [3H]flunitrazepam or [35S]TBPS was not altered by chronic treatment with ethanol or during withdrawal from ethanol. Neither the enhancing effect of GABA on the binding of [3H]flunitrazepam nor its inhibitory effect on the binding of [35S]TBPS were affected by chronic treatment with ethanol or its withdrawal at 24 h. These results suggest that the sensitivity of benzodiazepine and picrotoxin sites on the oligomeric GABA receptor complex is not affected during tolerance to, or withdrawal from ethanol. It is suggested that the effects of ethanol on GABAergic transmission may be produced at the level of coupled chloride ion channels.

Animals↗
PubMed1989

Gamma-aminobutyric acid and benzodiazepine receptors in cultured cerebellar granule cells: effects of taurine and its lipophilic derivatives.

The effects of taurine and some lipophilic derivatives of taurine on binding to GABA and benzodiazepine receptors were studied in intact cerebellar granule cells. The phenylsuccinylimido derivatives of taurine appeared to increase the binding of muscimol in micromolar concentrations, while taurine decreased it slightly. Only minor changes were seen in the basal binding of flunitrazepam, whereas stimulation of the binding by GABA was strongly reduced by piperidino, benzamido and phenyl-succinylimidotaurine with taurine itself again showing only a weak effect. Diphenylhydantoin, which bears structural resemblance to the phenylsuccinylimido group, had a strong effect on the stimulated binding of flunitrazepam and it also slightly reduced the basal level of binding. Thus, it seems possible that the effects of the phenylsuccinylimido derivatives of taurine on the binding of flunitrazepam were due to this chemical structure and not to the taurine-like core of the molecules. The phthalimido derivative of taurine, taltrimide, which has been tested in clinical trials with epileptic patients, did not show any activity in the binding studies.

Animals↗
PubMed1995

Autoradiographical study of types 1 and 2 of benzodiazepine receptors in rat brain after chronic ethanol treatment and its withdrawal.

The effect of chronic ethanol treatment, and its withdrawal on benzodiazepine binding sites in rat brain is described in this autoradiographical study using the benzodiazepine agonist [3H]flunitrazepam. Several areas of the rat cerebral cortex, hippocampus, mesencephalon, cerebellum and lateral geniculate nucleus were studied in animals, chronically treated with ethanol, and 24 or 48 hr after ethanol withdrawal. The [3H]flunitrazepam binding and the relative percentages of binding to BZ1 and BZ2 sites, using zolpidem as a BZ1 site inhibitor, are described. The cerebellum and red nucleus, which only express BZ1 binding sites, appear to be areas significantly modified by ethanol and its withdrawal. In no other structure did ethanol modify [3H]flunitrazepam binding nor change the relative percentage of BZ1 and BZ2 sites.

Animals↗
PubMed1986

Benzodiazepine binding sites in mice forebrain and kidneys: evidence for similar regulation by GABA agonists.

Benzodiazepine binding sites in mice forebrain and kidney homogenate were labelled either in vivo (SC injection) or in vitro by 3H-flunitrazepam. The binding in both cases was carried out in vitro in the presence or absence of 10 microM unlabelled flunitrazepam during 60 min at 0 degrees C. When benzodiazepine binding sites were labelled in vivo pretreatment of animals with muscimol (0.75 and 1.5 mg/kg, IP) and fenibut (25 and 100 mg/kg, IP) in a dose-dependent manner facilitated 3H-flunitrazepam binding both in mice forebrain and kidneys. In vitro labelling of benzodiazepine binding sites demonstrated similar to in vivo labelling in forebrain but not in kidneys. The peripheral benzodiazepine binding sites in kidneys are therefore modulated similarly to benzodiazepine binding sites in forebrain by GABA-ergic drugs.

Animals↗
PubMed1994

Development pattern of the GABAA-benzodiazepine receptor ionophore complex in primary cultures of cortical neurons.

The development pattern of the GABAA/benzodiazepine (BZ) receptor ionophore complex was characterized in mammalian cortical cultured neurons utilizing radioligand binding and GABA-induced 36Cl-influx. The specific binding of [3H]flunitrazepam, [3H]Ro15-1788 and [3H]Ro15-4513 increased with time from day 3 to day 21. The EC50 value and Emax of the GABA, muscimol and pentobarbital to enhance [3H]-flunitrazepam binding did not change during the development. Furthermore, GABA-induced 36Cl- influx also did not change during development from day 3 to day 21. However, the potency of ligands that bind to type-1 BZ receptors (alprazolam, zolpidem and C1218,872) to inhibit [3H]flunitrazepam binding increased from day 7 to day 21. Taken together, these data suggest the presence of type-II BZ receptors in early stages of the development which appears to change to type-I BZ receptors with age in the cortical neurons in culture.

Affinity Labels↗
PubMed1990

Thymopentin antagonizes stress-induced changes of GABA/benzodiazepine receptor complex.

Intraperitoneal administration of thymopentin, a thymopentin II-derived pentapeptide, had no stable and evident effect in the two anxiety models (elevated plus-maze and licking-conflict test) studied. However, in the elevated plus-maze test thymopentin antagonized the behavioral effects of DMCM, a beta-carboline derivative with anxiogenic properties. Further, it was demonstrated that the licking-conflict test procedure itself produced a significant elevation of plasma corticosterone levels, increased the number of [3H]flunitrazepam and decreased the number of [3H]muscimol binding sites in rat hippocampus. The forced-swimming stress similarly to the licking-conflict test also caused an increase in hippocampal [3H]flunitrazepam binding sites. Although ineffective behaviorally in the tests for anxiety, thymopentin pretreatment effectively reversed the changes in corticosterone levels caused by the licking-conflict test. Moreover, it normalized the changed number of benzodiazepine and GABA receptors after stressful stimuli. It is well known that not all anxiolytic drugs (i.e. buspirone) are equally active in behavioral tests for anxiety. According to our data we propose that thymopentin has stress-protective activity. As in vivo and in vitro thymopentin did not change [3H]-flunitrazepam and [3H]muscimol binding, the direct effect of this peptide on the GABA-benzodiazepine-Cl- ionophore receptor complex is unlikely. The action of this peptide on GABA release and/or metabolism can be suggested.

Animals↗
PubMed1994

Agonist administration in ovo down-regulates cerebellar GABAA receptors in the chick embryo.

Chick embryos with an undeveloped blood-brain barrier were used to examine the down-regulation of GABAA receptors in vivo. The GABAA receptor agonist isoguvacine (5 mumol) was applied to the vascularized chorioallantoic membrane of 8 day embryos. This treatment was repeated on embryonic days 11, 14, and 17, and the embryos were sacrificed on day 18 (stage 42). Isoguvacine administration reduced the clonazepam-displaceable binding of [3H]flunitrazepam to washed cerebellar membranes by 34.0 +/- 3.0% compared to vehicle-treated controls. Binding reductions of lower magnitude were found in membranes from the cerebrum and optic lobes. Administration of isoguvacine had no significant effect on the wet weights of whole embryos or cerebella, the yield of cerebellar membranes, or the binding of [3H]N-methylscopolamine. The reduction of [3H]flunitrazepam binding to cerebellar membranes was dose-dependent, allowing a half saturation value of 8 microM isoguvacine to be estimated. Scatchard analysis showed that the Bmax for [3H]flunitrazepam binding was reduced by 28.3 +/- 6.7% compared to controls, without a change in the Kd. Embryonic exposure to isoguvacine also caused a reduction of 43.6 +/- 6.0% in the binding of the GABAA receptor channel ligand [35S]t-butylbicyclophosphorothionate to washed cerebellar membranes. Taken together, these results indicate that isoguvacine induces a down-regulation of the receptor subunits in vivo. However, measurements of cerebellar GABAA receptor mRNAs for the alpha 1, beta 2L, beta 2S, beta 4, gamma 1, gamma 2L, and gamma 2S subunits by reverse transcriptase-polymerase chain reaction (RT-PCR) revealed no significant alterations by isoguvacine administration. The data suggest that translational or post-translational mechanisms, rather than those modulating the synthesis or stability of subunit mRNAs, take precedence in establishing GABAA receptor down-regulation.

Allantois↗
PubMed1994

Effects of thyroxine and its related compounds on cerebral GABA receptors: inhibitory action on benzodiazepine recognition site in GABAA receptor complex.

The effects of thyroxine and its related derivatives on gamma-aminobutyric acid (GABA) receptors in the rat brain were examined. D-Thyroxine strongly inhibited [3H]flunitrazepam binding to benzodiazepine receptor in crude synaptic membrane from the rat brain. The Scatchard analysis of the [3H]flunitrazepam binding in the presence of D-thyroxine indicated the decreases in the affinity and maximum number of binding site. Furthermore, D-thyroxine inhibited the enhancing effect of flunitrazepam on GABA-stimulated 36Cl- influx into membrane vesicles, although GABA-stimulated 36Cl- influx alone was not affected by D-thyroxine. On the other hand, the effects of thyroxine and its related derivatives on cerebral GABAB receptor binding were not noted. These results suggest that D-thyroxine may be a drug which is able to modulate the function of GABAA receptor complex via the inhibitory action on benzodiazepine recognition site.

Animals↗
PubMed1988

Benzodiazepine receptors in human brain: characterization, subcellular localization and solubilization.

1. Benzodiazepine receptors have been characterized in human brain mainly using [3H]-Ro 15-1788 and [3H]-flunitrazepam. Both ligands present a very high affinity for the receptor sites (Kd values of 0.56 and 1.53 nM respectively). 2. GABA enhanced the affinity of [3H]-flunitrazepam and [3H]-diazepam, but not that of [3H]-Ro 15-1788 and [3H]-methyl-beta-carboline 3-carboxylate for their specific binding sites as well in cerebral as in cerebellar human cortex. 3. Subcellular distribution of the benzodiazepine receptors revealed a main synaptosomal localization in human cerebral cortex, cerebellum and striatum. 4. Solubilized benzodiazepine receptors were obtained using 0.5% sodium deoxycholate and were characterized with [3H]-Ro 15-1788. The solubilized receptors are still coupled to GABA receptors since the [3H]-flunitrazepam specific binding was enhanced in the presence of micromolar concentrations of GABA.

Brain↗