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PubMed1986

Acute, stress-induced changes in the benzodiazepine/gamma-aminobutyric acid receptor complex are confined to the chloride ionophore.

Rapid and robust changes in the chloride ionophore component of the benzodiazepine/gamma-aminobutyric acid receptor complex ("supramolecular complex") were observed in the central nervous system of rats exposed to a brief, ambient temperature swim stress. Stress-induced modification of the chloride ionophore was manifest as an increase in the efficacy of halides (Cl-, Br- and I-) to enhance [3H]flunitrazepam binding. In contrast, neither gamma-aminobutyric acid-enhanced [3H]flunitrazepam binding nor [3H] flunitrazepam binding assayed in the absence of halide ions was altered by stress. Furthermore, the number of [35S]t-butylbicyclophosphorothionate binding sites and the apparent affinity of this radioligand were increased as a result of stress, as was the ability of Cl- and low concentrations of muscimol to increase the binding of this radioligand. These changes could represent the physiological attempt of an organism to compensate for stressful changes in the environment.

Animals↗
PubMed1986

Transmembrane topology and subcellular distribution of the benzodiazepine receptor.

The distribution and transmembrane topology of benzodiazepine receptors were investigated in situ using intact and saponin-treated neurons of brain cell cultures. Reversible ligand binding and photoaffinity labeling, using 3H-flunitrazepam as a probe, were employed in conjunction with trypsin-induced exhaustive proteolysis and competition binding using a novel benzodiazepine (Ro7-0213) that contains a quaternary ammonium moiety bearing a full positive charge. About 80% of the benzodiazepine receptors, with apparent subunit molecular weights of 48,000 and 51,000, are located in the surface membrane and contain one or more trypsin-sensitive sites exposed at the extracellular surface. The ligand recognition sites of the surface receptors are orientated toward the extracellular space and are sensitive to both competition by Ro7-0213 and trypsin attack. Approximately 20% of the receptors are intracellular or sequestered and are insensitive to both trypsin and competition by Ro7-0213 in intact cells. Strikingly, all of the 3H-flunitrazepam photolabeled sites inaccessible to competition by Ro7-0213 are also resistant to extracellular trypsin, but are sensitive to trypsin and Ro7-0213 in saponin-treated cells. This result provides strong evidence for protected receptors. Surface receptors are differentially sensitive to trypsin-induced inactivation such that 57% (of total) are inactivated, while 24% (of total) are cleaved but, surprisingly, retain the capacity to bind 3H-flunitrazepam. The observation that the ability of the receptor fragment to bind ligand is unaltered demonstrates that the integrity of the benzodiazepine binding site is not contingent upon the presence of about half of the intact polypeptide chain.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Interaction of carbolines and some GABA receptor ligands with the GABA and the benzodiazepine receptors.

The binding of different drugs were investigated on benzodiazepines and GABA receptors using P2 fraction or 0.05% Triton X-100 treated membrane preparation (TX-100 P) obtained from rat's CNS. Bicuculline and picrotoxin have the ability to modulate the specific 3H-flunitrazepam binding to its receptor present in P2 fraction; this modulation decreases for bicuculline and disappears for picrotoxin when a TX-100 P was used. Bicuculline at the opposite of picrotoxin displaces 3H-GABA binding on TX-100 P. The beta-CCE binds to the brain benzodiazepines receptor with a high affinity (IC50 = 8.5 nM on TX-100 P) and does not inhibit the binding of 3H-GABA on TX-100 P. On the contrary, other related carbolines such as harmine, harmaline, harmane and harmalol have a much lower ability to inhibit flunitrazepam binding (IC50 between 28 and 130 microM with TX-100 P) and can also inhibit 3H-GABA binding (IC50 between 75 and 186 microM with TX-100 P). But the inhibition of 3H-GABA binding by those related carbolines can't be reversed by a benzodiazepine like flunitrazepam or a benzodiazepine antagonist like Ro 15-1788.

Animals↗
PubMed1987

[Independent benzodiazepine and beta-carboline binding sites in the brain of aggressive and anxious-defensive mice].

Distribution of specific 3H-flunitrazepam and 3H-beta-carboline-3-carboxylate binding sites in the brain regions of aggressive and timid-defensive mice was investigated before and after subchronic injection of diazepam (5 mg/kg). The absence of differences between the affinity and concentration of 3H-flunitrazepam binding sites in diencephalon and brain cortex in aggressive and defensive mice may be explained by general benzodiazepine receptor reaction on isolation and agonistic interaction stress. Significant predominance of 3H-beta-carboline-3-carboxylate binding sites in the brain cortex, as compared to the concentration of 3H-flunitrazepam binding sites suggests the presence of specific binding sites for beta-carbolines, which have specific distribution in the brain.

Aggression↗
PubMed1988

Isoquinoline and peripheral-type benzodiazepine binding in gliomas: implications for diagnostic imaging.

Binding of the isoquinoline PK 11195 and of the benzodiazepines Ro5-4864 and flunitrazepam was compared in glioma cells and tissues. In human and rat glioma cell cultures [3H]PK 11195 bound with higher affinity (Kd = 14.01 and 15.76 nM, respectively) than either Ro5-4864 (Ki = 1200 and 84.9 nM, respectively) or flunitrazepam (Ki greater than 10,000 and = 848 nM, respectively). Autoradiograms of postmortem human brain sections containing glioma revealed that [3H]PK 11195 bound specifically to intact tumor cells and not to cells of normal cerebral cortex or necrotic areas of the tumor. Total [3H]Ro5-4864 or [3H]flunitrazepam binding to these sections was indistinguishable from nonspecific binding, and regions of tumor and normal brain could not be delineated. These results support the use of radiolabeled PK 11195 for clinical trials of imaging human gliomas by positron emission tomography.

Benzodiazepines↗
PubMed1980

A comparative study between two new benzodiazepine hypnotics.

Flunitrazepam (Rohypnol) 2,0 mg and triazolam (Halcion) 0,5 and 1,0 mg were compared clinically as hypnotics in 120 patients the night before operation. The patients were divided into three groups of 40 each. Both substances proved to be active and resulted in the patients experiencing a better quality of sleep than normal. Triazolam 0,5 mg induced sleep in 65% of patients within 30 minutes. The corresponding figures for triazolam 1,0 mg and flunitrazepam 2,0 mg were 60% and 55%, respectively. Flunitrazepam 2,0 mg had a pronounced soporific action on the trial population and the majority of patients slept for longer than 8 hours.

Adult↗
PubMed1984

[Changes in the number of benzodiazepine receptors in different parts of the brain of rats after neuroleptic withdrawal].

It has been demonstrated in experiments on rats receiving chronic (16 days) treatment with haloperidol (1.0 mg/kg/day), sulpiride (50 mg/kg/day) and clozapine (10 mg/kg/day) that binding of 3H-flunitrazepam in the striatum, limbic system, and cortex is reduced at the 5th day after withdrawal of the neuroleptics. That release was determined by the diminution of the number of receptors without changing in the dissociation constant. The reduction in the density of benzodiazepine receptors (BD-receptors) after withdrawal of the neuroleptics attests to their agonistic effect on BD-receptors. Apparently these changes are not linked with a direct effect of the neuroleptics on BD-receptors, since they displace 3H-flunitrazepam in experiments in vitro only at micromolar concentrations. It is assumed that the reduction in 3H-flunitrazepam binding is mediated via the GABAergic system transsynaptically in response to increase in the number of dopamine (neuroleptic) receptors.

Animals↗
PubMed1982

Temperature dependence of the benzodiazepine-receptor interaction.

The temperature dependence of the interaction of three benzodiazepines with their receptors in rat brain membranes containing about 2 microM (endogenous) gamma-aminobutyric acid was investigated. van't Hoff plots of the equilibrium dissociation constants were linear for [3H]diazepam and its N-desmethyl derivative (N-desmethyldiazepam, NDz), whereas for [3H]flunitrazepam a break between two linear portions occurred at about 10 degrees. Binding of diazepam, NDz, and flunitrazepam (for the latter, at temperature greater than 10 degrees) is enthalpy-driven (delta H approximately -40 to -50 kJ/mole with a negligible contribution from delta S. The latter result indicates that the interaction is not a simple hydrophobic association, but that it may be more complex in nature, possibly involving a conformational transition of the receptor-ligand complex. The activation energy for dissociation of the [3H]flunitrazepam- and [3H]diazepam-receptor complexes is about 100 kJ/mole. Consequently, the complexes dissociate about 100 times faster on changing temperature from 0 degrees to 37 degrees.

Animals↗
PubMed1983

A gamma-aminobutyric acid/benzodiazepine receptor complex of bovine cerebral cortex.

The gamma-aminobutyric acid/benzodiazepine receptor from bovine cerebral cortex was solubilized with sodium deoxycholate and purified by affinity chromatography on benzodiazepine-agarose and ion exchange chromatography. The benzodiazepine binding protein was enriched 1800-fold. Polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate and dithiothreitol showed the presence of two major bands of Mr = 57,000 and 53,000. [3H]Flunitrazepam, after UV irradiation, was incorporated irreversibly into both bands of the isolated protein. A high affinity binding site for gamma-aminobutyric acid was co-purified with the benzodiazepine binding site and the two sites were shown to reside on the same physical structure. The dissociation constants were 10 +/- 4 nM for [3H] flunitrazepam and 12 +/- 3 nM for the gamma-aminobutyric acid agonist [3H]muscimol. The maximum specific activity for [3H] muscimol binding was 4.3 nmol/mg of protein. The ratio of [3H]muscimol to [3H]flunitrazepam binding sites was between 3 and 4. Gel filtration and sucrose density gradient sedimentation studies gave a Stokes radius of 7.3 +/- 0.5 nm and a sedimentation coefficient of 11.1 +/- 0.3 S, respectively. The purified complex had a pharmacological profile that corresponds to the receptor specificity found in membranes and crude soluble extracts.

Animals↗
PubMed1984

A gamma-aminobutyric acid/benzodiazepine receptor complex from bovine cerebral cortex. Improved purification with preservation of regulatory sites and their interactions.

A gamma-aminobutyrate/benzodiazepine receptor complex has been purified from bovine cerebral cortex by an improved procedure using a zwitterionic detergent. A high affinity binding site for the chloride ion channel-blocking ligand [35S]t-butyl bicyclophosphorothionate ( TBPS ) was co-purified with the high affinity binding sites for gamma-aminobutyrate and benzodiazepines. The latter two have previously been shown to reside on the same physical structure ( Sigel , E., Stephenson , F.A., Mamalaki , C., and Barnard , E. A. (1983) J. Biol. Chem. 258, 6965-6971). The dissociation constants, as measured in assay medium containing zwitterionic detergent were 90 +/- 20 nM for TBPS and 11 +/- 4 nM for [3H]flunitrazepam, whereas the binding of [3H]muscimol, a gamma-aminobutyrate agonist, showed a more complex binding behavior with more than one site. If the same preparation was assayed in a medium containing instead Triton X-100 as the detergent, the binding of TBPS was strongly inhibited, [3H]flunitrazepam binding was unaffected, and [3H]muscimol bound to a single class of sites with a dissociation constant of 33 +/- 3 nM. Regulatory interactions were retained in the complex isolated by the improved method: [3H]flunitrazepam binding was stimulated by gamma-aminobutyrate or by pentobarbital, and in a dose-dependent manner. The same two subunit types of Mr = 53,000 and 57,000 are present in the purified receptor complex as previously reported.

Animals↗
PubMed1982

[Hemodynamic analysis of 6 different anesthesia induction procedures in coronary surgery patients].

We investigated the cardiovascular effects of intravenous thiopentone (3.0 mg/kg), etomidate (0.3 mg/kg), althesin (0.07 ml/kg), ketamine (1.5 mg/kg), diazepam (0.15 mg/kg) and flunitrazepam (0.015 mg/kg) alone and after the addition of fentanyl (0.01 mg/kg) during induction of anaesthesia in 46 premedicated patients subjected to coronary artery bypass surgery. Thiopentone, etomidate or diazepam caused only small changes in the haemodynamic determinants of myocardial oxygen supply and demand (arterial pressure, heart rate, left and right ventricular filling pressure) in patients with coronary artery disease in whom global resting left ventricular function was normal. Althesin and flunitrazepam produced a significant fall in arterial pressure, cardiac index and stroke index; heart rate increased after the administration of althesin. Ketamine markedly elevated systemic and pulmonary pressure, heart rate, systemic and pulmonary vascular resistance, right and left ventricular filling pressure. The subsequent administration of fentanyl was associated with a further decrease in arterial pressure in the althesin and flunitrazepam group. The circulatory stimulating effects of ketamine were largely abolished by fentanyl. None of the induction procedures was associated with cardiovascular stimulation during laryngoscopy and tracheal intubation.

Alfaxalone Alfadolone Mixture↗
PubMed1982

Effects of hypnotics on memory.

The influence on memory of 7.5 mg zopiclone, given in single and repeated doses was compared with that of 2 mg flunitrazepam, 5 mg nitrazepam and placebo. Compared with placebo, all three drugs induced some impairment of memory especially after the first day of administration. Effects were more pronounced for the two benzodiazepines and more marked for flunitrazepam. There was one report of an anterograde amnestic episode after flunitrazepam.

Adult↗
PubMed1995

NMDA-mediated modulation of gamma-aminobutyric acid type A receptor function in cerebellar granule neurons.

GABAA receptors are ligand-gated CI- ion channels with multiple clinically relevant drug-recognition sites. We have previously shown that stimulation of N-methyl-D-aspartic acid (NMDA)-specific glutamate receptors quantitatively alters selected GABAA receptor subunit mRNAs and proteins in primary cultures of rat cerebellar granule neurons. We used whole-cell recordings of GABA-elicited CI- currents and flunitrazepam binding experiments in granule cell cultures maintained in low K+ (12.5 mM), cells maintained in low K+ and treated with a single dose of NMDA (10 microM), and cell cultures maintained in depolarizing concentrations of K+ (25 mM). The EC50 obtained from the dose-response curves for GABA in eliciting a maximal response was comparable in neurons maintained in high K+ or in low K+ and treated with a single dose of NMDA, but that it increased significantly in cells maintained in low K+. The potentiation of GABA-gated CI- currents by flunitrazepam increased significantly, while the negative allosteric modulator methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) was significantly more effective in cultures either maintained in high K+ or treated with NMDA. This was coincident with a twofold increase in the Bmax associated with flunitrazepam binding. To further characterize the receptor assemblies present in the depolarization and NMDA induced paradigms, the Zn(2+)-induced inhibition of GABA-gated CI- currents was reduced as was the inhibition mediated by furosemide. Our data indicate that GABAA receptor assemblies alter their composition in response to excitatory afferent receptor stimulation.

Animals↗
PubMed1997

Sequestration of gamma-aminobutyric acidA receptors on clathrin-coated vesicles during chronic benzodiazepine administration in vivo.

Chronic administration of benzodiazepine agonists produces behavioral tolerance. For induction of tolerance, the use-dependent down-regulation of gamma-aminobutyric acidA (GABA[A])/ benzodiazepine receptors is a potential cellular mechanism. We previously identified GABA(A) receptors on clathrin-coated vesicles from rat brain, suggesting that surface receptors can be internalized via endocytosis. To examine a role for coated vesicles in GABA(A) receptor down-regulation in vivo, fractions were obtained from mouse brain microsomes through density centrifugation and treatment with 0.1% Triton X-100. This coated vesicle preparation was enriched in clathrin subunits and clathrin light-chain kinase and had twice the level of [3H]flunitrazepam binding as did vesicles not exposed to Triton. Adult mice were treated with lorazepam (2 mg/kg/day) for 7 days via osmotic minipump, achieving a serum level of 103 +/- 8.9 ng/ml. The level of flunitrazepam bound to coated vesicles was increased by 83 +/- 13% in the lorazepam-treated mice compared with vehicle-treated controls. The Bmax value for [3H]flunitrazepam binding to synaptic membranes from lorazepam-treated animals was 33 +/- 4% lower than that of controls. The amount of GABA(A) receptor alpha-1 subunits, as quantified by Western blotting, followed a similar pattern. Relative to controls, immunoreactivity for alpha-1 subunits in coated vesicles from lorazepam-treated mice was increased by 60.0 +/- 10.3%, whereas that in synaptic membranes declined by 12 +/- 6%. These results indicate that lorazepam-dependent GABA(A) receptor sequestration occurs in mouse brain. Furthermore, it is suggested that this sequestration may play a role in GABA(A) receptor down-regulation in vivo.

Animals↗
PubMed1998

Adaptation of gamma-aminobutyric acid type A receptors to alcohol exposure: studies with stably transfected cells.

We studied the adaptation of gamma-aminobutyric acid type A (GABAA) receptor function to chronic ethanol exposure in cells stably transfected with the following GABAA receptor subunits: alpha-1 beta-2 gamma-2L, alpha-1 beta-2 gamma-2S, alpha-1 beta-3 gamma-2S, alpha-1 beta-1, alpha-5 beta-3 gamma-3 and alpha-6 beta-3 gamma-2S. Chronic exposure to ethanol resulted in a decrease in muscimol-stimulated 36Cl- flux and a decrease in modulation of that flux by ethanol, flunitrazepam, methyl-6,7-4-dimethoxy-4-ethyl-beta-carboline-3-carboxylate and pregnanolone without any change in the modulation by pentobarbital or zinc. Direct activation of the GABAA receptor by pentobarbital was enhanced by chronic ethanol treatment. Reduction of the action of muscimol, ethanol and flunitrazepam differed in the duration and amount of ethanol required to see an effect. Reduction of the action of ethanol of alpha-1 beta-2 gamma-2L cells occurred within 15 min and was near-maximal for 25 mM ethanol, whereas reduction of the actions of muscimol and flunitrazepam actions required hours of exposure and higher concentrations of ethanol. Chronic ethanol exposure produced a reduction in the Emax value for the action of muscimol for all six subunit combinations, but quantification of surface receptors by immunolabeling showed no change in GABAA receptor density. The differences in alcohol sensitivity and time courses for different effects of ethanol indicate multiple mechanisms of adaptation of GABAA receptors. Use of stably transfected cells rules out "subunit substitution" as a mechanism for these changes and points to post-translational changes (e.g., phosphorylation, receptor assembly) as the most likely mechanisms. These in vitro findings are compared with results from in vivo studies.

Animals↗
PubMed1998

Effects of ketoconazole on triazolam pharmacokinetics, pharmacodynamics and benzodiazepine receptor binding in mice.

We previously demonstrated that ketoconazole is a potent inhibitor of triazolam biotransformation in vitro and in vivo. Despite significant elevations in triazolam plasma levels with coadministration of ketoconazole, the pharmacodynamic enhancement was lower than predicted based on plasma levels of triazolam. The present study examines the effects of ketoconazole on benzodiazepine receptor binding in vitro as well as on open-field behavior in male CD-1 mice. Triazolam alone inhibited [3H]flunitrazepam binding with an IC50 value of 0.85 nM and a Ki value of 0.50 nM. Ketoconazole alone also competitively antagonized [3H]flunitrazepam binding in a concentration-dependent manner with an IC50 value of 1.56 microM and a Ki value of 1.17 microM. In the presence of 1, 3 or 9 microM ketoconazole, the IC50 value of triazolam was increased to 1.11, 1. 58 and 5.73 nM, respectively, whereas maximal binding was reduced by 36%, 69% and 89%. Coadministration of 50 mg/kg ketoconazole and triazolam (0.1-0.3 mg/kg) to intact animals significantly elevated plasma and brain triazolam levels. Ketoconazole could be measured in mouse brain at levels averaging 31% of those in plasma. Ketoconazole alone had minimal or no effect on open field activity, but it significantly potentiated the decreased activity seen with triazolam administration. The ability of ketoconazole to inhibit triazolam displacement of [3H]flunitrazepam binding may explain the muted pharmacodynamic effect of this benzodiazepine in the presence of ketoconazole. Based on these results, it is likely that ketoconazole acts as a neutral ligand at the benzodiazepine receptor.

Animals↗
PubMed1994

The effect of cyclopyrrolones on GABAA receptor function is different from that of benzodiazepines.

The effects of the cyclopyrrolones zopiclone and suriclone on the function of the central gamma-amino-butyric acid type A (GABAA) receptor complex in mouse brain were evaluated both in vitro and in vivo. Added in vitro to mouse cerebral cortical membranes, these compounds potently inhibited [3H]flumazenil binding with IC50 (50% inhibitory concentration) values of 35.8 nM (zopiclone) and 1.1 nM (suriclone). Similar results were obtained with cerebellar membranes, indicating that these drugs do not discriminate between putative type I and type II benzodiazepine receptors. The interaction of cyclopyrrolones with recognition sites present at the level of the GABA receptor complex appears to be competitive, because zopiclone decreased the affinity of the receptors for [3H]flumazenil without affecting the maximal number of binding sites. Moreover, zopiclone and suriclone did not affect the rate of dissociation of [3H]flumazenil from benzodiazepine receptors. The in vitro efficacy of zopiclone appeared different from that of suriclone and the benzodiazepines diazepam and flunitrazepam. Thus, zopiclone failed to affect muscimol-stimulated 36Cl- uptake and only slightly inhibited t-[35S]butylbicyclophosphorothionate ([35S]TBPS) binding. In contrast, like diazepam and flunitrazepam, suriclone increased muscimol-stimulated 36Cl- uptake and markedly inhibited [35S]TBPS binding. In contrast, like diazepam and flunitrazepam, suriclone increased muscimol-stimulated 36Cl- uptake and markedly inhibited [35S]TBPS binding. On the other hand, suriclone, like zopiclone, did not modify [3H]muscimol binding to mouse cerebral cortical membranes. Moreover, zopiclone antagonized the reduction in [35S]TBPS binding elicited by the benzodiazepine receptor full of agonist diazepam. Consistent with its low efficacy in vitro, oral administration of zopiclone (2.5 to 100 mg/kg, p.o.) in mice failed to modify [35S]TBPS binding subsequently measured in cerebral cortical membranes "ex vitro".(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Utilization of benzodiazepines in Chile during 1982-1986.

The consumption of benzodiazepine drugs (BDZ) in Chile in the period 1982-1986 has been studied by the DDD method. National use was assessed using drug import forms as a source of information, assuming that the total amount imported was manufactured and consumed in the same year. The utilization did not show a constant pattern, being 32.7, 33.6, 50.2, 34.9, and 31.3 DDD 1000 per inhabitants per day in 1982, 1983, 1984, 1985 and 1986, respectively. During the study period, diazepam was the most commonly used agent amongst anxiolytic BDZ, reaching a peak of 27.1 DDD per 1000 inhabitants per day in 1984, and flunitrazepam was the most popular hypnotic, attaining its maximum in 1986 (6.4 DDD per 1000 inhabitants per day). The use of BDZ at community pharmacy level was also evaluated, employing the International Marketing System (IMS) as the source of information. At that level the pattern of utilization showed a constant increase during the study period, being 14.9 and 25.8 DDD/1000 inhabitants/per day in 1982 and 1986, respectively. In community pharmacies the anxiolytic BDZ most often consumed was diazepam (maximum 9.1 DDD per 1000 inhabitants per day in 1985), and the commonest hypnotic was flunitrazepam (peak 6.0 DDD per 1000 inhabitants per day in 1986). National consumption of BDZ appeared higher and more variable than use at the community pharmacy level, but in both there was greater usage of anxiolytic than of hypnotic BDZ, and diazepam and flunitrazepam were the most popular agents.

Anti-Anxiety Agents↗