SEARCH · Search PubMed

Results for “Flunitrazepam”

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.

SourceResearch connectionFrom yearThrough year

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

At least 505 records · Page 28Linked to original sources

PubMed1983

Photoaffinity labeling of benzodiazepine receptors in rat brain with flunitrazepam alters the affinity of benzodiazepine receptor agonist but not antagonist binding.

Recently, it was proposed that beta-carbolines interact with a subset of benzodiazepine (BZD) binding sites in mouse brain. This postulate was based upon evidence showing changes in binding properties of the BZD receptor following photoaffinity labeling of membranes with flunitrazepam (FLU). Under conditions in which 80% of specific [3H]diazepam binding was lost in photolabeled membranes, specific [3H]propyl beta-carboline-3-carboxylate [( 3H]PCC) binding was spared. In this study, the binding of the BZD antagonists [3H]PCC, [3H]Ro15 1788 and [3H]CGS 8216 was examined in rat brain membranes following photoaffinity labeling with FLU. No significant changes in the apparent KD and small reductions in the Bmax of 3H antagonist binding were observed. However, in the same membranes, up to 89% of specific [3H]FLU binding was lost. When [3H]PCC (0.05 nM) was used to label the receptors in control and photolabeled membranes, the ability of BZD receptor agonists to inhibit [3H]PCC binding was greatly diminished in the photolabeled membranes. In contrast, the potency of BZD antagonists remained the same in both control and treated membranes. Based upon PCC/[3H]Ro15 1788 competition experiments, the ability of PCC to discriminate between BZD receptor subtypes was unaffected by photoaffinity labeling of cortical membranes.(ABSTRACT TRUNCATED AT 250 WORDS)

Affinity Labels↗

PubMed1985

Allosteric modulation of flunitrazepam binding to rat brain benzodiazepine receptors by methyl beta-carboline-3-carboxylate.

The inhibition of flunitrazepam (FNP) binding to rat brain benzodiazepine (BZ) receptors by methyl beta-carboline-3-carboxylate (MCC) was studied. Biphasic dissociation was observed for [3H]FNP and [3H]MCC in cerebral cortex, cerebellum, and hippocampus, although the dissociation of [3H]MCC was much faster. The dissociation rate of [3H]FNP was increased by MCC in the cerebellum, but was not altered in cerebral cortex or hippocampus. [3H]FNP binding stimulated by gamma-aminobutyric acid was enhanced in the presence of MCC in all three regions examined. These results indicate that MCC exerts these effects by interacting with allosteric sites that are different from the FNP recognition sites on the BZ receptors.

Animals↗

PubMed1993

Involvement of a disulfide bond in the binding of flunitrazepam to the benzodiazepine receptor from bovine cerebral cortex.

The effects of chemical modification of a disulfide bond(s) (-SS-) or sulfhydryl group(s) (-SH) on the [3H]-flunitrazepam ([3H]FNZ) binding to membrane-bound or immunoprecipitated benzodiazepine (BZD) receptors (BZD-R) from bovine cerebral cortex were examined. Reduction of -SS- with dithiothreitol (DTT) brought about a reversible, time- and dose-dependent inhibition of [3H]FNZ binding to the membrane-bound BZD-R. Alkylation of the membranes with the -SH-modifying reagent iodoacetamide (IAA) or 5,5'-dithiobis-(2-nitrobenzoic acid) (DTNB) produced a slight inhibition of [3H]FNZ binding in a dose-dependent manner. Scatchard analysis of saturation curves of [3H]FNZ binding in the presence and absence of 5 mM DTT revealed changes in affinity without modification in the maximal binding capacity, thus indicating a competitive mode of interaction. DTT pretreatment of both the membrane-bound and the immunoprecipitated BZD-R led to [3H]FNZ binding inhibition. Consistent with the modification of a binding site is the observation that reduction of -SS- does not bear on the binding affinity, but rather reduces the number of sites. Complete protection from DTT inhibition of [3H]FNZ binding by FNZ (an agonist) or by Ro 15-1788 (an antagonist) suggests the presence of -SS- at, or very close to, the BZD recognition binding site. No protection against IAA or DTNB inhibition was provided by FNZ. Photoaffinity labeling experiments with [3H]FNZ revealed a clear-cut band of 50 kDa in native and alkylated membranes but an extremely weak label in 5 mM DTT/IAA-treated membranes. The present results provide evidence for the participation of a disulfide bond in the recognition binding site of the bovine cerebral cortex BZD-R.

Animals↗

PubMed1993

Lindane administration to the rat induces modifications in the regional cerebral binding of [3H]Muscimol, [3H]-flunitrazepam, and t-[35S]butylbicyclophosphorothionate: an autoradiographic study.

The effect of lindane administration on the specific binding of ligands to different sites on the GABAA receptor-ionophore complex was studied in the rat brain by receptor mapping autoradiography. [3H]Muscimol (Mus), [3H]flunitrazepam (Flu), and t-[35S]butylbicyclophosphorothionate (TBPS) were used as specific ligands of GABA, benzodiazepine, and picrotoxinin binding sites, respectively. Rats received a single oral dose of 30 mg/kg lindane and they were classified into two groups according to the absence or presence of convulsions. Vehicle-treated groups acted as controls. The effect of the xenobiotic on ligand binding was measured in different brain areas and nuclei 12 min or 5 h after its administration. Lindane induced a generalized decrease in [35S]TBPS binding, which was present shortly after dosing. In addition, [3H]Flu binding was increased in lindane-treated animals, this modification also appearing shortly after administration but diminishing during the studied time. Finally, lindane induced a decrease in [3H]Mus binding, which became more evident over time. These modifications were observed both in the presence and in the absence of convulsions. However, an increase in [3H]-Mus binding was detected shortly after lindane-induced convulsions. The observed decrease in [35S]TBPS binding is in agreement with the postulated action of lindane at the picrotoxinin binding site of the GABAA receptor chloride channel. The effects observed on the binding of [3H]Flu and [3H]Mus may be secondary to the action of lindane as an allosteric antagonist of the GABAA receptor.

Animals↗

PubMed1977

A repeated dose comparison of three benzodiazepine derivative (nitrazepam, flurazepam and flunitrazepam) on subjective appraisals of sleep and measures of psychomotor performance the morning following night-time medication.

Repeated doses of 5 mg nitrazepam, 15 mg flurazepam, and 1 mg flunitrazepam improved subjective assessments of the ease of getting to sleep and the perceived quality of induced sleep in a population of 30 healthy volunteers. The subjective reports of improved sleep inducement were related to a perceived difficulty in awakening from sleep the morning following medication. This subjectively reported "hangover" is also shown in the impairment of mental arithmetic abilities as measured on the serial subtraction of sevens technique. However, complex psychomotor performance is unaffected by repeated administration of these three benzodiazepine derivatives, although these later results are somewhat equivocal. Evidence of a "rebound phenomenon" following 4 nights' withdrawal of active medication is shown in both subjective and objective measures of sleep and early morning behaviour.

Adult↗

PubMed1989

Effects of flunitrazepam and triazolam in man: are they influenced by the time of ingestion?

Five healthy young volunteers were given flunitrazepam 1 mg, triazolam 0.25 mg or placebo at 2 a.m. or 9 a.m. in a double blind, cross-over study. The aim was to investigate the cyclic variations mainly in residual effects of the drugs, but also in sleep onset latency and pharmacokinetics. The study suggested cyclic variations in mood, psychometric tests and in sleep onset latency.

Adult↗

PubMed1999

Long-term changes in brain following continuous phencyclidine administration: an autoradiographic study using flunitrazepam, ketanserin, mazindol, quinuclidinyl benzilate, piperidyl-3,4-3H(N)-TCP, and AMPA receptor ligands.

Phencyclidine induces a model psychosis which can persist for prolonged periods and presents a strong drug model of schizophrenia. When given continuously for several days to rats, phencyclidine and other N-methyl-D-aspartate (NMDA) antagonists induce neural degeneration in a variety of limbic structures, including retrosplenial cortex, hippocampus, septohippocampal projections, and piriform cortex. In an attempt to further clarify the mechanisms underlying these degeneration patterns, autoradiographic studies using a variety of receptor ligands were conducted in animals 21 days after an identical dosage of the continuous phencyclidine administration employed in the previous degeneration studies. The results indicated enduring alterations in a number of receptors: these included decreased piperidyl-3,4-3H(N)-TCP (TCP), flunitrazepam, and mazindol binding in many of the limbic regions in which degeneration has been reported previously. Quinuclidinyl benzilate and (AMPA) binding were decreased in anterior cingulate and piriform cortex, and in accumbens and striatum. Piperidyl-3,4-3H(N)-TCP binding was decreased in most hippocampal regions. Many of these long-term alterations would not have been predicted by prior studies of the neurotoxic effects of continuous phencyclidine, and these results do not suggest a unitary source for the neurotoxicity. Whereas retrosplenial cortex, the structure which degenerates earliest, showed minimal alterations, some of the most consistent, long term alterations were in structures which evidence no immediate signs of neural degeneration, such as anterior cingulate cortex and caudate nucleus. In these structures, some of the receptor changes appeared to develop gradually (they were not present immediately after cessation of drug administration), and thus were perhaps due to changed input from regions evidencing neurotoxicity. Some of these findings, particularly in anterior cingulate, may have implications for models of schizophrenia.

Animals↗

PubMed1995

The effect of phencyclidine on [3H]GABA and [3H]flunitrazepam binding in the brain of naive and handling-habituated rats.

The effects of handling and handling combined with phencyclidine (PCP) treatment on GABAergic neurotransmission were studied in Sprague-Dawley rats. The animal material consisted of handling-habituated (HH, for 11 d), acutely handled (naive, N), handling-habituated and PCP-treated (10 mg kg-1 i.p., HH + PCP) and acutely handled (naive) PCP-treated (N + PCP) and unhandled 'control' rats. The binding of [3H]GABA and [3H]flunitrazepam (FLU) was studied with membranes and the release of [3H]GABA with slices prepared from the striatum and frontal cortex. In the striatum the maximal binding capacity (Bmax) and the binding constant (KD) of [3H]GABA were the same in N and HH rats, but in the frontal cortex KD was lower in N rats. KD constants of [3H]FLU were significantly lower in both brain areas in N rats than in HH rats. After PCP treatment both Bmax and KD for [3H]FLU increased in these two brain areas in handling-habituated rats, whereas Bmax of [3H]GABA diminished. Neither handling nor PCP had any effect on [3H]GABA release from striatal and frontal cortical slices. Handling prior to killing thus affects differently the GABAergic parameters studied and modulates the PCP-induced effects.

Animals↗

PubMed1982

Flunitrazepam binding sites in rat diaphragm. Receptors for direct neuromuscular effects of benzodiazepines?

The evidence for direct muscle relaxant effects of benzodiazepines is controversial. We now show that a crude membrane preparation of rat diaphragm possesses binding sites for [3H]flunitrazepam (FNZ). Scatchard analysis gave a binding site density of 1689 +/- 143 fmol/mg protein (Kd = 25.6 +/- 2.6 nM). These sites are of the "peripheral" type since clonazepam fails to displace [3H]FNZ as effectively as R05-4864 (IC50 values: 7.5 x 10(-6) M and 8 x 10(-9) M, respectively). Diazepam is almost as effective as R05-4864 and potently displaces [3H]FNZ binding (IC50 = 3 x 10(-8) M). We propose that the previously described effects of diazepam on rat diaphragm are mediated through high-affinity binding sites.

Animals↗

PubMed1991

Characterization by saturation studies of the in vivo binding of [3H]flunitrazepam in mouse brain.

The in vivo binding of [3H]flunitrazepam [( 3H]Fln) was characterized in seven regions of the mouse brain. The binding showed saturability and linear Scatchard plots. Hill coefficients were close to unity. Data fitting to a hyperbola by least squares yielded consistent Kd values for all regions studied (0.36-0.6 pmol/mg protein). Bmax values ranged from 0.14 to 0.89 pmol/mg protein, a sixfold regional variation. The order of binding is as follows: cortex greater than hippocampus greater than midbrain = thalamus/hypothalamus greater than striatum much greater than cerebellum greater than brainstem, consistent with that obtained by in vitro binding. The in vivo receptor density and affinity are apparently lower in comparison with in vitro parameters. This is consistent with the observation that the Kd increases and Bmax decreases in vitro when the incubation temperature is increased from 0 degrees C. Non-specific binding has been estimated by displacement of in vivo binding by unlabelled ligand in vitro as well as by pretreatment with unlabelled ligand. The two alternative methods were compared and evaluated. It is concluded that the displacement method provides more reliable estimates of the nonspecific binding. Diazepam-sensitive mice did not differ from the control mice in the in vivo [3H]Fln binding. However, mice pretreated with diazepam 1 or 2 days before have binding reduced by 70 or 30%, respectively. The reduced binding may be explained by receptor occupancy by residual oxazepam. However, the low concentration of the residual oxazepam is an unlikely cause of the phenomenon of "acute tolerance" observed in these mice.

Animals↗

PubMed1987

A 3H-flunitrazepam binding inhibitor is present in psychiatric patients' sera.

We investigated the possible existence of endogenous compounds acting on benzodiazepine central receptors in the serum of patients with panic attacks or depression. Our results show the presence of a substance which inhibits the 3H-flunitrazepam binding specifically in the samples taken from the patients' groups, and which is not present in normal controls, in the range of concentrations used. This compound has a molecular weight below 1,000 daltons, is heat-stable, and resistant to proteolytic degradation. The demonstration of this inhibitor opens new perspectives in the study of the biochemistry of anxiety.

Adolescent↗

PubMedDate not supplied

EEG sleep activities react topographically different to GABAergic sleep modulation by flunitrazepam: relationship to regional distribution of benzodiazepine receptor subtypes?

Spectral analysis was performed to study the response of various EEG sleep activities to a modification of GABAergic sleep regulation by flunitrazepam. We observed sleep stage- and sleep cycle-dependent differences in the topographic distribution of the reactions. An increase in power density was found in the frontal regions for the alpha 2 and sigma 1 frequency band whereas a decrease in power density was emphasized in the posterior regions for the delta and alpha 1 frequency band. These topographic differences might be related to the regional distribution of benzodiazepine receptor subtypes.

Adult↗

PubMed1983

Characterization of flunitrazepam and beta-carboline high affinity binding in bovine pineal gland.

High affinity binding of 3H-flunitrazepam (FNZP) to crude membrane preparations of bovine pineal membranes was examined by a rapid filtration procedure through Whatman GFB paper. At 0 degrees C binding reached equilibrium in about 20 min. Scatchard analysis of data at equilibrium revealed a single population of binding sites with dissociation constant (Kd) = 3.14 +/- 0.45 nM and binding site concentration (Bmax) = 55.6 +/- 5.6 fmol/mg protein. Kinetic analysis of the association and dissociation curves indicated a kinetic Kd = 1.13 nM, in reasonable agreement to that obtained at equilibrium. When various benzodiazepine (BZP) analogues were tested for their ability to inhibit 3H-FNZP binding, the following Ki (nM) were obtained: clonazepam (0.22), Ro 15-1788 (0.48), FNZP (0.95), Ro 5-4864 (greater than 10,000). When the beta-carboline derivative 3H-ethyl-beta-carboline-3-carboxylate ester (E beta CEE) was used as a radioligand, Kd at equilibrium (0.98 nM), kinetic Kd (1.69 nM) and affinity order for analogues were in close agreement to those found for FNZP binding; however, Bmax was about 60% that observed for 3H-FNZP binding. Addition of GABA or pentobarbital (100 microM) to pineal membranes increased 3H-FNZP binding by 55 and 72%. These results suggest the existence of a mixed population of type 1 and type 2 central BZP receptor subclass in bovine pineal gland.

Animals↗

PubMed1994

Influence of the behaviorally active peptides ACTH1-10 and ACTH4-10 on the melatonin modulation of 3H-flunitrazepam receptor binding in the rat cerebral cortex.

Possible interactions of ACTH-like peptides with melatonin regulation of central-type benzodiazepine (BNZ) receptors have been studied by means of high-affinity 3H-flunitrazepam binding to rat cerebral cortex membrane preparations. Intracerebroventricular injections of melatonin produce a dose-dependent increase in Bmax in pinealectomized rats, without changes in KD. Analogous effects were obtained after intracerebroventricular injection of melatonin in adrenalectomized and in adrenalectomized plus pinealectomized rats, which indicated the lack of participation of adrenal steroids in this response. Moreover, intracerebroventricular injection of ACTH1-10 induced a similar dose-dependent increased Bmax in sham-operated animals, whereas pinealectomy, but not adrenalectomy, partially counteracted this effect of ACTH1-10 administration. Besides, simultaneous injection of ACTh1-10 plus melatonin reverses the effects of pinealectomy, resulting in an additive effect of both compounds on Bmax. The response obtained when using ACTh4-10 was somewhat different, because no dose response was obtained in any experiment. Although lack of endogenous melatonin partially reduced the increasing effect of ACTH4-10 on Bmax, there were no additive effects at the different doses used. The results strongly suggest that ACTH-like peptides, in addition to melatonin, play a role in regulating central-type rat BNZ receptors.

Adrenalectomy↗

PubMed1979

Long-term sleep laboratory evaluation of flunitrazepam.

A sleep laboratory hypnotic drug evaluation study was conducted in which 2 mg flunitrazepam, a benzodiazepine with a half life of intermediate duration, was administered nightly to 6 insomniac subjects for 4 consecutive weeks. The drug was effective with short-term use. However, tolerance developed for sleep maintenance during the intermediate- and long-term drug administration periods. Following drug withdrawal, a significant worsening of sleep above baseline levels occurred. These data are consistent with our previous findings of rebound insomnia following withdrawal of short- and intermediate-acting benzodiazepines.

Adult↗

PubMed1994

Pentobarbital differentially enhances the affinity of [3H]flunitrazepam binding across brain regions.

The present study used saturation binding analyses to test the hypothesis that pentobarbital would differentially increase the affinity of benzodiazepine binding across brain regions. The results showed that there were significant (p < 0.05) regional differences in the dissociation constant (KD) for tritiated flunitrazepam ([3H]FLU) and that pentobarbital differentially decreased the KD for [3H]FLU across 6 brain regions. Pentobarbital caused the greatest decrease (-43%) in KD in the medulla. The results support the concept that type A gamma-aminobutyric acid (GABAA) receptor subtypes are localized differentially throughout the brain. Defining the regional specificity of interactions between benzodiazepines and barbiturates at the GABAA receptor will be important for understanding the mechanisms by which these drugs produce their behavioral effects in vivo.

Animals↗

PubMed1976

Intravenous flunitrazepam as an anesthetic induction agent.

The effects of the fluorinated benzodiazepine compound flunitrazepam were studied in eighty patients. The drug was administered intravenously in a standard dose of 2 mg, 3 mg, or 4 mg to supplement lumbar epidural analgesia. Induction was smooth and pleasant. The sleep onset time was dose related and exceeded one minute in the majority of patients. Sleep was invariably produced in patients receiving 4 mg but at lower dosage some patients failed to become unconscious. Pain in the arm during injection was a common feature. The respiratory rate was slightly increased, but in two patients apnoea occurred at induction. The cardiovascular system was minimally depressed with a small decrease in systolic blood pressure and pulse rate. Recovery from sleep was slow but sequelae were minimal. The sedative and amnesic properties contributed significantly to the high rate of patient acceptance.

Adjuvants, Anesthesia↗

PubMed1978

The use of a kymograph in a comparative trial of flunitrazepam and meprobamate in elderly patients.

A double-blind crossover trial was carried out in 31 hospitalized elderly patients receiving night-time sedation to compare the effects of flunitrazepam (0.5 mg) and meprobamate (200 mg). After 1 week on placebo, patients received 1-week's treatment with each drug in random order. Quality of sleep was assessed by a nurse at hourly intervals over 8 hours each night. In 11 patients, the results were compared with those from kymographic recordings measuring patient restlessness (motility index). No statistically significant difference was found between the two active drug treatments, and there was a close correlation between the two methods of assessment. It is suggested that the kymograph may well be a useful and economic method of evaluating the effectiveness of hypnotics.

Aged↗