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PubMed1975

The actions of flunitrazepam (Rohypnol) on heart and respiratory rates and skin potential fluctuations during the sleep cycle in normal volunteers and neurotic patients with insomnia.

The actions of flunitrazepam (Rohypnol) were assessed on the sleep cycle, heart and respiratory rates and skin potential fluctuations of normal volunteers and neurotic patients with insomnia by means of all night recordings. The most conspicuous effect of flunitrazepam (2 mg p.o.) in the healthy subject's sleep cycle was an increase of the latency for the appearance of the first REM period. In the insomniacs the compounds was effective in inducing and maintaining sleep. Flunitrazepam diminished heart rates during the REM phases and significantly decreased the variability indices, this effect being more prominent in the normal subjects. Skin potential fluctuations during stages 2 and REM sleep were also decreased although tolerance developed rapidly in this connection.

Adult↗
PubMed1981

The effect of chronic diazepam treatment on discrimination performance and 3H-flunitrazepam binding in the brains of shocked and nonshocked rats.

The purpose of the present study was: (1) to investigate the effects of unavoidable shock on an appetitively motivated discrimination task; (2) to evaluate the effect of chronic diazepam treatment on the performance of a previously learned discrimination task in shocked and nonshocked animals; (3) to measure the binding of 3H-flunitrazepam (an analogue of diazepam) to selected brain regions of chronically diazepam-treated shocked and nonshocked rats, in comparison to saline-treated controls. Results indicated that unavoidable shock significantly interfered with the learning of a new, nonshock-related discrimination task. The effect of chronic diazepam treatment on the performance depended on the previous experience of the animal; chronic diazepam treatment significantly improved the maze performance of shocked animals. On the other hand, chronic diazepam treatment in the nonshocked animals tended to interfere with the performance of the discrimination task. Neurochemical data showed significant reduction in 3H-flunitrazepam binding to diazepam receptors in membranes from the brains of a nonshocked diazepam-treated (CD) group in comparison to a nonshocked saline-treated (CS) group. In contrast, the unavoidable shock-treated diazepam group (SD) showed opposite effects, the binding of 3H-flunitrazepam increasing significantly. A significant increase in the maximal binding sites in the frontal cortex from shocked rats treated with diazepam, compared to the nonshocked diazepam-treated rats, was detected by Scatchard analysis.

Animals↗
PubMed1994

Effects of flunitrazepam on responses to lateralized visual stimuli: evidence for cerebral asymmetry of execution of manual movements to targets in contralateral and ipsilateral visual space.

In order to examine the effects of benzodiazepines on response execution by the left and right hemisphere, flunitrazepam (1 mg) or placebo was administered to healthy, right handed volunteers in two separate experiments. In experiment 1, drug was administered daily during a treatment period of 8 days, and subjects were instructed to fixate vision centrally and to execute laterally directed manual responses corresponding to the position of visual stimuli presented in either the right or left hemifield. Experiment 2 was performed with a single dose and cross-over design, and subjects responded to the laterally presented visual stimuli by key press of a centrally positioned response device, i. e. neither detection of position of the stimulus in space nor response selection was required before initiation of the response. In experiment 1, intake of flunitrazepam generally increased reaction time more during response execution by the left as compared to the right hemisphere, and the most pronounced effect was observed on responses with the right hand, directed across the body axis, to visual stimuli presented in the left visual field. In contrast to these observations, in experiment 2, flunitrazepam impaired responses with the right and left hand practically to the same extent. Together, the results indicate that benzodiazepines may affect manual responses executed by left and right hemisphere differently, and that this asymmetry may be related to a stimulus-response compatibility effect in tasks that require response selection.

Adult↗
PubMed1994

Development of acute tolerance after oral doses of diazepam and flunitrazepam.

Flunitrazepam (1 and 2 mg), diazepam (10 and 20 mg) or placebo was administered to healthy, male volunteers, and the time course of psychomotor impairment, as indicated by simple and complex choice reaction time and movement time, was studied during a period of 6 h after drug intake. To examine whether acute tolerance developed, the observed performance during decreasing drug plasma concentration was compared to the predicted performance based on kinetic-dynamic modelling of the observed performance during the first 1.5 h after intake when the drug plasma concentrations were increasing or at peak level. Placebo corrections of the test scores were accomplished to adjust for diurnal variation and the possible influence of learning during the test day. After the flunitrazepam treatments, the predictions overestimated the actual performance significantly with respect to simple and choice reaction time at the 6-h session after intake. After the diazepam treatments, however, no significant deviation was detected between predicted and observed performance. The results indicate that acute tolerance develops with respect to impairment of attention demanding performance after medium to large doses of flunitrazepam, and that tolerance is expressed after approximately 4-6 h following intake.

Adult↗
PubMed1998

Effects of various factors including the CYP2D6 genotype and coadministration of flunitrazepam on the steady-state plasma concentrations of bromperidol and its reduced metabolite.

The effects of various factors, including the cytochrome P450 (CYP) 2D6 genotype and the coadministration of flunitrazepam, on the steady-state plasma concentrations (Css) of bromperidol and its reduced metabolite were studied in 62 schizophrenic inpatients receiving bromperidol 12 mg/day. By use of allele-specific PCR analysis, the wild type allele (CYP2D6*1A) and four mutated alleles causing either absent (CYP2D6*3, CYP2D6*4 and CYP2D6*5) or decreased (CYP2D6*10) CYP2D6 activity were identified. The means (ranges) of the Css of bromperidol and reduced bromperidol corrected to the median body weight were 7.2 (1.3-17.4) and 2.2 (0.4-8.9) ng/ml, respectively. Neither the Css of bromperidol nor that of reduced bromperidol significantly differed among the patients with no (n = 28), one (n = 30) and two mutated alleles (n = 4). The patients coadministered with flunitrazepam (n = 52) had significantly (P < 0.05) higher Css of bromperidol, but not reduced bromperidol, than those not (n = 10). Age, sex and smoking had no significant effects on the Css of these compounds. The present study thus suggests that the polymorphic CYP2D6 is not involved in the metabolism of bromperidol and reduced bromperidol to a major extent. The coadministration of flunitrazepam inhibits the metabolism of bromperidol, but age, sex and smoking do not affect it.

Adolescent↗
PubMed1983

Effect of GABA and benzodiazepine antagonists on [3H]flunitrazepam binding to cerebral cortical membrane.

The effects of GABA on the binding of [3H]flunitrazepam to bovine cerebral cortical membranes was investigated in presence and in absence of benzodiazepine antagonists. The percentage stimulation of [3H]flunitrazepam binding by GABA is higher when approximately 50% of the binding is displaced by benzodiazepine antagonists. The observed increase in percent stimulation of [3H]flunitrazepam binding by GABA might reflect the preferential displacement of the ligand by benzodiazepine antagonists from a GABA-insensitive conformational state or site of the receptor.

Animals↗
PubMed1981

The kinetics and displacement of [11C]flunitrazepam in the brain of the living baboon.

The distribution and kinetics of [11C]flunitrazepam in the brain were studied by positron emission tomography in the living baboon. Flunitrazepam was labelled on the methyl group with the 20 min positron emitter carbon 11. Fifteen to 25 mCi corresponding to 15-30 nmol were injected i.v. and sequential tomographic pictures of the brain were obtained. In some experiments, therapeutic doses of various benzodiazepines were injected i.v. subsequently in order to study the displacement of the radioactive ligand from brain structures. Lorazepam was shown to displace [11C]flunitrazepam from brain tissue, although other benzodiazepines (chlordiazepoxide, Ro 116896 and Ro 116893) led to a redistribution of the radioactive ligand in the body accompanied by an increase of brain radioactivity.

Animals↗
PubMed1988

Decrease in [3H]flunitrazepam receptor binding in rats tolerant to the effects of nitrazepam.

Studies were performed to evaluate the binding of [3H]flunitrazepam to cell membranes from the brain cortex of rats that were made tolerant, by the i.p. administration of nitrazepam once daily, to the anxiolytic and sedative effects (after 14 days) and the anticonvulsant action (electroshock, after 28 days) of nitrazepam. A significant decrease in the number of specific [3H]flunitrazepam binding sites was found only in the group that was tolerant to the anticonvulsant effect. The same experiments were also carried out with oxazepam. Since there were no signs of tolerance, the administration of the drug, 10 mg/kg once daily i.p., was continued for 6 weeks. No tolerance occurred and there were no changes in [3H]flunitrazepam binding site density. We conclude that tolerance to the anticonvulsant effect of nitrazepam could be related to the down-regulation of the benzodiazepine receptors.

Animals↗
PubMed1989

Chronic exposure to Ro 15-1788: differential effect on flunitrazepam binding to cortex and hippocampus.

The time course of changes in specific [3H]flunitrazepam binding following 2 weeks of treatment with the benzodiazepine antagonist Ro 15-1788 (2.7 and 4 mg/kg per day in drinking water) was studied in the rat neocortical and hippocampal synaptosomal membranes. Such a treatment produced regional increases in the density of benzodiazepine sites, which remained for up to 24 and 48 h after drug withdrawal in the hippocampus and cortex, respectively; the dissociation constant (Kd) was unchanged. In addition, a significant reduction in GABA enhanced [3H]flunitrazepam binding to cortical, but not to hippocampal, membranes from Ro 15-1788-treated animals was found 72 h after drug withdrawal. These data show that there is a regional difference in responses of the GABA/benzodiazepine receptor complex following chronic in vivo exposure to Ro 15-1788 and that, beside the increases in the maximal binding (Bmax) of [3H]flunitrazepam the coupling between the GABA and the benzodiazepine recognition sites was also affected.

Animals↗
PubMed1996

Mapping of GABAA receptor sites that are photoaffinity-labelled by [3H]flunitrazepam and [3H]Ro 15-4513.

The GABAA receptor in brain membranes prepared from bovine cerebral cortex and cerebellum has been photoaffinity-labelled by the classical benzodiazepine agonist, [3H]flunitrazepam, or by the partial inverse agonist [3H]Ro 15-4513. Following solubilization and precipitation with trichloroacetic acid, the photoaffinity-labelled receptor preparations were subjected to specific chemical cleavage using hydroxylamine, a reagent which cleaves specifically at a relatively rare Asn-Gly bond. The resulting peptides were resolved by denaturing polyacrylamide gel electrophoresis and mapping of these peptides to the known amino acid sequences of the GABAA receptor subunits has localized the photoaffinity-labelling sites for these two ligands to distinct portions of the alpha subunits. It is shown that the site for [3H]flunitrazepam photoaffinity-labelling in the receptor populations of both the cerebral cortex and cerebellum occurs within residues 1-103 of the bovine alpha 1 subunit sequence (or within analogous segments of homologous alpha subunits). In contrast, the site of photoaffinity-labelling by [3H]Ro 15-4513 in the cerebral cortex and in the diazepam-sensitive GABAA receptor population of the cerebellum lies between residues 104 and the carboxy-terminus of the bovine alpha 1 or homologous alpha subunits. However, the [3H]Ro 15-4513 photoaffinity-labelling site for the diazepam-insensitive receptors of the cerebellum is shown to occur within residues 1-101 (alpha 6 subunit numbering). These results demonstrate that the photoaffinity-labelling sites for [3H]flunitrazepam and [3H]Ro 15-4513 on the GABAA receptor are localized to distinct domains of the alpha 1 subunit and that [3H]Ro 15-4513 photoaffinity labels a site on the alpha 6 subunit that is unique from its site of labelling on the alpha 1 subunit.

Affinity Labels↗
PubMed1985

Partial chemical characterization of cyclopyrrolones ([3H] suriclone) and benzodiazepines ([3H]flunitrazepam) binding site: differences.

Rat hippocampus membranes were treated with several protein modifying reagents (iodoacetamide, N-ethylmaleimide, tetranitromethane and N-acetylimidazole). The effects of these treatments on the binding sites of cyclopyrrolones ([3H] suriclone), a new chemical family of minor tranquilizers, and benzodiazepines ([3H] flunitrazepam) were investigated. Here we show that both ligands are similarly sensitive to cysteine alkylation: [3H] suriclone and [3H] flunitrazepam binding are reduced by iodoacetamide and slightly increased by N-ethylmaleimide. On the contrary they are clearly differenciated by tyrosine modification: [3H] suriclone binding is not changed whereas [3H] flunitrazepam binding is increased by tetranitromethane and decreased by N-acetylimidazole. Our present findings and published evidence suggest cyclopyrrolones and benzodiazepines bind to distinct sites or to different allosteric forms of the benzodiazepine receptor.

Animals↗
PubMed1987

Correlation between the enhancement of flunitrazepam binding by GABA and seizure susceptibility in mice.

Various populations of mice exhibit differential sensitivity to seizure-inducing agents. The relationship of seizure susceptibility to alterations in the GABA receptor complex was investigated in six different populations of mice consisting of four inbred strains (C57BL, DBA, C3H, and BALB) and two selected lines (long sleep and short sleep). Seizure activity was induced by intraperitoneal administration of the GAD inhibitor, 3-mercaptopropionic acid, and latencies to seizure onset and tonus were measured. In naive mice of the same populations, GABA enhancement of 3H-flunitrazepam binding was measured in extensively washed whole brain membranes at several GABA concentrations. Both differential seizure sensitivity to 3-mercaptopropionic acid and differential enhancement of 3H-flunitrazepam binding by GABA were observed in these six populations of mice. Correlational analyses indicated a positive correlation between the degree of GABA enhancement of 3H-flunitrazepam binding and resistance to the seizure-inducing properties of 3-mercaptopropionic acid. These data suggest that genetic differences in sensitivity to seizure-inducing agents that disrupt the GABAergic system may be related to differences in coupling between the various receptors associated with the GABA receptor complex.

3-Mercaptopropionic Acid↗
PubMed1996

The specific binding of the platelet-activating factor (PAF) receptor antagonist WEB 2086 and the benzodiazepine flunitrazepam to rat hepatocytes.

Thieno-triazolodiazepines WEB 2086 and BN 50739 have been described as the potent PAF receptor antagonists. Binding of radiolabeled [3H]WEB 2086 has been widely employed to characterize PAF receptors in different cells. In a search for a PAF receptor in isolated rat hepatocytes, we discovered that the binding of [3H]WEB to rat hepatocytes was highly specific but had a relatively low affinity with a Kd of 113 nM and Bmax of 0.65 pmol/10(6) cells in freshly isolated cell suspension and Kd of 1.65 muM and Bmax of 2.0 pmol/plate in cultured hepatocytes. No consistent specific binding of [3H]PAF itself was found in the same cell preparations. The binding of [3H]flunitrazepam in the presence of the peripheral type of benzodiazepine receptor antagonist Ro 5-4864 was saturated and exhibited a K(i) of 3.8 nM and Bmax of 3.5 pmol/plate. The central type of benzodiazepine receptor antagonist clonazepam was competed for the [3H]flunitrazepam binding, however with a much lower affinity. Various antagonists inhibited the binding of [3H]WEB 2086 with a rank order BN 50739>>Ro 5-4864 > or = clonazepam. Interestingly, bicuculline, specific antagonist of GABA(A) recognition sites, also significantly reduced the binding of [3H]WEB 2086. The binding of [3H]flunitrazepam was inhibited with a rank potency BN 50739>>WEB 2086. Taken together, these findings suggest that the specific binding of PAF receptor antagonists WEB 2086 and BN 50739 in rat hepatocytes does not involve PAF receptors and occurs via peripheral benzodiazepine and, possibly GABA(A) receptor sites.

Animals↗
PubMed1993

Hypnotics as concurrent medication in depression. A placebo-controlled, double-blind comparison of flunitrazepam and lormetazepam in patients with major depression, treated with a (tri)cyclic antidepressant.

The addition of benzodiazepine hypnotics to a treatment with tricyclic antidepressants has received little systematic study. In a double-blind placebo-controlled design, the effects on mood and on sleep of two benzodiazepine hypnotics (lormetazepam and flunitrazepam) were studied in patients with major depression who were also treated with maprotiline or nortriptyline. After 4 weeks of combined treatment, lormetazepam resulted in a significantly greater decrease in the score on the Hamilton Depression Subscale than placebo, while there was a non-significant trend in favour of lormetazepam in comparison with flunitrazepam. With respect to sleep EEGs, lormetazepam resulted in a significantly greater suppression of REM sleep. The differences between lormetazepam and flunitrazepam may be partly explained by the shorter half-live of lormetazepam.

Adult↗
PubMed1986

A quantitative relationship between Cl- enhanced [3H]flunitrazepam and [35S]t-butylbicyclophosphorothionate binding to the benzodiazepine/GABA receptor chloride ionophore complex.

A quantitative relationship between the efficacy (i.e. maximum enhancement) of Cl- to increase [3H]flunitrazepam binding and the density of [35S]t-butylbicyclophosphorothionate binding sites was observed in well-washed membrane fragments of rat cerebral cortex previously exposed to phospholipase A2. This relationship (described by the equation y = ABx) was maintained when [3H]flunitrazepam was assayed at Cl- concentrations between 100 and 600 mM, and was not qualitatively altered by the presence of 100 microM pentobarbital. However, under experimental conditions that reduced the ratio of [35S]TBPS binding sites/benzodiazepine receptors, the effects of pentobarbital suggest that the conductance state of benzodiazepine receptor-coupled chloride channels may be the primary determinant of Cl- enhanced [3H]flunitrazepam binding.

Animals↗
PubMed1987

Interaction of a water-soluble derivative of delta-9-tetrahydrocannabinol with [3H]diazepam and [3H]flunitrazepam binding to rat brain membranes.

We have tested the effect of a psychoactive water-soluble derivative of delta-9-tetrahydrocannabinol, SP-111A, on the binding of [3H]diazepam and [3H]flunitrazepam to rat brain membranes. It was found that SP-111A reduced the specific binding of [3H]diazepam and [3H]flunitrazepam. The inhibition by SP-111A was dependent not only on the concentration of the ligand but also on the protein content of membrane preparations. The inhibition of the specific binding of [3H]diazepam by SP-111A was found to be competitive with Ki value of 3.1 microM. In the presence of 7.5 microM SP111A the apparent Kd of [3H]diazepam binding increased from 4.3 nM to 12.5 nM, without affecting the Bmax. The inhibition of the specific binding of [3H]flunitrazepam by SP-111A was also competitive, however, the IC50 was higher than with [3H]diazepam. The inhibition by SP-111A appeared to be caused by its tight binding to the benzodiazepine binding sites of brain membranes.

Animals↗
PubMed1988

Comparative study in mice of flunitrazepam vs. diazepam on morphine withdrawal syndrome.

1. There is some evidence that benzodiazepine may modify the opioid withdrawal syndrome. We have investigated the effect of two different benzodiazepines, diazepam and flunitrazepam, on the morphine withdrawal syndrome experimentally induced in mice. 2. Opiate dependence has been induced by administration of morphine s.c. over a period of five days. Two hours after last morphine administration withdrawal syndrome was induced by s.c. injection of naloxone (5mg/kg). The number of jumps, wet-dog-shakes and paw tremor, and the presence or absence of ptosis, diarrhea, teeth chattering and body tremor were evaluated after naloxone injection. 3. All the signs of morphine withdrawal syndrome was antagonized by flunitrazepam and diazepam, only wet-dog-shake was strongly increased by flunitrazepam.

Animals↗
PubMed1988

Various proteins from rat brain, specifically and irreversibly labeled by [3H]flunitrazepam, are distinct alpha-subunits of the GABA-benzodiazepine receptor complex.

gamma-Aminobutyric acid (GABA)-benzodiazepine receptors were purified from the brains of 5 to 10-day-old rats and photolabeled by [3H]flunitrazepam. After sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE), 3 different proteins with apparent molecular weight 51,000, 53,000 and 59,000 Da specifically and irreversibly labeled by [3H]flunitrazepam were revealed by autoradiography. The same 3 proteins were recognized by the alpha-subunit-specific monoclonal antibody bd-28. In contrast, a different protein with apparent molecular weight 56,000 Da was recognized by the beta-subunit-specific antibody bd-17. These results indicate that the various proteins specifically labeled by [3H]flunitrazepam are different alpha-subunits and distinct and different from the beta-subunit of the GABA-benzodiazepine receptor complex.

Animals↗