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PubMed1987

Bicuculline-sensitive and insensitive effects of THIP on the binding of [3H]flunitrazepam.

The gamma-aminobutyric acid (GABAA) receptor partial agonist THIP inhibits the binding of [3H]flunitrazepam to unwashed membranes from the forebrain of the rat at 0 degrees C in the absence of chloride ions, reducing the affinity and Bmax of benzodiazepine (BZ) receptors. The decrease in affinity of benzodiazepine receptors seems to be due to antagonism by THIP of the effects of endogenous GABA, present in the unwashed membrane preparation. When the binding with washed membranes was determined at 30 degrees C, in the presence of chloride ions, THIP like GABA enhanced the binding of [3H]flunitrazepam through an increase in the affinity of benzodiazepine receptors. The changes in the affinity of benzodiazepine receptors induced by THIP seem to be mediated by bicuculline-sensitive receptors. However, in the presence and absence of bicuculline, THIP reduced the total number of benzodiazepine binding sites, probably in a bicuculline insensitive manner.

Animals↗
PubMed1993

Differential antagonism by epipregnanolone of alphaxalone and pregnanolone potentiation of [3H]flunitrazepam binding suggests more than one class of binding site for steroids at GABAA receptors.

In rat brain membranes, the 3 alpha-hydroxy pregnane steroids, pregnanolone, allopregnanolone, alphaxalone and 5 beta-alphaxalone potentiated 1 nM [3H]flunitrazepam binding at the GABAA receptor, with maximal potentiations of 140-150% of control. The potencies of the 5 alpha isomers were greater than the 5 beta and the presence of an 11-keto group conferred lower potency. The potentiation produced by these steroids was antagonised by the 3 beta-OH isomers epipregnanolone, isopregnanolone and betaxalone (60 microM). The dose-effect curves for pregnanolone and allopregnanolone were shifted to the right, with no reduction in the maximal potentiation. In contrast, the maximal effect of alphaxalone and 5 beta-alphaxalone was reduced with no change in EC50. Alphaxalone (1 microM) caused an increase in the binding of [3H]flunitrazepam in the presence of maximal concentrations of pregnanolone or allopregnanolone. These results suggest multiple sites of action for neurosteroids in the brain.

Anesthetics↗
PubMed1986

Effects of flunitrazepam on passive avoidance behaviour in mice subjected to immobilization stress or familiarized with the testing apparatus.

The effects of flunitrazepam on passive avoidance behaviour were investigated in DBA/2 mice. In a first set of experiments retention performance impairment was observed in mice injected with the drug immediately but not 120 min after training. In a second set of experiments, immobilization stress enhanced, while familiarization with the apparatus decreased, the effects of flunitrazepam, suggesting involvement of emotional factors. All the effects observed were antagonized by naltrexone, showing involvement of opioid receptors.

Animals↗
PubMed1985

Binding of [3H]flunitrazepam and [3H]spiperone to melanoma cell membrane preparations.

Binding of [3H]flunitrazepam and [3H]spiperone to membrane preparations isolated by high speed centrifugation of hamster, rabbit and human melanoma cell homogenates was analyzed. All melanoma cell types expressed a high density of specific binding sites for [3H]flunitrazepam (3-4 pmol/mg protein) with a high affinity (Kd about 30 nM). This binding was independent of melanin content of cells and could be classified, based on competition experiments, as a Ro 5-4864-like binding type. Specific [3H]spiperone binding to these cell lines clearly revealed at least two types of binding sites: a low affinity, high capacity type of binding site (Kd greater than 100 nM, Bmax about 50 pmol/mg protein) and a high affinity, low capacity binding site (Kd less than 1 nm, Bmax 30 fmol/mg protein). Binding of spiperone to the low affinity, high capacity site appeared displaceable by NM 113 and dependent on melanin content of the cells and probably represents binding to melanin. Analysis of drug binding to melanoma membrane cell preparations and correlation with drug effects should include the possible involvement of binding to melanin.

Animals↗
PubMed1982

Postnatal development of proteins irreversibly labeled by [3H]flunitrazepam.

The irreversible labeling by [3H]flunitrazepam of three proteins with apparent molecular weights of 51,000 (P51), 55,000 (P55) and 59,000 (P59) was investigated using hippocampal membranes isolated from rats at various timepoints after birth. The present results indicate that [3H]flunitrazepam predominantly labels P55 and P59 in the early days after birth whereas labeling of P51 starts to increase significantly in the second postnatal week. A possible association of P55 and P59 with type 2 and of P51 with type 1 benzodiazepine receptors is suggested.

Aging↗
PubMed1990

Postnatal development of [3H]flunitrazepam and [3H]strychnine binding sites in rat spinal cord localized by quantitative autoradiography.

The development of inhibitory receptors in rat spinal cord was investigated by autoradiography using [3H]flunitrazepam as a ligand for benzodiazepine receptors and [3H]strychnine as a ligand for glycine receptors. The development of benzodiazepine receptors follows a similar pattern at all levels of the spinal cord. The density of [3H]flunitrazepam binding sites is already high at birth, increases 2-fold by days 3-7 and thereafter declines to levels already present at birth. In contrast, [3H]strychnine binding sites are weakly expressed at birth and increase up to 7-fold between days 4 and 21. A craniocaudal gradient in the development of glycine receptors is not apparent. However, maturation of [3H]strychnine binding in the ventral horn precedes that in the dorsal horn for 3-4 days. In summary, the developmental expression of these two inhibitory receptors in the spinal cord appears to be regulated differently.

Aging↗
PubMed1992

High-dose flunitrazepam anesthesia.

Benzodiazepines have receptors in the nervous system as well as in the kidney, liver, skeletal and ileal muscle, lungs and the heart. Flunitrazepam is a benzodiazepine with pronounced hypnotic effects in the usual dosage. High dose flunitrazepam anesthesia is suggested for prolonged surgical procedures as an alternative to the well known high-dose opiate anesthesia. Its reversal using flumazenil can shorten the post-operative anesthetic effect.

Anesthesia↗
PubMed1993

Flunitrazepam consumption among heroin addicts admitted for in-patient detoxification.

The use of benzodiazepines among 973 heroin addicts admitted for inpatient detoxification over a 10-year period was assessed in a cross-sectional study. A total of 780 (80.2%) patients had a history of benzodiazepine use; 666 (68.5%) were consuming benzodiazepines at the time of admission and 419 (43.1%) on an almost daily basis. Seventy-five (7.7%) patients fulfilled criteria for sedative-hypnotic abuse or dependence. Consumption of benzodiazepines began after subjects had become addicted to heroin. Flunitrazepam was ranked first by 68.4% of patients, followed by clorazepate (13%), and diazepam (12.4%). The prevalence of benzodiazepine use, in particular flunitrazepam, among heroin addicts is very high. Specific abuse liability studies are needed to determine whether pharmacologic reasons exist to explain heroin addicts' preference for this compound.

Anti-Anxiety Agents↗
PubMed1994

Determination of flunitrazepam in plasma by liquid chromatography.

A reversed-phase liquid chromatographic method has been used to determine flunitrazepam in plasma. Extraction was simple and there was no need to hydrolyse the drug. Separation was achieved on a 150 x 3.9 mm i.d. column packed with 4-microns Nova Pack C18 using a mobile phase of water-acetonitrile-triethylamine (700:300:4, v/v/v) (adjusted to pH 7.5 with orthophosphoric acid). The method was shown to be rapid and reliable with a lower limit of detection of 5 ng ml-1. Results are reported of simple experiments on the effects of temperature and light on the stability of flunitrazepam in plasma kept on the laboratory bench.

Chromatography, High Pressure Liquid↗
PubMed1991

Unilateral kindling of the inferior collicular cortex does not transfer to the contralateral seizure sensitive site or alter [3H]flunitrazepam and [35S]TBPS binding.

Acute electrical stimulation of a specific area in the inferior collicular cortex produced bilateral collicular afterdischarge and symmetrical wild running seizures. However, generalized seizures induced by kindling the inferior collicular cortex did not alter the kindling rate in the contralateral side. Furthermore, after both sides of the inferior collicular cortex have been kindled unilateral electrolytic lesions did not alter the seizure initiation or generalization elicited from the contralateral side. Since GABAergic function has been implicated in inferior collicular seizures, potential seizure-induced changes were measured for the chloride channel ([35S]TBPS) and the benzodiazepine receptor ([3H]flunitrazepam). Prior kindling did not alter [35S]TBPS or [3H]flunitrazepam binding in the central nucleus or cortex of the inferior colliculus, the medial geniculate, or the deep prepiriform cortex. Thus, the permanent neural change that subserves seizure generalization from the inferior collicular cortex is unilateral, but this change is not reflected by altered binding characteristics of the GABAA receptor complex.

Animals↗
PubMed1992

Total intravenous anesthesia for infants and children undergoing correction of tetralogy of Fallot: sufentanil versus sufentanil-flunitrazepam technique.

The effects of two total intravenous anesthetic techniques were compared in 20 infants and children undergoing primary correction of tetralogy of Fallot (TOF). All patients (mean body weight, 11.4 +/- 4.2 kg; range, 6 to 20 kg; mean age, 32 +/- 21 months, range, 7 to 85 months) were premedicated with atropine, 0.02, mg/kg, morphine, 0.2, mg/kg, and flunitrazepam, 0.04 mg/kg, intramuscularly, 1 hour preoperatively. Anesthesia was induced with 1 microgram/kg of sufentanil (S) and pancuronium, 0.1 mg/kg, intravenously. Patients were ventilated with 100% oxygen. Hemodynamic parameters, heart rate (HR), systolic (SBP), diastolic (DBP) and mean arterial blood pressure (MAP), central venous pressure (CVP), and peripheral arterial blood oxygen saturation (SaO2) were recorded. Plasma concentrations of S, epinephrine (E), norepinephrine (NE), and blood gases were determined. To obtain a further depth of anesthesia, 10 patients (SM group) received 4 micrograms/kg of S and 10 patients (SF group) received 4 micrograms/kg of S in combination with flunitrazepam, 40 micrograms/kg, in a randomized manner. Measurements were made before and after induction of anesthesia, before and after anesthetic loading, 2 minutes after sternotomy, 15 minutes after initiation of extracorporeal circulation (ECC), and at sternal closure. Peak values for plasma S concentrations of 3.14 +/- 1.13 (SM group) and 3.45 +/- 97 ng/mL (SF group) were found before sternotomy. Following intubation HR, SBP, DBP, and MAP remained close to values measured before induction, but SaO2 increased significantly (P less than 0.01) in all patients. HR, SBP, and MAP decreased during anesthetic loading in both groups. Hemodynamics and plasma E and NE remained essentially unchanged after sternotomy in the SF group.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia, Intravenous↗
PubMed2005

Learning deficits induced by sleep deprivation and recovery are not associated with altered [(3)H]muscimol and [(3)H]flunitrazepam binding.

Several studies have shown that sleep deprivation produces deficits in learning tasks, but mechanisms underlying these effects remain unclear. Other lines of evidence indicate an involvement of brain GABA systems in cognitive processes. Here, we investigated the possibility that alterations in GABA(A) or benzodiazepine (BDZ) receptor binding might underlie avoidance deficits induced by sleep deprivation. Rats were deprived of sleep for 96 h using the platform method and then trained in a step-through inhibitory avoidance task, or allowed to recover sleep for 24 h before training (sleep rebound group). Thirty minutes after training, animals were given a retention test. Both sleep-deprived and sleep-recovered animals showed a significant impairment in avoidance responding compared to cage controls, and the sleep-deprived group performed significant worse than the sleep-recovered group. A separate group of animals was sacrificed either immediately after 96 h of sleep deprivation or after 96 h of sleep deprivation followed by 24 h of sleep recovery. [(3)H]muscimol and [(3)H]flunitrazepam binding were examined by quantitative autoradiography in 42 brain regions, including areas involved in cognitive processes. No significant differences among groups were found in any brain region, except for a reduction in [(3)H]flunitrazepam binding in the frontal cortex of sleep-recovered animals. These results confirm the deleterious effects of sleep loss on inhibitory avoidance learning, but suggest that such deficits cannot be attributed to altered GABA(A) or BDZ binding in brain.

Animals↗
PubMed2006

Normal [3H]flunitrazepam binding to GABAA receptors in the locus coeruleus in major depression and suicide.

Major depression and suicide are associated with altered concentrations of specific noradrenergic proteins in the human locus coeruleus (LC). Based on experimental studies that can reproduce these LC abnormalities in laboratory animals, we hypothesized that noradrenergic pathobiology in depression is a result of overactivity of the LC. LC activity is under the control of both excitatory and inhibitory inputs. A major inhibitory input to the LC is GABAergic, arising from the nucleus prepositus hypoglossi. Numerous studies demonstrating low levels of GABA in the CSF and plasma of subjects with major depressive disorder (MDD) raise the possibility that LC overactivity in depression may be secondary to reduced GABAergic input to the LC. Here, GABAergic input to the LC in depression was evaluated by studying the binding of [(3)H]flunitrazepam to GABA(A) receptors at three anatomically defined levels of the human postmortem LC. LC tissues were collected from subjects with MDD, subjects with depressive disorders including MDD that died as a result of suicide, and psychiatrically normal control subjects. A modest rostral-caudal gradient of GABA(A) receptor binding density was observed among all subjects. No significant differences in the amount of binding to GABA(A) receptors were observed between control subjects (n=21) and MDD subjects (n=9) or depressed suicide victims (n=17). These results demonstrate that GABA(A) receptor binding in the LC measured with [(3)H]flunitrazepam is not altered in subjects with depressive illnesses.

Analysis of Variance↗
PubMed2006

The motor-impairing effects of GABA(A) and GABA(B) agonists in gamma-hydroxybutyrate (GHB)-treated rats: cross-tolerance to baclofen but not flunitrazepam.

gamma-Hydroxybutyrate (GHB) is believed to function as a neurotransmitter in the mammalian brain by binding to a GHB-specific binding site. In addition, GHB may also indirectly enhance the neuroinhibitory actions of gamma-aminobutyric acid (GABA) by converting to GABA at neuronal synapses. The purpose of the present study was to examine the effects of representative GABA(A) and GABA(B) receptor agonists in rats treated chronically with GHB. Using a rotorod apparatus, the motor-impairing effects of GHB, the indirect GABA(A) receptor agonist, flunitrazepam, and the direct GABA(B) receptor agonist, baclofen, were examined before, during and after chronic treatment with 1000 mg/kg GHB, b.i.d. Prior to chronic treatment, all three drugs produced dose-dependent decreases in motor performance at low (8 rpm) and high (32 rpm) rotational speeds. Chronic treatment with GHB significantly decreased the potency of baclofen at both speeds, but did not alter the potency of either GHB or flunitrazepam. Following termination of chronic treatment, the potency of baclofen increased significantly at both speeds and returned to that observed prior to chronic treatment. These data indicate that chronic treatment with GHB confers tolerance to a GABA(B) receptor agonist under conditions in which tolerance is not conferred to a GABA(A) receptor agonist. These findings are consistent with the in vivo behavioral profile of GHB, which reveals a greater role for GABA(B) receptors than for GABA(A) receptors in its behavioral effects.

Adjuvants, Anesthesia↗
PubMed2000

Deduction of amino acid residues in the GABA(A) receptor alpha subunits photoaffinity labeled with the benzodiazepine flunitrazepam.

Peptide mapping and microsequencing were used to infer the site of photoaffinity labeling by the gamma-aminobutyric acidA receptor modulator [3H]flunitrazepam. Peptide mapping with and without N-deglycosylation was used to restrict the domain for photoaffinity labeling to residues 74-123 of the bovine alpha1 subunit, in agreement with a previously predicted labeling domain between residues 59-148 based on cyanogen bromide fragmentation. Edman degradation of partially purified photolabeled peptides gave release of 3H counts in the ninth cycle of a tryptic peptide sequence. A second V8/chymotryptic peptide produced an impure sequence with release of 3H counts in the seventh through ninth cycle of sequence. The combined data support those previously reported, i.e., that the primary site for photoaffinity labeling by [3H]flunitrazepam is His102 of the bovine alpha1 subunit. In addition we also detected possible secondary labeling of Pro97.

Affinity Labels↗
PubMed2001

High-performance liquid chromatography determination of flunitrazepam and its metabolites in plasma by use of column-switching technique: comparison of two extraction columns.

A study, using on-line column-switching high-performance liquid chromatography, evaluated two different extraction columns for the determination of flunitrazepam and its major metabolites: 7-aminoflunitrazepam, 7-acetamidoflunitrazepam and desmethylflunitrazepam. The procedure was based on the enrichment of benzodiazepines on the extraction column, followed by transfer of the compounds to the analytical column. The two extraction columns were compared: the first column was a BioTrap 500 MS (hydrophobic polymer), 20x4 mm I.D., and the second was a LiChrospher RP-18 ADS, 25x4 mm I.D. The analytical column used was a LiChrospher select B RP-8, 125x3 mm I.D. with 5 microm particle size. The extraction conditions for the two pre-concentration columns, such as extraction temperature, buffer concentration, buffer pH, acetonitrile percentage and flow-rate, were studied for the extraction from plasma of flunitrazepam and its metabolites mentioned above. The mobile phase of the analytical column was isocratic and composed of acetonitrile-20 mM phosphate buffer at pH 2.1 (35:65, v/v) and at a flow-rate of 0.3 ml/min.

Acetonitriles↗
PubMed1986

Improved qualitative method for establishing flunitrazepam abuse using urine samples and column liquid chromatography with fluorimetric detection.

The abuse of flunitrazepam (Rohypnol), a potent benzodiazepine-type hypnotic, cannot be established with the widely used immunoassays for urine analysis owing to lack of specificity. A simple method is described which is based on the formation of acridine derivatives and measures the sum of metabolites of flunitrazepam in urine samples using column liquid chromatography with fluorimetric detection.

Biotransformation↗
PubMed1998

Quantification of flunitrazepam's oxidative metabolites, 3-hydroxyflunitrazepam and desmethylflunitrazepam, in hepatic microsomal incubations by high-performance liquid chromatography.

A high-performance liquid chromatographic assay for the quantification of the oxidative metabolites of flunitrazepam, 3-hydroxyflunitrazepam and desmethylflunitrazepam, in human liver microsomal incubations was developed. Both metabolites were quantifiable in a single assay following a solvent extraction and reversed-phase high-performance liquid chromatography with UV detection. Standard curve concentrations for both metabolites ranged from 0.2 to 10 microM. Assay performance was determined using quality control samples and the intra- and inter-day accuracy and precision as determined by the coefficient of variations which were less than 15% (0.5-6 microM) for both metabolites. This method provides good precision and accuracy for use in kinetic studies of the oxidative metabolism of flunitrazepam in human liver microsomes.

Anti-Anxiety Agents↗