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PubMed1983

Suriclone: a new cyclopyrrolone derivative recognizing receptors labeled by benzodiazepines in rat hippocampus and cerebellum.

Suriclone (RP 31,264), like zopiclone (RP 27,267), belongs to the family of cyclopyrrolones and is chemically entirely different from the benzodiazepines (BZDs). However, it possesses a pharmacological profile close to that of the BZDs and proved to be useful in therapeutics as an anxiolytic agent. In the present paper it is shown that suriclone possesses a high affinity for flunitrazepam binding sites and that tritiated suriclone binds specifically with high affinity in rat hippocampus (KD = 0.44 +/- 0.03 nM) and rat cerebellum (KD = 0.53 +/- 0.12 nM). Further, suriclone binding sites are recognized by BZDs or zopiclone, similarly in the two regions. The affinities of four BZD derivatives--nitrazepam, flunitrazepam, diazepam, and chlordiazepoxide--are similar for suriclone and flunitrazepam binding sites. Suriclone binding sites are, like flunitrazepam sites, protected from thermal inactivation by gamma-aminobutyric acid (GABA) (10 microM), but only flunitrazepam binding is enhanced by GABA. It could be postulated from this that suriclone interacts with a subpopulation of receptors that might be modulated differently from flunitrazepam binding sites. Our results indicate that suriclone could be a new probe for investigating the so-called BZD receptors.

Animals↗

PubMed1987

Stress-induced changes in t-[35S]butylbicyclophosphorothionate binding to gamma-aminobutyric acid-gated chloride channels are mimicked by in vitro occupation of benzodiazepine receptors.

The allosteric modulation of t-[35S]butylbicyclophosphorothionate binding by flunitrazepam was studied in well-washed brain membranes prepared from control and swim-stressed rats. Swim stress has been reported to decrease the KD and increase the Bmax of this radioligand. Flunitrazepam increased radioligand binding with equal potency (EC50 approximately 11 nM) in both groups, but the maximal enhancement (efficacy) produced by this drug was significantly greater in control than in swim-stressed rats. Ro 15-1788 (a benzodiazepine receptor antagonist) blocked the effect of flunitrazepam on t-[35S]butylbicyclophosphorothionate binding in both groups. This increase in t-[35S]butylbicyclophosphorothionate binding resulted from a significant reduction in KD with no alteration in Bmax. The KD values obtained in cortical membranes of control rats after addition of flunitrazepam were not significantly different from those in the swim-stressed group. Preincubation of cortical homogenates from control animals with flunitrazepam prior to extensive tissue washing resulted in Bmax and KD values of t-[35S]butylbicyclophosphorothionate similar to those obtained in stressed animals. These findings suggest that stress and flunitrazepam may share a common mechanism in regulating t-[35S]butylbicyclophosphorothionate binding and support the concept that stress-induced modification of gamma-aminobutyric acid (GABA)-gated chloride channels in the CNS results from the release of an endogenous modulator (with benzodiazepine-like properties) of the benzodiazepine-GABA receptor chloride ionophore receptor complex.

Animals↗

PubMed1996

[Sedation with flunitarazepam at magnetic resonance imaging in the elderly patients with dementia].

Magnetic resonance imaging (MRI) of the brain is useful in diagnosing senile dementia, but to avoid the creation of artifacts the patient should be kept immobile. We studied the effects of pretreatment with flunitrazepam, a sleep inducer of the benzodiazepine class, as a sedative prior to imaging. The subjects consisted of 108 patients with senile dementia admitted to the Dementia Ward of Kyoto Higashiyama Geriatric Hospital. Their ages ranged from 64-95 years (mean, 81) and the mean body weights of the 76 women and 32 men were 36 and 47 kg, respectively. Immediately before undergoing MRI the patients were given a slow intravenous injection of flunitrazepam (2 mg/ml diluted in 19 ml of saline). Immediately before the patients fell asleep, administration was discontinued and the dose was noted: mean 0.008 mg/kg. In all patients sleep induction and sedation were achieved. No adverse reactions such as apnea were observed. The flunitrazepam dose in our study was much lower than that in previous reports on adults. As body weights of the elderly are also lower than those of younger adults, the optimum dose of flunitrazepam for the elderly may be much lower. Intravenous flunitrazepam may be a useful and safe premedication for MRI in elderly patients with dementia. To avoid serious adverse reactions the dose should be minimized by: 1) determining body weight before MRI, 2) administering diluted flunitrazepam, and 3) discontinuing the drug before the patient falls asleep.

Aged↗

PubMed1999

Altered GABA(A)-benzodiazepine receptor number and pharmacology in the adult guinea pig cerebral cortex after chronic prenatal ethanol exposure.

BACKGROUND: The effects of chronic prenatal ethanol exposure on GABA(A)-benzodiazepine receptor number and binding pharmacology were examined in the cerebral cortex of the postnatal guinea pig. METHODS: [3H]Flunitrazepam binding to GABA(A)-benzodiazepine receptors was measured in a cerebral cortical cell membrane preparation obtained at postnatal days 11 (preweaning), 21 (postweaning), and 61 (adulthood). Zolpidem, a GABA(A)-benzodiazepine type 1 receptor-selective ligand, was used in a [3H]flunitrazepam competition study. 3a-Hydroxy-5alpha-pregnan-20-one (allopregnanolone) potentiation of [3H]muscimol and [3H]flunitrazepam binding, and GABA potentiation of [3H]flunitrazepam binding were measured in these same animals. RESULTS: At postnatal day 61, but not at the younger ages studied, the following was observed: (1) [3H]Flunitrazepam binding exhibited an increased receptor number (Bmax) and decreased affinity (increased K(D)) in the ethanol-treated offspring compared with isocaloric-sucrose (with pair-feeding) and water-treated controls; and (2) the relative proportion of GABA(A)-benzodiazepine receptors that had high-affinity binding sites for zolpidem was decreased in the ethanol-treated offspring by 31% and 38% compared with the isocaloric-sucrose/pair-fed and water-treated controls, respectively. Chronic prenatal ethanol exposure did not alter the efficiency of coupling between GABA, benzodiazepine, and neurosteroid binding sites at any postnatal ages studied. CONCLUSIONS: These results suggest that, in the cerebral cortex of the adult guinea pig, chronic prenatal exposure to ethanol results in increased GABA(A)-benzodiazepine receptor number, decreased affinity for flunitrazepam, and decreased relative proportion of the GABA(A)-benzodiazepine type 1 receptor.

Animals↗

PubMed1984

[Stress reduction by i.m. premedication with 6 different single substances].

In three prospective randomized studies six substances for intramuscular premedication were investigated and compared to placebo (NaCl 0.9%): diazepam (10-20 mg), flunitrazepam (1-2 mg), droperidol (2.5-5 mg), triflupromazin (10-20 mg), pethidin (50-100 mg) and buprenorphin (0.15-0.3 mg). The effects on preoperative stress were evaluated with psychometrical methods (ESB), heart rate, blood pressure and plasma-cortisol levels. Degree of sedation and side effects were recorded. Good effects on anxiety were found after flunitrazepam, diazepam and triflupromazin. The worst effects were found after droperidol and pethidin. Good effects on depression were found after pethidin, buprenorphin, diazepam and triflupromazin. The worst effects were found after droperidol. Asthenic patients were improved with diazepam and flunitrazepam, but deteriorated after placebo, pethidin, triflupromazin and droperidol. The physiological stress parameters were positively influenced by diazepam and flunitrazepam, but not after placebo and droperidol. Nausea and vomitus were found after buprenorphin, pethidin and droperidol; psychological and neurological problems occurred after droperidol. The highest degree of sedation was found after flunitrazepam, diazepam and droperidol. The day after surgery the patients found placebo, flunitrazepam, diazepam and triflupromazin to be the best premedications, pethidin and buprenorphin were inferior and droperidol was the poorest premedication.

Adolescent↗

PubMed1990

Decreased benzodiazepine receptor binding in epileptic El mice: a quantitative autoradiographic study.

Benzodiazepine receptors and subtypes were examined in El mice and normal ddY mice with a quantitative autoradiographic technique. Specific [3H]flunitrazepam binding in stimulated El mice, which had experienced repeated convulsions, was significantly lower in the cortex and hippocampus than in ddY mice and unstimulated El mice. In the amygdala, specific [3H]flunitrazepam binding in stimulated El mice was lower than in ddY mice. There was a tendency for the [3H]flunitrazepam binding in these regions in unstimulated El mice to be intermediate between that in stimulated El mice and that in ddY mice, but there was no significant difference between unstimulated El mice and ddY mice. [3H]Flunitrazepam binding displaced by CL218,872 was significantly lower in the cortex of stimulated El mice than in that of the other two groups, and in the hippocampus of stimulated than of unstimulated El mice. These data suggest that the decrease in [3H]flunitrazepam binding in stimulated El mice may be due mainly to that of type 1 receptor and may be the result of repeated convulsions.

Animals↗

PubMed2005

Effects of kava-kava extract on the sleep-wake cycle in sleep-disturbed rats.

RATIONALE: Kava-kava extract may be useful as an herbal medicine for treatment of insomnia and anxiety. OBJECTIVES: The present study was undertaken to investigate the effects of kava-kava extract on the sleep-wake cycle in comparison with that of flunitrazepam using sleep-disturbed rats. METHODS: Electrodes for measurement of electroencephalogram (EEG) and electromyogram (EMG) were implanted into the frontal cortex and the dorsal neck muscle of rats. EEG and EMG were recorded with an electroencephalogram. SleepSign ver.2.0 was used for EEG and EMG analysis. Total times of wakefulness, non-rapid eye movement (non-REM) and REM sleep were measured from 09:00 to 15:00. RESULTS: A significant shortening of the sleep latency in sleep-disturbed rats was observed following the administration of kava-kava extract at a dose of 300 mg/kg, while no effects were observed on the total waking and non-REM sleep time. On the other hand, flunitrazepam showed a significant shortening in sleep latency, decrease in total waking time and increase in total non-REM sleep time. Although the effects of flunitrazepam were antagonized by the benzodiazepine receptor antagonist flumazenil, the effect of kava-kava extract was not antagonized by flumazenil. Kava-kava extract showed a significant increase in delta activity during non-REM sleep in sleep-disturbed rats, whereas a significant decrease in delta power during non-REM sleep was observed with flunitrazepam. Flumazenil caused no significant effect on the changes in delta activity induced by both kava-kava extract and flunitrazepam. CONCLUSIONS: Kava-kava extract is an herbal medicine having not only hypnotic effects, but also sleep quality-enhancement effects.

Animals↗

PubMed2003

Benzodiazepine and kainate receptor binding sites in the RCS rat retina.

BACKGROUND: The effect of age and photoreceptor degeneration on the kainate subtype of glutamate receptors and on the benzodiazepine-sensitive gamma-aminobutyric acid-A receptors (GABA(A)) in normal and RCS (Royal College of Surgeons) rats were investigated. METHODS: [(3)H]Kainate and [(3)H]flunitrazepam were used as radioligands for kainate and GABA(A)/benzodiazepine()receptors, respectively, using the quantitative receptor autoradiography technique. RESULTS: In both normal and RCS rat retina we observed that [(3)Eta]flunitrazepam and [(3)Eta]kainate binding levels were several times higher in inner plexiform layer (IPL) than in outer plexiform layer (OPL) at all four ages studied (P17, P35, P60 and P180). Age-related changes in receptor binding were observed in normal rat retina: [(3)Eta]flunitrazepam binding showed a significant decrease of 25% between P17 and P60 in IPL,and [(3)Eta]kainate binding showed significant decreases between P17 and P35 in both synaptic layers (71% in IPL and 63% in OPL). Degeneration-related changes in benzodiazepine and kainate receptor binding were observed in RCS rat retina. In IPL, [(3)Eta]flunitrazepam and [(3)Eta]kainate binding levels were higher than in normal retina at P35 (by 24% and 86%, respectively). In OPL, [(3)Eta]flunitrazepam binding was higher in RCS than in normal retina on P35 (74%) and also on P60 (62%). CONCLUSIONS: The results indicate that postnatal changes occur in kainate and benzodiazepine receptor binding sites in OPL and IPL of the rat retina up to 6 months of age. The data also suggest that the receptor binding changes observed in the RCS retina could be a consequence of the primary photoreceptor degeneration.

Animals↗

PubMed1993

Early postnatal treatment with muscimol transiently alters brain GABAA receptors and open-field behavior in rat.

The long-term effects of treatment with muscimol, a GABAA agonist, and with ethanol, also shown to have a GABAergic profile of action, on subsequent behavior and on the binding parameters of GABAA receptors were studied in Wistar rats. Rats were given two daily injections of muscimol (0.1 mg/kg M1 group of 0.2 mg/kg M2 group) or ethanol (1.5 g/kg) between the 1st and 21st postnatal days, with saline-treated animals serving as controls. At the age of one month, the activity of the M2 rats was decreased in the open-field arena. At the age of four months, ethanol-treated rats consumed less 10% ethanol solution in a free choice situation. No changes were seen in the elevated plus-maze test. Maximal GABA stimulation of [3H]flunitrazepam binding was decreased in the cerebellum and hippocampus in M2 rats at the age of one month but not four months. A significant positive correlation was found in all rats between maximal GABA-stimulated [3H]flunitrazepam binding in the cerebellum and ambulation in the open-field arena at the age of one month. Ethanol intake correlated negatively with maximal GABA stimulation of [3H]flunitrazepam binding in the cerebral cortex. None of the treatments affected the cerebellar binding of an imidazobenzodiazepine, [3H]Ro 15-4513. There was an age-dependent decline in the efficacy and potency (EC50) of the GABA enhancement of [3H]flunitrazepam binding in the cerebellum in all treatment groups. Basal binding of [3H]flunitrazepam to hippocampal and cerebellar membranes as well as binding of [3H]Ro 15-4513 to cerebellar membranes was also decreased as a function of age.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗

PubMed1996

Down-regulation of benzodiazepine receptors by ethyl beta-carboline-3-carboxylate in cerebrocortical neurons.

Effect of exposure of primary cultured cerebral cortical neurons to ethyl beta-carboline-3-carboxylate (beta-CCE) on the function of benzodiazepine receptors was studied. Exposure of neurons to beta-CCE (0.1-10 microM) decreased the binding of [3H]flunitrazepam to extensively washed membrane fractions in a dose- and time-dependent manner, whereas the binding of [3H]flunitrazepam to the cytosolic fractions increased (180%) under the same conditions as described above. Ethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a] [1,4] benzodiazepine-3-carboxylate (Ro15-1788), an antagonist of the central type of benzodiazepine receptors, completely abolished the beta-CCE-induced decrease in [3H]flunitrazepam binding and the IC50 value for [3H]flunitrazepam binding to the extensively washed membrane fractions prepared from beta-CCE-treated neurons was similar to that from non-treated neurons. Scatchard analysis revealed that only the Bmax value for [3H]flunitrazepam binding decreased after the exposure to beta-CCE (1 microM) for 12 h, although the Kd value was not altered. These results indicate that beta-CCE induces the down-regulation of benzodiazepine receptors by an increase in benzodiazepine receptor internalization.

Animals↗

PubMed1983

Enhanced binding of radioligands to receptors of gamma-aminobutyric acid and benzodiazepine by a new anticonvulsive agent, LY81067.

A diaryltriazine, LY81067, effectively protects against pentylenetetrazole- and picrotoxin-induced convulsions in mice, with ED50 values of 5.7 and 5.8 mg/kg i.p., respectively. LY81067 enhances the binding of both 3H-GABA and 3H-flunitrazepam to specific sites in rat brain membranes. The degree of enhancement by LY81067 varies from one brain region to another and is different for the binding of 3H-GABA and 3H-flunitrazepam. In cortical membranes, LY81067 increases the affinity of 3H-GABA for both high and low affinity sites and increases the number of sites. LY81067 increases the affinity of 3H-flunitrazepam for its binding sites without greatly increasing the number of sites. Like the pyrazolopyridines, the enhancement of 3H-flunitrazepam binding by LY81067 is dependent on chloride or related anions and is reversed by picrotoxin, suggesting that LY81067 exerts its anticonvulsant effects by binding to or near picrotoxin binding sites. The differential effects of LY81067 on the enhancements of 3H-GABA and 3H-flunitrazepam binding in several brain regions suggest extensive multiplicity of GABA/benzodiazepine/picrotoxin/anioin receptor complexes.

Animals↗

PubMed1982

Characterization of solubilized benzodiazepine and muscimol binding sites from rat brain.

Binding sites for muscimol and flunitrazepam were solubilized and their properties studied by ultrafiltration, isoelectro-focusing and cation-exchange chromatography methods. The heterogenity of binding sites for flunitrazepam was demonstrated in the ultrafiltration experiments: the binding sites with a molecular weight of more than 300,000 dalton were sensitive to stimulation by gamma-aminobutyric acid (GABA) and those with a molecular weight of less than 300,000 dalton were not. The binding sites for flunitrazepam appeared to be low acidic molecules with pI 5.6-6.0 and binding sites for muscimol an apparently more heterogenous distribution in the range of pH 4.6 to 5.9 was detected. Cation-exchange chromatography revealed two subpopulations of binding sites for muscimol one of which copurified together with binding sites for flunitrazepam. Each subpopulation exhibited only one class of binding site with Kd = 20 nM for a subpopulation copurifying together with binding sites for flunitrazepam and Kd = 9 nM for the other.

Animals↗

PubMed1989

The ontogeny of benzodiazepine receptors in selected regions of the rat brain: effect of perinatal exposure to diazepam.

The postnatal development of the binding of [3H]flunitrazepam to benzodiazepine receptors has been studied in the frontal cortex, cerebellum, striatum, hypothalamus and hippocampus of the rat after prenatal, perinatal and postnatal exposure to diazepam. The dams were injected subcutaneously with single daily doses of 1 mg/kg of diazepam from day 7-20 of gestation or from day 15 of gestation day 6 after birth. Offspring of untreated dams were injected in the same way from postnatal day 7-20. The developmental profiles of the binding of [3H]flunitrazepam obtained in both control and diazepam-treated groups of animals were very similar. This supported the idea of a sequential development of benzodiazepine receptors in relation to the different rates of maturation of certain structures of the brain. Prenatal administration of diazepam resulted in an increase of the binding of [3H]flunitrazepam in the frontal cortex by 20% at postnatal day 90 and in a decrease of binding in the hippocampus by 14% at postnatal day 60 and an increase of binding by 18% at postnatal day 90. Perinatal exposure to diazepam did not affect the binding of [3H]flunitrazepam in the hippocampus in young adult offspring. Postnatal application of diazepam resulted in a transiently decreased binding of [3H]flunitrazepam in the cerebellum by 20% at postnatal day 28. The results obtained point to the necessity for a prolonged evaluation of events after exposure to diazepam in early stages of development of the brain.

Animals↗

PubMed1992

The effect of benzodiazepines on the binding of [3H]SCH 23390 in vivo.

The effect of flunitrazepam upon the binding of [3H]SCH 23390 in vivo was investigated. Acute treatment with flunitrazepam decreased the binding of [3H]SCH 23390 in the striatum in a dose-dependent manner. The time course of radioactivity in the striatum, cerebral cortex and cerebellum in controls and flunitrazepam (1 mg/kg)-treated mice was measured after intravenous injection of [3H]SCH 23390. The binding kinetics were calculated, using the cerebellum as a reference region for the estimation of the amount of free ligand in the brain. Flunitrazepam significantly decreased the input rate constant to the receptor compartment and the dissociation rate constant in vivo. An in vivo displacement study, using carrier SCH 23390, also showed significant reduction in the dissociation rate constant of [3H]SCH 23390 in vivo. The drug Ro 15-1788 reversed the effect of flunitrazepam, suggesting that this reduction in binding of [3H]SCH 23390 was mediated by benzodiazepine receptors. To evaluate the relationship between the reduction in binding of [3H]SCH 23390 in vivo and in vivo occupancy of benzodiazepine receptors, in vivo occupancy of benzodiazepine receptors was measured using [3H]Ro 15-1788. A non-linear relationship was found between the reduction in dopamine D1 receptor binding in vivo and the occupancy of benzodiazepine receptors in vivo, indicating that benzodiazepines exerted the maximum change in dopamine receptor binding at a low fractional occupancy of receptors.

Animals↗

PubMed1989

In vivo and in vitro modulation of central type benzodiazepine receptors by phosphatidylserine.

The in vivo and in vitro modulation of central benzodiazepine binding sites (BDZ-R) by phosphatidylserine purified from bovine cerebral cortex (BC-PS) was studied. Five days i.p. administration of 15 mg/kg/day of BC-PS liposomes increased the maximal number of binding sites (Bmax) for [3H]flunitrazepam in cerebral cortical membranes. In contrast, the density of hippocampal benzodiazepine recognition binding sites decreased. In cerebellar membranes, BC-PS treatment did not alter the characteristics of [3H]flunitrazepam binding. Similar experiments using phosphatidylcholine extracted from bovine brain (BC-PC) resulted in no changes in the [3H]flunitrazepam binding in the 3 neural structures studied. Confirming previous results, rats submitted to an acute swimming stress showed a decrease in the density of cerebral cortex BDZ-R. Animals treated with BC-PS liposomes before stress showed cortical [3H]flunitrazepam binding significantly below treated, unstressed animals but not below controls. The effects of BC-PS liposomes appeared to be selective for the central type of BDZ-R since no changes were observed in [3H]RO 5-4864 binding, a radioligand specific for the peripheral type BDZ-R. Preincubation of cerebral cortical and cerebellar synaptosomal membranes with BC-PS liposomes (1-300 micrograms per assay) significantly increased in a concentration-dependent manner (up to 100 micrograms) the [3H]flunitrazepam binding. Scatchard analysis revealed changes in the apparent affinity without alterations in the Bmax. Very similar results were obtained using a purified PS from spinal cord. BC-PC, phosphatidylinositol, phosphatidic acid and the lyso derivatives of PS and PC (lysoPS and lysoPC) were found to be ineffective.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

3 alpha-hydroxy-5 alpha-pregnan-20-one modulation of solubilized GABA/benzodiazepine receptor complex.

The allosteric modulation of the progesterone metabolite 3 alpha- hydroxy-5 alpha-pregnan-20-one (DHP) on [3H]Flunitrazepam and [35S]t-butylbicyclophosphorothionate (TBPS) binding was investigated on a soluble receptor preparation. Better results in the solubilization occurred by the use of the zwitterionic detergent CHAPS with the inclusion of the phospholipid asolectin: this treatment was found suitable to study the steroidal modulation on [3H]Flunitrazepam and [35S]TBPS binding. We found that DHP was able to enhance [3H]Flunitrazepam binding in the presence of Cl- ions, while [35S]TBPS binding was inhibited by DHP. Scatchard analysis of specific [35S]TBPS and [3H]Flunitrazepam binding yielded in a single straight line both in the controls and in the presence of the hormone; DHP increased the apparent affinity of [3H]Flunitrazepam binding without altering the apparent Bmax value. In the case of [35S]TBPS, DHP decreased the apparent Bmax value whereas the Kd value remained nearly the same.

Animals↗

PubMed1998

Effects of the GABAergic system on in vivo binding of [3H]N-methylspiperone.

The effects of flunitrazepam, a benzodiazepine receptor agonist and those of NNC-711, a GABA transporter blocker, on the in vivo binding of [3H]N-methylspiperone, a dopamine D2 receptor antagonist, were investigated in mouse brain. Treatment with either flunitrazepam or NNC-711 reduced the specific binding of [3H]N-methylspiperone in the striatum. Flumazenil, a central benzodiazepine receptor antagonist, blocked the effect of flunitrazepam, indicating that the reduction in specific binding in the striatum was mediated via the GABAergic system. The flunitrazepam significantly decreased the specific binding of [3H]N-methylspiperone in the striatum at all time points studied after tracer injection, whereas specific binding in the cerebellum and cerebral cortex was unaltered. This decrease in specific binding in the striatum was found to be due to a reduced input rate constant (k3) of [3H]N-methylspiperone. The maximum number of the binding sites available for dopamine D2 receptors in the striatum was not changed by the flunitrazepam treatment.

Animals↗

PubMed2002

Effects of etifoxine on ligand binding to GABA(A) receptors in rodents.

The GABA(A) receptor/chloride ionophore is allosterically modulated by several classes of anxiolytic and anticonvulsant agents, including benzodiazepines, barbiturates and neurosteroids. Etifoxine, an anxiolytic and anticonvulsant compound competitively inhibited the binding of [(35)S]t-butylbicyclophosphoro-thionate (TBPS), a specific ligand of the GABA(A) receptor chloride channel site. To investigate the etifoxine modulatory effects on the different binding sites of the GABA(A) receptor complex, we have examined the effects of etifoxine on binding of the receptor agonist [(3)H]muscimol and the benzodiazepine modulator [(3)H]flunitrazepam in rat brain membrane preparations. The anticonvulsant properties of etifoxine combined with muscimol and flunitrazepam were performed in mice with picrotoxin-induced clonic seizures. Etifoxine modestly enhanced binding of [(3)H]muscimol and of [(3)H]flunitrazepam by increasing the number of binding sites without changing the binding affinity of [(3)H]flunitrazepam. In contrast, the compound decreased the affinity of muscimol for its binding site. In vivo, the combination of subactive doses of etifoxine with muscimol or flunitrazepam produced an anticonvulsant additive effect against the picrotoxin-induced clonic seizures in mice. These results suggest that the interaction of etifoxine on the GABA(A) receptor complex would allosterically modify different binding sites due to conformational changes. Functionally, the resulting facilitation of GABA transmission underlies the pharmacological properties of etifoxine.

Animals↗