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11.
Effects of protein kinase C (PKC) activation on the function of the GABA/benzodiazepine receptor-chloride complex were analyzed by quantitative autoradiography using [3H]muscimol, [3H]flunitrazepam and [35S]TBPS in rat brain slices. The density of [3H]muscimol binding was highest in cerebellar granular layers and high in both the frontal cortex and thalamus, but binding levels in the hippocampus were low. After activation of PKC by 100 nM phorbol-12,13-dibutyrate (PDBu), [3H]muscimol binding was decreased in the frontal cortex, striatum and thalamus, but binding levels were not changed in the hippocampus or cerebellum. The density of [3H]flunitrazepam binding was high in the cortex, hippocampus and molecular layers of cerebellum but was low in thalamus. PDBu increased the [3H]flunitrazepam binding only in the striatum and in part of the cortex and thalamus after activation of PKC. After activation of PKC by PDBu, [35S]TBPS binding was increased in most areas, but binding levels were not changed in the brainstem or cerebellum. The receptor binding was markedly decreased in almost all areas by the addition of 2.5 mM Mg2+. Elevated [35S]TBPS binding produced by PDBu was significantly inhibited by the addition of Mg2+. These results suggest that the activation of PKC potentiates benzodiazepine and TBPS binding, but decreases muscimol binding in a region-specific manner in the rat brain. 相似文献
12.
The action of flunitrazepam (Ro 5-4200), a benzodiazepine derivative, was assessed on the sleep cycle of insomniac patients by means of all-night reeordings. Baseline placebo nights were compared with the drug (2–8 mg p.o.) and with the placebo post-drug nights.Flunitrazepam induced a shift to faster frequencies of the EEG and a disappearance of sleep stages 3 and 4 while stage 2 was increased. In 10 out of 12 studied insomniacs the compound was effective in inducing and maintaining sleep (decrease in NREM sleep latency, wake time and number of wakes) throughout the drug administration period. Both NREM and REM sleep were increased, the latter most likely in relation to a blockade of processes precluding NREM emergence.The hypnotic action of flunitrazepam was still present during the first withdrawal night, pointing out to a carry over effect.Supported by a grant from Hoffman-La Roche. 相似文献
13.
The effects of 5-500 μM concentrations of neutral ammonium salts on the binding of ligands to components of the GABAA receptor complex were investigated. [3H]Flunitrazepam binding to the benzodiazepine receptor was enhanced by ammonium (10–500 μM), but not sodium tartrate with EC50 = 98 μM and Emax = 31%. Further increasing ammonium tartrate concentrations (500–2500 μM) decreased [3H]flunitrazepam binding to control levels. The ammonium tartrate-induced increase in [3H]flunitrazepam binding was manifested as a 50% decrease in Kd. Furthermore, GABA increased the potency of ammonium tartrate in enhancing [3H]flunitrazepam binding by 63%. [3H]Ro 15-1788 and [3H]Ro 15-4513 binding to the benzodiazepine receptor was not significantly enhanced by ammonium tartrate (Emax ≈ 13%). Ammonium tartrate also increased, then decreased the binding of 500 nM [3H]muscimol to the GABAA receptor (EC50 = 52 μM, Emax = 30%) in a concentration-dependent manner, but had no effect on [3H]SR 95-531 binding (Emax < 16%). The ammonium tartrate-induced alterations in [3H]muscimol binding were demonstrated in saturation assays as the loss of the high affinity binding site and a 27% increase in the Bmax of the low affinity binding site. These results indicate that ammonia biphasically enhances, then returns ligand binding to both the GABA and benzodiazepine receptor components of the GABAA receptor complex to control levels in a barbiturate-like fashion. This suggests that ammonia may enhance GABAergic neurotransmission at concentrations commonly encountered in hepatic failure, an event preceding the suppression of inhibitory neuronal function observed at higher ( > 1 mM) ammonia concentrations. This increase in GABAergic neurotransmission is consistent with the clinical picture of lethargy, ataxia and cognitive deficits associated with liver failure and congenital hyperammonemia. 相似文献
14.
Michael Adams Sarah-Vanessa Schneider Martin Kluge Michael Kessler Matthias Hamburger 《Journal of ethnopharmacology》2012
Ethnopharmacological relevance
Before modern anticonvulsive drugs were developed people in central Europe used herbal remedies to treat epilepsy. Hundreds of different plants for this indication can be found in German herbals of the 16th and 17th centuries. Here we compile these plants and discuss their use from a pharmacological perspective.Materials and methods
Nine of the most important European herbals of the 16th and 17th century including Bock (1577), Fuchs (1543), Mattioli (1590), 103 and 104, Brunfels (1532), Zwinger (1696), and Tabernaemontanus (1591, 1678) were searched for terms related to epilepsy, and plants and recipes described for its treatment were documented. We then searched scientific literature for pharmacological evidence of their effectiveness. Additionally the overlapping of these remedies with those in De Materia Medica by the Greek physician Dioscorides was studied.Results
Two hundred twenty one plants were identified in the herbals to be used in the context of epilepsy. In vitro and/or in vivo pharmacological data somehow related to the indication epilepsy was found for less than 5% of these plants. Less than 7% of epilepsy remedies are in common with De Materia Medica.Conclusions
Numerous plants were used to treat epilepsy in the 16th and 17th centuries. However, few of these plants have been investigated with respect to pharmacological activity on epilepsy related targets. 相似文献15.
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. 相似文献
16.
17.
Hagai Rottenberg 《Alcohol》1985,2(2):203-207
The effects of ethanol-feeding and in vitro ethanol addition on the binding of 3H-diazepam and 3H-flunitrazepam in synaptosomal membrane preparations from rat cerebral cortex were investigated. Long-term ethanol-feeding (liquid-diet, 14 g/kg/day, pair-feeding, 35 days) significantly increased the diazepam dissociation constant (from 3.80 to 4.62 nM at 4°C and from 29.3 to 35.2 nM at 37°C). Similarly, the flunitrazepam dissociation constant was also increased (from 0.80 to 0.98 nM at 4°C and from 6.52 to 8.90 nM at 37°C). However, there was no significant difference in the number of receptors after ethanol feeding. γ-Aminobutyric acid (GABA) and pentobarbital increased the binding affinity by the same magnitude in control and ethanol-fed rats. Alcohol, in vitro (100 mM), did not have a significant effect on the binding parameters under most conditions. These findings suggest that long-term ethanol-feeding reduced the binding affinity of benzodiazepines without alteration of other properties of the receptors or their number. 相似文献
18.
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. The results suggest that muscimol exposure induces a transient change in GABAA receptor sensitivity. Also, open-field behavior, ethanol consumption and GABAA receptor mechanisms may be interrelated in the rat. 相似文献
19.
The action of flunitrazepam (Ro 5-4200) a benzodiazepine derivative was assessed on the sleep cycle of normal volunteers by means of all-night recordings. Baseline placebo nights were compared with the drug (2 mg p.o.) and with the placebo postdrug nights.Flunitrazepam induced a shift to faster frequencies of the EEG and increased non-rapid eye movement sleep. REM sleep was decreased at the expense of a smaller number of REM periods and shifted to the last two thirds of the night. During drug administration an adaptation was seen to the depressive action on REM sleep. Following withdrawal, an REM rebound was observed only during the first thirds of the night.This study was supported by a grant from Hoffmann-La Roche. 相似文献
20.
Eighteen non-pregnant woman complaining about insomnia were polysomnographically investigated for 3 nights with weekly intervals. They received placebo, 2 mg flunitrazepam or 10 mg zolpidem according to a cross-over double blind design. The patients were selected by general practitioners on the basis of subjective complaints. Zolpidem is a recently introduced short-acting imidazopyridine hypnotic, binding to a subunit of the benzodiazepine 1 receptor. Flunitrazepam is a well-known hypnotic, binding to both the benzodiazepine 1 and 2 receptor subtypes. Objective recording did not substantiate the subjective complaint of insomnia. Sleep patterns during placebo differed only little from that expected from age matched healthy persons. Both flunitrazepam and zolpidem significantly shortened sleep onset (5 min of continuous sleep beginning with NREM 1 sleep). The sleep composition following flunitrazepam was characterized by an increase in NREM 2, a prolongation of the time to REM sleep, a reduction of REM sleep and an increase in NREM 3–4 sleep during the first 2 h of sleep. The sleep composition following zolpidem resembled more that seen in persons without sleep complaints. However, as compared to placebo, there was a decrease of the time spent awake during sleep and an increase in NREM 3–4 during the first 2 of sleep. 相似文献