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Ted H. Chiu - One of the best experts on this subject based on the ideXlab platform.
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Rapid down-regulation of [3H]zolpidem binding to rat brain benzodiazepine receptors during Flurazepam treatment
European journal of pharmacology, 1995Co-Authors: Howard C. Rosenberg, Ted H. ChiuAbstract:Abstract In a previous study, it was found that down-regulation of benzodiazepine (BZ) binding in rats treated 4 weeks with Flurazepam was relatively greater and more widespread when measured with [ 3 H]zolpidem, a selective ‘BZ 1 receptor’ ligand, than that measured with the non-selective ligand, [ 3 H]flunitrazepam. In the present study, the time course for down-regulation of [ 3 H]zolpidem binding was studied in rats treated with Flurazepam. [ 3 H]Zolpidem binding was also studied in rats given a midazolam treatment shown to cause tolerance. Rats were chronically treated with Flurazepam for 1 or 2 weeks, or with midazolam for 3 weeks, then killed immediately after the treatment. Another group of rats was acutely treated with desalkyl-Flurazepam and killed 30 min later. After 2 weeks of Flurazepam treatment, the B max of [ 3 H]zolpidem binding was decreased by 22% in cerebral cortex, 26% in cerebellum and 33% in hippocampus, with no change in the K d in any region. After 1 week of Flurazepam treatment, the B max was decreased by 23% in cerebellum and 14% in hippocampus, but not changed in cerebral cortex. The K d was increased in cerebral cortex, but not in cerebellum or hippocampus. Neither the B max nor the K d of [ 3 H]zolpidem binding was affected by acute desalkyl-Flurazepam treatment, or by 3 weeks of midazolam treatment. These results, in combination with previous findings, which showed no change in [ 3 H]flunitrazepam binding after 1 or 2 week Flurazepam treatment, and no change in cerebellum even after the 4 week treatment, may indicate a shift in BZ receptor subtypes in Flurazepam-tolerant rats. Such a shift could be based on possible changes in the subunit composition or conformation of GABA A /BZ receptors after 1 or 2 week Flurazepam treatment.
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reduced expression of gamma aminobutyric acid type a benzodiazepine receptor gamma 2 and alpha 5 subunit mrnas in brain regions of Flurazepam treated rats
Molecular Pharmacology, 1994Co-Authors: Taijun Zhao, Ted H. Chiu, H C RosenbergAbstract:Previous studies showed that chronic benzodiazepine administration in rats affected the gamma-aminobutyric acid (GABA)A/benzodiazepine receptor. The present experiment investigated the effects of chronic Flurazepam treatment on the mRNA levels for alpha 1, alpha 5, gamma 2, and gamma 2L (an alternatively spliced product of the gamma 2 gene) subunits of the GABAA/benzodiazepine receptor in rat cerebral cortex, cerebellum, and hippocampus. Rats were treated with Flurazepam for 2 or 4 weeks, and the mRNA levels were measured while rats were still receiving drug or 48 hr after 4-week Flurazepam treatment had been stopped. The level of alpha 5 mRNA was also measured in other rats 4 hr after a single injection of Flurazepam or diazepam. The levels of mRNAs were analyzed by Northern blotting using digoxigenin-labeled oligonucleotide probes. Compared with the pair-handled controls, the levels of gamma 2 subunit mRNA in cortex and hippocampus were not changed after Flurazepam treatment for 2 weeks. However, with rats treated with Flurazepam for 4 weeks the levels of gamma 2 subunit mRNA were significantly reduced in cortex (31%) and hippocampus (39%) but not in cerebellum. The values returned to control levels by 48 hr after termination of the treatment. The regional distribution and time course of reduced gamma 2 levels matched the decrease in benzodiazepine binding produced by the same chronic Flurazepam treatment. The amounts of alpha 5 mRNA were reduced in cortex (23%) and hippocampus (18%) 4 hr after a single dose of Flurazepam but not diazepam. The levels of alpha 5 mRNA remained reduced in cerebral cortex and hippocampus (about 50%) after 2 weeks but returned to control after 4 weeks of chronic treatment with Flurazepam. No change in alpha 1 or gamma 2L subunit mRNAs was observed in any of the three brain regions examined after 4 weeks of Flurazepam treatment. These results suggest that benzodiazepine receptor down-regulation after chronic benzodiazepine treatment may be related to the reduced expression of gamma 2 subunit mRNA, and they also suggest differential temporal and regional regulation of alpha 5 and gamma 2 subunit mRNAs in rat brain.
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regional changes in 3h zolpidem binding to brain benzodiazepine receptors in Flurazepam tolerant rat comparison with changes in 3h flunitrazepam binding
Journal of Pharmacology and Experimental Therapeutics, 1994Co-Authors: Howard C. Rosenberg, Ted H. Chiu, V RamseywilliamsAbstract:Regional downregulation of brain benzodiazepine (BZ) receptors was studied in rats treated with Flurazepam or diazepam protocols known to produce anticonvulsant tolerance. Zolpidem, a selective BZ1 receptor agonist, was used to detect BZ1 receptors; flunitrazepam, a nonselective BZ receptor agonist, was used to detect the total BZ receptor population. Rats were treated 4 weeks with Flurazepam, then sacrificed immediately or 48 hr later. After Flurazepam treatment, the maximal binding capacity of [3H]zolpidem binding decreased 22% in the cerebral cortex, 32% in the cerebellum and 25% in the hippocampus. The Kd increased in the cerebellum. The maximal binding capacity of [3H]flunitrazepam binding decreased by 13% in the cerebral cortex and 14% in the hippocampus, but did not change in the cerebellum. The Kd increased in the hippocampus. At 48 hr after Flurazepam treatment, there was no significant difference in [3H]zolpidem binding between treated and control rats. In rats treated 3 weeks with diazepam released from s.c. reservoirs, there was no change in [3H]zolpidem binding. The data suggest that chronic Flurazepam treatment causes downregulation primarily involving BZ1 receptors. The differing effects on [3H]-zolpidem and [3H]flunitrazepam binding, especially in the cerebellum in which more than 90% of the receptors are the BZ1 subtype, may indicate a shift in BZ receptor subtypes in Flurazepam-tolerant rats, suggesting a change in the subunit composition or conformation of gamma-aminobutyric acidA/BZ receptors.
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decreased expression of gamma aminobutyric acid type a benzodiazepine receptor beta subunit mrnas in brain of Flurazepam tolerant rats
Journal of Molecular Neuroscience, 1994Co-Authors: Taijun Zhao, Ted H. Chiu, Howard C. RosenbergAbstract:The expression of GABAA/benzodiazepine β subunit mRNAs was studied in cerebral cortex, hippocampus, and cerebellum of Flurazepam-treated rats. Immediately following 4 wk of treatment, β2 and β3 subunit mRNAs were significantly reduced in cerebellum and hippocampus, whereas only β2 was decreased in cortex. These decreases had largely reversed 48 h following Flurazepam treatment. After 2 wk of treatment, both β2 and β3 mRNAs were reduced in cerebellum, and β3 mRNA was reduced in hippocampus, but neither was changed in cortex. Four hours after an acute Flurazepam treatment, the only change was a decrease in β3 mRNA in hippocampus. These results indicate that the expression of GABAA receptor β subunit mRNAs in different brain regions is differentially regulated during chronic Flurazepam treatment, and some changes occur within hours after a single large dose.
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tolerance to the effects of diazepam clonazepam and bretazenil on gaba stimulated cl influx in Flurazepam tolerant rats
European Journal of Pharmacology, 1993Co-Authors: Howard C. Rosenberg, Ted H. ChiuAbstract:Abstract The effect of chronic Flurazepam treatment on the GABA (γ-aminobutyric acid) receptor / chloride channel complex was studied using GABA-stimulated 36Cl− influx into brain microsacs, and its potentiation by diazepam, clonazepam and bretazenil. Rats were given Flurazepam for 1 week, then microsacs were prepared from cerebral cortices of rats that were still receiving Flurazepam, and from those that had stopped treatment 48 h earlier. Diazepam and clonazepam produced concentration-dependent increases in GABA-stimulated 36Cl− influx while bretazenil produced a much smaller, which did not reach statistical significance in the tissue from control rats. There was no significant change in the basal or 10 μM GABA-stimulated 36Cl− influx between control and treated groups. Tolerance was shown by a significantly reduced effect of diazepam and clonazepam to enhance GABA-stimulated 36Cl− influx in the tissue prepared from non-withdrawn rats. However, for both diazepam and clonazepam, there was no tolerance 48 h after chronic treatment. The results suggest that changes in the GABA receptor/Cl− channel complex on cerebral cortical neurons contribute to cross-tolerance from Flurazepam to other benzodiazepines.
Howard C. Rosenberg - One of the best experts on this subject based on the ideXlab platform.
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Rapid down-regulation of [3H]zolpidem binding to rat brain benzodiazepine receptors during Flurazepam treatment
European journal of pharmacology, 1995Co-Authors: Howard C. Rosenberg, Ted H. ChiuAbstract:Abstract In a previous study, it was found that down-regulation of benzodiazepine (BZ) binding in rats treated 4 weeks with Flurazepam was relatively greater and more widespread when measured with [ 3 H]zolpidem, a selective ‘BZ 1 receptor’ ligand, than that measured with the non-selective ligand, [ 3 H]flunitrazepam. In the present study, the time course for down-regulation of [ 3 H]zolpidem binding was studied in rats treated with Flurazepam. [ 3 H]Zolpidem binding was also studied in rats given a midazolam treatment shown to cause tolerance. Rats were chronically treated with Flurazepam for 1 or 2 weeks, or with midazolam for 3 weeks, then killed immediately after the treatment. Another group of rats was acutely treated with desalkyl-Flurazepam and killed 30 min later. After 2 weeks of Flurazepam treatment, the B max of [ 3 H]zolpidem binding was decreased by 22% in cerebral cortex, 26% in cerebellum and 33% in hippocampus, with no change in the K d in any region. After 1 week of Flurazepam treatment, the B max was decreased by 23% in cerebellum and 14% in hippocampus, but not changed in cerebral cortex. The K d was increased in cerebral cortex, but not in cerebellum or hippocampus. Neither the B max nor the K d of [ 3 H]zolpidem binding was affected by acute desalkyl-Flurazepam treatment, or by 3 weeks of midazolam treatment. These results, in combination with previous findings, which showed no change in [ 3 H]flunitrazepam binding after 1 or 2 week Flurazepam treatment, and no change in cerebellum even after the 4 week treatment, may indicate a shift in BZ receptor subtypes in Flurazepam-tolerant rats. Such a shift could be based on possible changes in the subunit composition or conformation of GABA A /BZ receptors after 1 or 2 week Flurazepam treatment.
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regional changes in 3h zolpidem binding to brain benzodiazepine receptors in Flurazepam tolerant rat comparison with changes in 3h flunitrazepam binding
Journal of Pharmacology and Experimental Therapeutics, 1994Co-Authors: Howard C. Rosenberg, Ted H. Chiu, V RamseywilliamsAbstract:Regional downregulation of brain benzodiazepine (BZ) receptors was studied in rats treated with Flurazepam or diazepam protocols known to produce anticonvulsant tolerance. Zolpidem, a selective BZ1 receptor agonist, was used to detect BZ1 receptors; flunitrazepam, a nonselective BZ receptor agonist, was used to detect the total BZ receptor population. Rats were treated 4 weeks with Flurazepam, then sacrificed immediately or 48 hr later. After Flurazepam treatment, the maximal binding capacity of [3H]zolpidem binding decreased 22% in the cerebral cortex, 32% in the cerebellum and 25% in the hippocampus. The Kd increased in the cerebellum. The maximal binding capacity of [3H]flunitrazepam binding decreased by 13% in the cerebral cortex and 14% in the hippocampus, but did not change in the cerebellum. The Kd increased in the hippocampus. At 48 hr after Flurazepam treatment, there was no significant difference in [3H]zolpidem binding between treated and control rats. In rats treated 3 weeks with diazepam released from s.c. reservoirs, there was no change in [3H]zolpidem binding. The data suggest that chronic Flurazepam treatment causes downregulation primarily involving BZ1 receptors. The differing effects on [3H]-zolpidem and [3H]flunitrazepam binding, especially in the cerebellum in which more than 90% of the receptors are the BZ1 subtype, may indicate a shift in BZ receptor subtypes in Flurazepam-tolerant rats, suggesting a change in the subunit composition or conformation of gamma-aminobutyric acidA/BZ receptors.
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decreased expression of gamma aminobutyric acid type a benzodiazepine receptor beta subunit mrnas in brain of Flurazepam tolerant rats
Journal of Molecular Neuroscience, 1994Co-Authors: Taijun Zhao, Ted H. Chiu, Howard C. RosenbergAbstract:The expression of GABAA/benzodiazepine β subunit mRNAs was studied in cerebral cortex, hippocampus, and cerebellum of Flurazepam-treated rats. Immediately following 4 wk of treatment, β2 and β3 subunit mRNAs were significantly reduced in cerebellum and hippocampus, whereas only β2 was decreased in cortex. These decreases had largely reversed 48 h following Flurazepam treatment. After 2 wk of treatment, both β2 and β3 mRNAs were reduced in cerebellum, and β3 mRNA was reduced in hippocampus, but neither was changed in cortex. Four hours after an acute Flurazepam treatment, the only change was a decrease in β3 mRNA in hippocampus. These results indicate that the expression of GABAA receptor β subunit mRNAs in different brain regions is differentially regulated during chronic Flurazepam treatment, and some changes occur within hours after a single large dose.
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tolerance to the effects of diazepam clonazepam and bretazenil on gaba stimulated cl influx in Flurazepam tolerant rats
European Journal of Pharmacology, 1993Co-Authors: Howard C. Rosenberg, Ted H. ChiuAbstract:Abstract The effect of chronic Flurazepam treatment on the GABA (γ-aminobutyric acid) receptor / chloride channel complex was studied using GABA-stimulated 36Cl− influx into brain microsacs, and its potentiation by diazepam, clonazepam and bretazenil. Rats were given Flurazepam for 1 week, then microsacs were prepared from cerebral cortices of rats that were still receiving Flurazepam, and from those that had stopped treatment 48 h earlier. Diazepam and clonazepam produced concentration-dependent increases in GABA-stimulated 36Cl− influx while bretazenil produced a much smaller, which did not reach statistical significance in the tissue from control rats. There was no significant change in the basal or 10 μM GABA-stimulated 36Cl− influx between control and treated groups. Tolerance was shown by a significantly reduced effect of diazepam and clonazepam to enhance GABA-stimulated 36Cl− influx in the tissue prepared from non-withdrawn rats. However, for both diazepam and clonazepam, there was no tolerance 48 h after chronic treatment. The results suggest that changes in the GABA receptor/Cl− channel complex on cerebral cortical neurons contribute to cross-tolerance from Flurazepam to other benzodiazepines.
Jean Bourgouin - One of the best experts on this subject based on the ideXlab platform.
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Comparison of zopiclone and Flurazepam treatments in insomnia
Human Psychopharmacology: Clinical and Experimental, 1990Co-Authors: Amarendra N. Singh, Jean BourgouinAbstract:In this double-blind study the efficacy and safety of two doses (7·5 and 11·25 mg) of zopiclone were compared to that of Flurazepam (30 mg) in 60 insomniac patients divided into three groups. After an initial 4-day washout period, placebo was administered single-blind to all patients followed by 24 consecutive days of either one of the three drug levels. No significant difference was shown between the two zopiclone dosages at any time during the study for sleep efficacy and psychomotor performance. Compared to Flurazepam, zopiclone was slightly less effective for sleep induction and sleep soundness variables. However, Flurazepam was constantly worse than zopiclone for daytime performance. This study shows that both zopiclone dosages are shown to be active and safe in the treatment of insomnia, and exhibit a true advantage over Flurazepam by its low incidence of residual effects.
John L. Falk - One of the best experts on this subject based on the ideXlab platform.
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Behavioral tolerance to Flurazepam.
Pharmacology biochemistry and behavior, 1991Co-Authors: Chyan E. Lau, Sherri Dolan, Maisy Tang, John L. FalkAbstract:Rats were trained to earn 180 food pellets in daily, fixed-interval 1-min sessions. When performance had stabilized, a Before group was given a weekly 16 mg/kg Flurazepam injection IP for 3 weeks immediately before the sessions, while an After group received their weekly injections immediately after the sessions. Then, the After group received 3 such weekly injections before the sessions. Behavioral tolerance developed by the 2nd Flurazepam injection for the Before group, but for the After group, the 3 postsession Flurazepam injections resulted in subsequent tolerance to presession Flurazepam injection for session lever presses, but not for the time taken to earn 180 pellets. Dispositional tolerance to the serum elimination rate of Flurazepam did not develop over the course of 3 injections. Behavioral suppression still evident in the initial portion of sessions with the 2nd and 3rd presession injection coincided with the duration of rising and high levels of serum Flurazepam.
Amarendra N. Singh - One of the best experts on this subject based on the ideXlab platform.
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Comparison of zopiclone and Flurazepam treatments in insomnia
Human Psychopharmacology: Clinical and Experimental, 1990Co-Authors: Amarendra N. Singh, Jean BourgouinAbstract:In this double-blind study the efficacy and safety of two doses (7·5 and 11·25 mg) of zopiclone were compared to that of Flurazepam (30 mg) in 60 insomniac patients divided into three groups. After an initial 4-day washout period, placebo was administered single-blind to all patients followed by 24 consecutive days of either one of the three drug levels. No significant difference was shown between the two zopiclone dosages at any time during the study for sleep efficacy and psychomotor performance. Compared to Flurazepam, zopiclone was slightly less effective for sleep induction and sleep soundness variables. However, Flurazepam was constantly worse than zopiclone for daytime performance. This study shows that both zopiclone dosages are shown to be active and safe in the treatment of insomnia, and exhibit a true advantage over Flurazepam by its low incidence of residual effects.