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PubMed1991

Ethanol-induced alterations in the function of cerebral GABAA receptor complex: effect on GABA-dependent 36Cl- influx into cerebral membrane vesicles.

Effect of addition in vitro of ethanol on the functions of the GABAA receptor complex was investigated using synaptic membrane preparation obtained from mouse brain. Ethanol (50-200 mM) had no significant effect on the specific bindings of [3H]muscimol to GABAA receptor and [3H]flunitrazepam to benzodiazepine receptor in cerebral particulate preparations. However, ethanol induced an inhibition of [3H]TBOB binding to Cl- channel and a suppression of flunitrazepam-induced enhancement of [3H]muscimol binding and of salsolinol-induced accentuation of [3H]flunitrazepam binding to cerebral particulate fraction. In contrast, ethanol facilitated GABA-dependent 36Cl- influx but eliminated the stimulatory effects of flunitrazepam and salsolinol on GABA-dependent 36Cl- influx into cerebral membrane vesicles. These results suggest that ethanol may facilitate the function of GABA-gated chloride channel in spite of inducing deteriorations of antagonist binding capacity of chloride channel as well as of the functional coupling between GABAA receptor and benzodiazepine receptor in the brain.

Animals↗
PubMed1990

Binding interactions of convulsant and anticonvulsant gamma-butyrolactones and gamma-thiobutyrolactones with the picrotoxin receptor.

Alkyl-substituted gamma-butyrolactones (GBLs) and gamma-thiobutyrolactones (TBLs) are neuroactive chemicals. beta-Substituted compounds are convulsant, whereas alpha-alkyl substituted GBLs and TBLs are anticonvulsant. The structural similarities between beta-alkyl GBLs and the convulsant picrotoxinin suggested that alkyl substituted GBLs and TBLs act at the picrotoxin receptor. To test this hypothesis we examined the interactions of convulsant and anticonvulsant GBLs and TBLs with the picrotoxin, benzodiazepine and gamma-aminobutyric acid (GABA) binding sites of the GABA receptor complex. All of these convulsants and anticonvulsants studied competitively displaced 35S-t-butylbicyclophosphorothionate (35S-TBPS), a ligand that binds to the picrotoxin receptor. This inhibition of 35S-TBPS binding was not blocked by the GABA antagonist bicuculline methobromide. The convulsant GBLs and TBLs also partially inhibited [3H]muscimol binding to the GABA site and [3H]flunitrazepam binding to the benzodiazepine site, but they did so at concentrations substantially greater than those that inhibited 35S-TBPS binding. The anticonvulsant GBLs and TBLs had no effect on either [3H]muscimol or [3H]flunitrazepam binding. In contrast to the GBLs and TBLs, pentobarbital inhibited TBPS binding in a manner that was blocked by bicuculline methobromide, and it enhanced both [3H]flunitrazepam and [3H]muscimol binding. Both ethosuximide and tetramethylsuccinimide, neuroactive compounds structurally similar to GBLs, competitively displaced 35S-TBPS from the picrotoxin receptor and both compounds were weak inhibitors of [3H] muscimol binding. In addition, ethosuximide also partially diminished [3H]flunitrazepam binding. These data demonstrate that the site of action of alkyl-substituted GBLs and TBLs is different from that of GABA, barbiturates and benzodiazepines. We suggest that the GBLs and TBLs act at the picrotoxin receptor.

4-Butyrolactone↗
PubMed1990

The activity of zolpidem and other hypnotics within the gamma-aminobutyric acid (GABAA) receptor supramolecular complex, as determined by 35S-t-butylbicyclophosphorothionate (35S-TBPS) binding to rat cerebral cortex membranes.

The present study compares the effects of different hypnotics acting at omega 1/omega 2 sites (zolpidem, zopiclone, flunitrazepam and triazolam) on 35S-t-butylbicyclophosphorothionate (35S-TBPS) binding to well-washed rat cerebral membranes, in the presence of 1M NaCl. Under these conditions, all compounds enhanced 35S-TBPS binding in the 0.05 to 10 microM range with EC50 values and maximal enhancement of: zolpidem, 84 nM and 36%; flunitrazepam, 8 nM and 41%; zopiclone, 171 nM and 51%; triazolam, 2 nM and 42%. Under these conditions, gamma-aminobutyric acid enhanced 35S-TBPS binding with an EC50 of 240 nM and a 38% maximal increase. The EC50 values for the stimulation of 35S-TBPS binding are well correlated, with (r = 0.97) the affinity of these compounds at omega 1/omega 2 sites, and are in the same concentration range. This enhanced binding was due to an altered apparent affinity for the 35S-TBPS recognition site without any change in the number of sites (Scatchard analysis). The effect of zolpidem and other hypnotics was antagonized by flumazenil. This was an apparently competitive antagonism in the case of zolpidem or flunitrazepam, whereas for zopiclone, increasing the concentration of the hypnotic did not overcome the antagonism. Bicuculline only partially antagonized the hypnotic-induced enhancement of 35S-TBPS binding. This antagonism was more effective for zopiclone (-57%) than for either zolpidem (-33%) or flunitrazepam (-30%). Zolpidem and the other hypnotics studied induced a fast component of dissociation which was not observed in the control membranes. These findings are consistent with the hypothesis that omega 1/omega 2 agonists increase the frequency of openings of the chloride ionophore, with both gamma-aminobutyric acid-A receptor-dependent and -independent mechanisms.

Animals↗
PubMed1985

[Adverse medical aspects of hypnotic therapy with temazepam].

In a double blind comparison the driving ability of 32 outpatients with disomnia was investigated in psychometrical tests and standardized trial runs in road traffic every morning after a single dose and after a 7-day therapy with 20 mg temazepam compared with 2 mg flunitrazepam. As well as standardized driving performance observation a test car was fitted with a drive-recorder which synchronically recorded and digitally registered at 1 s intervals during a 60 min run the speed, the steering wheel velocity, fore-hand-aft and lateral acceleration amongst other data. The individual optimal quotient, as a measure of the degree of efficiency of the information processed in the driver-vehicle-road system, deteriorated significantly after the single dose of flunitrazepam as opposed to temazepam. In a trial run on a well defined test course under strictly standardized conditions, the steering wheel velocity, signifying the quality of steering ability, was highly significantly increased after the single dose as well as after the 7-day treatment with flunitrazepam therefore showing a distinct deterioration of steering ability compared to the temazepam group. The number of errors in technical handling was significantly highly with flunitrazepam at both control time checks than with temazepam.

Adult↗
PubMed1986

Saccadic eye movements in determination of the residual effects of the benzodiazepines.

Saccadic eye movements and the volunteers' subjective assessments were used in the determination of the residual effects of a single high evening dose of flunitrazepam 2 mg, midazolam 30 mg, and lorazepam 2.5 mg as well as in that of placebo. Sleep inducing and maintaining effects were subjectively assessed, too. Both flunitrazepam 2 mg, midazolam 30 mg, and lorazepam 2.5 mg possessed sleep inducing and increasing effects (n = 9), but in the number of nocturnal awakenings and quality of sleep no significant differences between placebo and the active medications were reported. Flunitrazepam 2 mg and lorazepam 2.5 mg produced distinct subjective residual effects thus differing from placebo and midazolam 30 mg. Despite this, saccadic eye movement recording could further differentiate midazolam 30 mg from placebo in this respect 10 hours after drug intake. After three repeated 2 mg evening doses, flunitrazepam accumulated in the serum of the volunteers (n = 6), but the effect on saccadic eye movements as well as subjective side effects began to decrease already after one day's treatment. Thus, saccadic eye movement recording proved to be a useful tool in determining the residual effects and development of tolerance of benzodiazepines. No correlation was detected between the serum levels (radioreceptor assay) and saccadic eye movement recordings or subjective residual sequelae.

Benzodiazepines↗
PubMed1985

[Modulating effect of cerulein on benzodiazepine receptors].

Subcutaneous administration of caerulein (100-500 micrograms/kg) significantly reduced the development of picrotoxin (8 mg/kg) seizures in male mice. The same doses of caerulein inhibited 3H-flunitrazepam binding in in vivo experiments. Proglumide, an antagonist of cholecystokinin receptors, in low dose (5 mg/kg) potentiated the effects of caerulein (100 micrograms/kg), whereas the administration of proglumide in high dose (25 mg/kg) reduced the action of caerulein on 3H-flunitrazepam binding and picrotoxin seizures. Caerulein (5-1000 nM) decreased 3H-flunitrazepam binding in in vitro experiments only after supplementation of the binding medium with 120 mM NaCl and 5mM KCl. The results suggest the possible interaction of caerulein with chloride ionophor. It seems probable that the direct interaction of caerulein with chloride ionophor in involved in the inhibitory effect of caerulein on picrotoxin seizures and 3H-flunitrazepam binding.

Animals↗
PubMed1987

Identification, characterization, and developmental regulation of embryonic benzodiazepine binding sites.

We report the identification and characterization of 2 classes of benzodiazepine binding sites in the embryonic chick CNS. Binding was examined by competition and saturation binding experiments, using as radioligands 3H-flunitrazepam, a classical benzodiazepine anxiolytic, and 3H-Ro5-4864, a convulsant benzodiazepine. The results demonstrate that high-affinity (KD = 2.3 nM) 3H-flunitrazepam binding sites (site-A) are present by embryonic day 5 (Hamburger and Hamilton stage 27) and increase throughout development (Bmax = 0.3 and 1.3 pmol/mg protein in 7 and 20 d brain membranes, respectively). When 7 or 20 d brain membranes are photoaffinity-labeled with 3H-flunitrazepam and ultraviolet light, the radioactivity migrates as 2 bands on SDS-PAGE, consistent with Mrs of 48,000 and 51,000. GABA potentiates 3H-flunitrazepam binding at both 7 and 20 d of development, indicating that site-A is coupled to receptors for GABA early in development. Importantly, we have also identified a novel site (site-B) that binds classical benzodiazepine agonists with low affinity (micromolar) but displays high affinity for Ro5-4864 (KD = 41 nM). Site-B displays characteristics expected for a functional receptor, including stereospecificity and sensitivity to inactivation by heat and protease treatment. Saturation binding studies employing 3H-Ro5-4864 indicate that the levels of site-B are similar in 7 and 20 d brain (ca. 2.5 pmol/mg protein). The function of site-B is not known, but its preponderance in 7 d brain, relative to site-A, suggests that it might be important during early embryonic development.

Affinity Labels↗
PubMed1982

Comparison of old and new types of premedications.

By random allocation 41 patients received 1 mg flunitrazepam orally the night before operation and 1 mg on the morning of operation (group 1), and another 41 received 100 mg pentobarbital orally the night before operation, followed by intramuscular scopolamine (0.006 mg/kg) + morphine (0.02 mg/kg) on the morning of operation (group 2). All patients received 0.5 mg atropine intravenously just before the induction of anesthesia. The patients in group 2 were better sedated and had less salivary secretion than those in group 1, but otherwise both were comparable. In group 2 the induction requirements of thiopentone were significantly decreased in comparison with group 1, again indicating a more potent sedative effect. Because even in the total scoring of the results there was no significant difference between the two groups, the easy oral route of administration of flunitrazepam offers a clinically relevant alternative to the conventional premedication. In some of these E.N.T. patients who received flunitrazepam, intravenous atropine given just before the induction of anesthesia was unable to prevent salivary secretion. Oral benzodiazepine derivatives (flunitrazepam) appear to be useful before surgery as the old type of premedication (oral pentobarbital + i.m. scopolamine and morphine).

Administration, Oral↗
PubMed1983

Photoaffinity labeling of benzodiazepine receptors causes altered agonist-antagonist interactions.

Previous studies have shown that [3H]flunitrazepam forms irreversible cross-links with brain tissue when exposed to ultraviolet irradiation. Comparison of the amount of [3H]flunitrazepam irreversibly incorporated and the number of benzodiazepine binding sites blocked after photolabeling has indicated that several binding sites are inactivated for each molecule of [3H]flunitrazepam incorporated. To learn the cause of this discrepancy, binding to the benzodiazepine binding sites has been examined using several radiolabeled benzodiazepine antagonists. Binding of a beta-carboline ester, CGS-8216, and Ro 15-1788 was not altered by photolabeling; however, displacement studies revealed that photolabeling converted a homogeneous set of benzodiazepine binding sites into two subsets: one of high affinity (unaltered sites) and one of low affinity. The low affinity sites could be detected by displacement studies of antagonist binding by benzodiazepines, and conversion to a low affinity form accounts for the discrepancy observed after photolabeling using [3H]flunitrazepam as ligand.

Animals↗
PubMed1978

[Respiratory depression after fentanyl and antagonism by naloxone (author's transl)].

The postoperative respiratory depressant effect of fentanyl in combination with flunitrazepam (Rohypnol) was assessed in awake and in unconscious patients. In awake patients respiratory function was measured with blood-gas analyses. For measurements in unconscious patients the administration of nitrous oxide/oxygen was continued postoperatively and the respiratory depression was judged from the increase in respiratory minute volume after the i.v. administration of 0.05 mg naloxone (Narcan). In the group of awake patients blood-gasvalues were within the normal range after anaesthesia with flunitrazepam (1 mg) and fentanyl (0.80 mcg/kg body weight/10 min anaesthesia; last fentanyl given 40 min before the end of the operation), and the administration of naloxone was without any effect. If, however, naloxone was given while the patients were kept under light nitrous oxide/oxygen anaesthesia, the effect was different. The respiratory minute volume was considerably less than its predicted value in all groups of patients having received fentanyl, and naloxone caused a marked increase in respiratory minute volume and in respiratory rate. In a group of patients which have received no opiate but enflurane, naloxone showed no effect. After premedication with pethidine as compared with flunitrazepam the effect of naloxone on ventilation was more pronounced. This marked difference in the postoperative effect of fentanyl on ventilation depending on the state of consciousness has to be attributed to an interaction between a residual respiratory depressant effect of fentanyl and the effect of unconsciousness. Since after the combined use of flunitrazepam and fentanyl deep postoperative sleep occurs quite frequent, a residual effect of fentanyl should always be antagonized with naloxone to protect the patients from a possible hazardous effect of this interaction.

Adolescent↗
PubMed1995

Regulation of allosteric coupling and function of stably expressed gamma-aminobutyric acid (GABA)A receptors by chronic treatment with GABAA and benzodiazepine agonists.

Chronic treatments with drugs that stimulate or potentiate gamma-aminobutyric acid (GABA)A receptor function cause uncoupling of allosteric sites and downregulation of the GABAA receptors expressed in neurons. To study these effects on receptors having a defined subunit composition, we treated stably transfected mouse Ltk- cells (PA3 cells) with drugs known to uncouple GABAA receptors. Because dexamethasone controls the expression of bovine alpha-1, beta-1 and gamma 2L GABAA receptor subunit genes in PA3 cells, this expression system provides a way to study receptors in the absence of neuronal subunit gene promoters. We assayed binding of [3H]flunitrazepam to measure allosteric coupling and uptake of 36Cl- to measure GABAA receptor function. Chronic (4 day) treatment of PA3 cells with muscimol, GABA or flunitrazepam reduced the GABA enhancement of binding of [3H]flunitrazepam to PA3 cells. Chronic flurazepam or muscimol treatments also caused downregulation of benzodiazepine potentiation of muscimol-stimulated 36Cl- uptake. Chronic treatment with muscimol did not affect levels of subunit mRNAS and alpha 1- or beta 1-subunit protein of GABAA receptors and chronic flunitrazepam did not affect subunit mRNAs or alpha 1 protein. We conclude that chronic drug treatments regulate allosteric coupling and function of GABAA receptors in stably transfected cells and this regulation cannot be attributed to decreases in the expression of receptor subunits or to expression of subunits other than alpha 1 beta 1 or gamma 2L.

Allosteric Regulation↗
PubMed1993

Full and partial agonism displayed by benzodiazepine receptor ligands at recombinant gamma-aminobutyric acidA receptor subtypes.

The differences in intrinsic activity and receptor subtype specificity of the newly developed benzodiazepine receptor ligands bretazenil, divaplon and abecarnil were assessed in recombinant gamma-aminobutyric acidA (GABAA) receptors expressed in mammalian cells from the subunit-cDNA combinations alpha 3 beta 2 gamma 2 and alpha 5 beta 2 gamma 2. Chloride currents induced by rapid application of GABA in the presence or absence of drugs were measured using the whole-cell configuration of the patch-clamp technique. Bretazenil displayed an intrinsic activity which amounted only to 58 +/- 7% and 35 +/- 11% of that of flunitrazepam at the alpha 3 beta 2 gamma 2 and alpha 5 beta 2 gamma 2 combination, respectively. The maximum potentiation by divaplon was only 28 +/- 5% and 21 +/- 9% of that of flunitrazepam at the respective subunit combinations. Thus, the partial agonism postulated for bretazenil and divaplon on pharmacological grounds is shown to be operative on the level of single GABAA receptors. Most strikingly, abecarnil potentiated the GABA response to the same degree as flunitrazepam at the alpha 3 beta 2 gamma 2 combination but to only 52 +/- 14% compared to flunitrazepam at the alpha 5 beta 2 gamma 2 combination. This finding demonstrates that the intrinsic activity of benzodiazepine receptor ligands can vary among the receptor subtypes with the degree of receptor modulation being influenced by the type of alpha subunit.

Benzodiazepinones↗
PubMed1996

[Vigilance-decreasing effects of 2 plant-derived sedatives].

Previous studies on the efficacy of valerian extracts have given occasional hints of possible side effects involving impaired vigilance. Because of the currently insufficient knowledge about potential impairment of vigilance by plant-based sedatives, we have conducted a controlled study to assess the effects of two plant-based sleep remedies in comparison with flunitrazepam and placebo after single oral administration. Aim of the study was to derive recommendations concerning potential hazards in driving or operating machinery. Residual sedative effects (hangover) were examined in four groups of 20 healthy volunteers, receiving either tablets containing valerian and hops or syrup containing valerian only or flunitrazepam or placebo; furthermore, immediate sedative effects of the two plant preparations have been examined in comparison with placebo (three groups of twelve healthy volunteers). The tests included objective measurements of cognitive psychomotor performance as well as subjective questionnaires on well-being. Tolerability was assessed from spontaneous reports of side effects and a verbal inquiry at the end of the tests. We found that objectively measurable impairment of performance on the morning after medication occurred only in the flunitrazepam group, a finding which was even more pronounced in the subjective questionnaires. In addition, 50% of the volunteers in the flunitrazepam group reported mild side effects in the inquiry at the end of the tests, compared with only 10% from the other groups. The subjective perception of sleep quality was improved in all three medication groups, when compared to placebo. Examination of acute effects of the plant remedies 1 to 2 hours after administration revealed no changes in the more important lead variables; however, a very slight impairment of vigilance after taking syrup was statistically significant as well as a retardation in the processing of complex information for the tablets. The subjective perception of effects was more pronounced (shaky legs, feeling less active). In conclusion, the residual sedative effects (hangover) observed in some earlier studies cannot be confirmed for the recommended doses of the two plant-based sleep remedies which we have examined with respect to vigilance and cognitive performance. On the contrary: our findings show improved subjective self-assessment (more alert, more active, feeling better). Hangover effects on the following morning need not be a cause for concern, which is of particular interest to car drivers; however, a slight impairment of performance during the first few hours after ingestion should be anticipated. Impairment of vigilance on the morning after ingestion of benzodiazepines, frequently reported and confirmed by our results, constitutes a potential hazard. In this situation, plant remedies such as those examined in this study should be considered as viable alternatives.

Adult↗
PubMed1991

Influence of different benzodiazepines on the experimental morphine abstinence syndrome.

The abuse of benzodiazepines by narcotic addicts has been well documented. However, the pharmacological basis of this abuse is not clear. In this study the effects of different benzodiazepines (flunitrazepam: 0.5, 1 and 2 mg/kg; nitrazepam: 0.5, 1, 2.5, 5 and 10 mg/kg; diazepam: 0.5, 1, 2.5, 5 and 10 mg/kg; chlordiazepoxide: 0.5, 1, 2.5, 5 and 10 mg/kg; and triazolam: 0.5, 1 and 2 mg/kg) on the morphine withdrawal syndrome in mice have been compared. Drugs were administered 30 min before naloxone-induced withdrawal. All benzodiazepines tested induced similar changes in some of the signs of morphine abstinence: decreased jumping behavior and increased wet dog shake frequency. Jumping behavior was particularly decreased by triazolam and wet dog shakes were mainly increased by flunitrazepam and nitrazepam. Forepaw treading was reduced by flunitrazepam, diazepam and triazolam, increased by nitrazepam and not changed by chlordiazepoxide. Tremor was effectively reduced by diazepam but less reliably by the other benzodiazepines. Teeth chattering was reduced by flunitrazepam and diazepam. These results indicate that benzodiazepines can interfere with the expression of the morphine withdrawal syndrome.

Animals↗
PubMed2004

Effects of pregnanolone alone and in combination with other positive GABAA modulators on complex behavior in rats.

RATIONALE: Although positive modulators of gamma-aminobutyric acid(A) (GABA(A)) receptors generally produce similar behavioral effects, regardless of which modulatory site on the GABA(A) receptor complex mediates these effects, some differences have been observed between the effects of neuroactive steroids and those of other positive GABA(A) modulators. OBJECTIVE: The current study was designed to compare the behavioral effects of a neuroactive steroid to those of other positive GABA(A) modulators. METHODS: Rats responded under a multiple schedule of repeated acquisition and performance of response chains, with responding maintained under a second-order fixed-ratio 2 schedule of food presentation. RESULTS: Pregnanolone, flunitrazepam, pentobarbital and ketamine, an antagonist at NMDA receptors, dose-dependently decreased response rates and increased the percentage of errors in both components of the multiple schedule. Although the rate-decreasing and error-increasing effects of pregnanolone, pentobarbital and ketamine were quantitatively similar to each other, flunitrazepam was less effective in decreasing response rates and more effective in increasing errors than the other three drugs. A dose of 3.2 mg/kg pregnanolone potentiated the effects of flunitrazepam and pentobarbital, producing 2- to 3-fold shifts to the left in the dose-effect curves. In contrast, pregnanolone did not alter the ketamine dose-effect curves. CONCLUSIONS: The disruptive effects of the neuroactive steroid pregnanolone are qualitatively similar to those of other positive GABA(A) modulators as well as ketamine; however, the potentiation of the effects of flunitrazepam and pentobarbital, and not ketamine, emphasizes the importance of GABA(A) receptors in the behavioral effects of pregnanolone.

Anesthetics↗
PubMed2004

Effects of three hypnotics on the sleep-wakefulness cycle in sleep-disturbed rats.

RATIONALE: New sleep disturbance model in rats is useful for estimating the characteristics of some hypnotics. OBJECTIVES: The present study was undertaken to investigate the utility of a sleep disturbance model by placing rats on a grid suspended over water using three kinds of hypnotics, that is, short-acting benzodiazepine (triazolam), intermediate-acting benzodiazepine (flunitrazepam) and long-acting barbiturate (phenobarbital). METHODS: Electrodes for measurement of EEG and 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-REM and REM sleep were measured from 0900 to 1500 hours. RESULTS: In rats placed on the grid suspended over water up to 1 cm under the grid surface, not only triazolam but also flunitrazepam and phenobarbital caused a shortening of sleep latency. Both flunitrazepam and phenobarbital were effective in increasing of total non-REM sleep time in rats placed on sawdust or the grid, and the effects of both drugs in rats placed on the grid were larger than those in rats placed on sawdust. Measurement of the hourly non-REM sleep time was useful for investigating the peak time and duration of effect of the three hypnotics. Phenobarbital showed a decrease in total REM sleep time in rats placed on the grid, although both triazolam and flunitrazepam were without effect. CONCLUSIONS: The present insomnia model can be used as a sleep disturbance model for testing not only the sleep-inducing effects but also the sleep-maintaining effects including non-REM sleep and REM sleep of hypnotics.

Analysis of Variance↗
PubMed1990

Noninvasive assessment of cardiac performance of intravenous benzodiazepines by systolic time intervals.

The effects of anesthetic induction by diazepam, flunitrazepam and midazolam on cardiac performance were evaluated in 33 ASA class I surgical patients (average age was 36 years). The patients were divided according to the 3 drug groups, and the effects of each drug assessed utilizing measurements of systolic time intervals. An increase in heart rate and decrease in blood pressure was observed following flunitrazepam and midazolam induction. There was no changes in PEPI (pre-ejection period index) and LVETI (left ventricular ejection time index) by benzodiazepines induction. The PEP/LVET ratio was increased by diazepam while the DPTI (diastolic pressure time index)/TTI (tension time index) was reduced by flunitrazepam and midazolam. However, these changes in PEP/LVET and DPTI/TTI were within normal limits. These data indicate that in healthy humans the induction dose of either diazepam, flunitrazepam or midazolam does not extremely influence either PEP/LVET for cardiac performance or DPTI/TTI for cardiac oxygen balance. The results also suggest that the simultaneous use of PEP/LVET and DPTI/TTI is more informative than any single variable for the evaluation of cardiac effects of anesthetics.

Journal Article↗
PubMed1992

Effects of lorazepam tolerance and withdrawal on GABAA receptor operated chloride channels in mice selected for differences in ethanol withdrawal severity.

Withdrawal seizure prone (WSP) and withdrawal seizure resistant (WSR) mice were treated with 5 mg/kg lorazepam for 7 days via implanted osmotic mini pumps. Following chronic drug treatment, brains were assayed for GABA-mediated chloride flux (GABA-Cl-). Under control (drug naive) conditions, brain membranes prepared from WSP and WSR lines did not differ in flunitrazepam or ethanol stimulation of GABA-mediated 36Cl- uptake, but the WSP lines were more sensitive to inhibition of 36Cl- flux by the inverse agonist, FG-7142. Membranes from lorazepam tolerant WSP and WSR mice were resistant to flunitrazepam- and ethanol-stimulation of GABA-Cl-. Withdrawal from chronic treatment, by an acute injection with the benzodiazepine antagonist RO15-1788, returned flunitrazepam stimulation of GABA-Cl- to near control levels in WSR membranes but not in WSP membranes and restored ethanol modulation of the channel to control levels in both lines. Inhibition of chloride flux by the benzodiazepine partial inverse agonist, FG-7142 was greater in membranes from WSP mice compared with WSR mice. Tolerance to lorazepam increased sensitivity of the WSR membranes to FG-7142 without altering the response in the WSP line. Again, withdrawal restored the Cl- flux response to FG-7142 back to near control levels. Lorazepam tolerance lowered [3H]-flunitrazepam binding affinity slightly only in the WSR strain with no change in binding number. Withdrawal from chronic lorazepam treatment produced no significant change in binding affinity or number. The initial genotypic differences in benzodiazepine inverse agonist sensitivity, may be related to the selection for withdrawal seizure severity. Chronic administration of lorazepam reduces the coupling between the benzodiazepine agonist site and the chloride channel and concomitantly increases coupling between the channel and the inverse agonist site, while withdrawal resets the receptor coupling back to control response levels. However, for the WSP line, this drug environment dependent shift in channel coupling bias appears to be deficient compared with the WSR line.

Animals↗