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PubMed2000

Pretreatment with diazepam suppresses the reduction in defensive freezing behavior induced by fluvoxamine in the conditioned fear stress paradigm in mice.

The effects of the selective serotonin (5-hydroxytryptamine (5-HT)) reuptake inhibitor fluvoxamine, given alone or in combination with the benzodiazepine anxiolytic diazepam on the defensive freezing behavior of mice in the conditioned fear stress paradigm were examined. Fluvoxamine (5-20 mg/kg, i.p.) induced a dose-dependent reduction in freezing behavior. In contrast, while low doses of diazepam (0.125 and 0.25 mg/kg, i.p.) reduced the freezing behavior, such effects were not observed with high doses of diazepam (0.5 and 1 mg/kg, i.p.). In the combination study, fluvoxamine (20 mg/kg, i.p. ) did not reduce the freezing behavior in mice that had been pretreated with diazepam (0.125-1 mg/kg, i.p.). None of the doses of fluvoxamine and diazepam used in the present study had any effects on motor activity under non-stressed conditions. These results suggest that benzodiazepines may negatively influence the clinical efficacy of selective 5-HT reuptake inhibitors in the treatment of anxiety disorders.

Animals↗

PubMedDate not supplied

Diazepam versus midazolam for colonoscopy: a prospective evaluation of predicted versus actual dosing requirements.

We performed a prospective, randomized, double-blind study to evaluate the efficacy of the currently recommended low doses of midazolam for conscious sedation compared with diazepam for colonoscopy. Each agent was administered in a fixed ratio dose in combination with meperidine, and titrated incrementally to allow for adequate sedation prior to initiating and during the procedure. The currently recommended starting dose of midazolam (0.03 mg/kg) proved to be very appropriate for pre-medication. In contrast, the currently recommended starting dose of diazepam (0.10 mg/kg) proved excessive in 21% of patients (especially in those aged > 65). The low initial and incremental doses of midazolam compared favorably with diazepam in all efficacy parameters studied and exceeded diazepam in post-procedure amnesia scores (p = 0.01). Moreover, the sedative effects of midazolam at these lower doses were not lost despite long duration procedures (> 40 min). We conclude that midazolam, given in small incremental doses, in combination with meperidine, produces effective conscious sedation for colonoscopy and exceeds diazepam in its amnestic effect.

Adult↗

PubMedDate not supplied

Venous complications of midazolam versus diazepam.

Although some studies have suggested fewer venous complications are associated with midazolam than with diazepam for endoscopic procedures, this variable has not been well documented. We prospectively evaluated the incidence of venous complications after intravenous injection of diazepam or midazolam in 122 consecutive patients undergoing colonoscopy and esophagogastroduodenoscopy. Overall, venous complications were more frequent with diazepam (22 of 62 patients) than with midazolam (4 of 60 patients) (p < 0.001). A palpable venous cord was present in 23% (14 of 62) of patients in the diazepam group, compared with 2% (1 of 60 patients) in the midazolam group (p < 0.002). Pain at the injection site occurred in 35% (22 of 62) of patients in the diazepam group compared with 7% (4 of 60 patients) in the midazolam group (p < 0.001). Swelling and warmth at the injection site were not significantly different between the two groups. Smoking, nonsteroidal anti-inflammatory drug use, intravenous catheter site, dwell time of the needle, alcohol use, and pain during the injection had no effect on the incidence of venous complications.

Colonoscopy↗

PubMed1999

A comparison of midazolam and diazepam for conscious sedation during colonoscopy in a prospective double-blind study.

BACKGROUND: Midazolam and diazepam are commonly used for conscious sedation, but their comparative respiratory depressive effects have not been accurately studied. We used a novel real-time, on-line, computerized data acquisition system to compare the two agents in a randomized double-blind study. METHODS: One hundred patients undergoing colonoscopy were studied. The maximum end-tidal carbon dioxide tension (PetCO2) and the minimum oxygen saturation by pulse oximetry (SpO 2) were recorded by computer every minute. Patients received meperidine (25 to 50 mg) and incremental doses of either midazolam or diazepam to an identical end point of slurred speech and/or ptosis. Sedation was scored from 1 (unarousable) to 5 (wide awake). RESULTS: Sedation scores were 3.6 +/- 0.1 (mean +/- standard error) after each agent. The doses of midazolam and diazepam were 0. 031 +/- 0.002 and 0.106 +/- 0.009 mg/kg, respectively. In the first 45 minutes (PetCO2) was significantly higher with midazolam than with diazepam (p < 0.05). SpO2 was significantly depressed for 80 minutes after each agent, and the number of minutes when the minimum Sp O2 was less than 90% did not differ between the two agents. CONCLUSIONS: Midazolam was 3.4 times more potent than diazepam. The duration of oxygen desaturation emphasizes the importance of monitoring SpO2 until ventilation and oxygenation have recovered. Although the degree of hypoxemia was comparable, midazolam led to higher end-tidal carbon dioxide tensions.

Adult↗

PubMed1999

Intraseptal injection of scopolamine increases the effect of systemic diazepam on passive avoidance learning and emotionality in rats.

This experiment was designed to assess the role of the septo-hippocampal cholinergic (ACh) system in the deleterious effects produced by systemic benzodiazepine injection on learning processes in rats. Retention of a step through passive avoidance task was analysed after systemic injection of increasing doses of either scopolamine or diazepam applied alone 30 min before the acquisition phase. Results indicated a dose related impairment of retention by each drug: in addition, sub-threshold doses of scopolamine and diazepam applied in combination (diazepam: 2mg/kg plus scopolamine: 0.3mg/kg) produced a decrease of retention latencies, thus showing an additive effect of the combined treatment. Secondly, a sub-threshold dose of scopolamine (15microg/0.5microl) was also administered into the medial septal area, together with an i.p. injection of 2mg/kg of diazepam. This combined treatment produced a severe impairment of retention, in parallel with a large reduction in emotionality (number of faeces). The data are consistent with the hypothesis that peripheral administration of behaviorally effective doses of diazepam on passive avoidance learning might act partially via a septal ACh-GABA/benzodiazepine mechanism. It is also suggested that this mechanism subserves both anxiety and the memorisation of contextual stimuli associated with passive avoidance acquisition, through the modification of the septo-hippocampal activity.

Animals↗

PubMed1999

Diazepam reduces action potential duration in guinea-pig papillary muscle by a cAMP-dependent mechanism.

In this study, we have analyzed the role of cyclic AMP (cAMP) as the mediator of the decrease in action potential duration induced by diazepam. Diazepam (1-100 microM) reduced, in a dose-dependent manner, the duration of intracellular action potential recorded in the papillary muscle obtained from the right ventricle of the guinea pig heart. This effect was mimicked by the analog of cyclic AMP, 8-Br-cAMP (100 microM), but not by gamma-amino-butyric acid (GABA). Also, the selective antagonist of the benzodiazepine receptors, flumazenil did not modify the effect of diazepam. The diazepam-induced shortening of action potential duration was partially antagonized by the inhibitor of cAMP synthesis carbachol (1 microM) or the blocker of the cAMP-dependent protein kinase A, Rp-cAMP[S] (1 microM). These results indicate that cyclic AMP is involved in the diazepam-induced shortening of the action potential duration of the guinea pig papillary muscle.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1999

Diazepam effects of peritoneal macrophage activity and corticosterone serum levels in Balb/C mice.

In the present experiment we investigate the effects of diazepam on macrophage activity and serum corticosterone levels in mice. Adult mice were treated with diazepam (1.5 mg/kg/day - group E) or with control solution (group C1) for 7 days; some animals were only handled, receiving no treatment (group C2). Oral onco-BCG was used for peritoneal macrophage activation. Diazepam treatment: 1-decreased macrophage spreading and phagocytosis; 2-decreased the concentrations of H2O2 spontaneously but not phorbol myristate-acetate-induced release. In relation to mice of group C1, diazepam treatment increased the serum levels of corticosterone. No differences were detected between data of groups C1 and C2 both for macrophage activity and serum corticosterone levels. The present data were explained on the basis of a synergistically action for diazepam through peripheral type binding sites (PBR) present in both adrenals and macrophages, stimulating adrenal glucocorticoid production and altering the macrophage cytokine network.

Administration, Oral↗

PubMed2001

The acute effects of zolpidem compared to diazepam and lorazepam using radiotelemetry.

The present study used a radiotelemetric method to compare the muscle relaxant, hypothermic and locomotor depressant actions of the imidazopyridine zolpidem, with those of the benzodiazepines lorazepam and diazepam. Rats, n=7 per group, were divided into 3 dose-dependent treatment groups (highest, middle, and lowest). Each rat within a treatment group received a single dose of diazepam, lorazepam, zolpidem and vehicle. All three drugs induced dose-dependent decreases in body temperature, locomotor activity and electromyographic (EMG) activity. Administration of zolpidem (5 and 10 mg/kg) resulted in maximal decrements in locomotor activity that were comparable to those elicited by both diazepam (10 and 20 mg/kg) and lorazepam (12.5 and 25 mg/kg). Zolpidem (10 mg/kg) decreased EMG activity levels to approximately 45% of vehicle treated controls; a value similar to that induced by diazepam (2.5 mg/kg). These data suggest that the imidazopyridine zolpidem has a similar profile of acute effects in comparison to the benzodiazepines diazepam and lorazepam. However, the relative magnitude of the effects differed, with zolpidem producing less hypothermia and muscle relaxation than the two benzodiazepines.

Animals↗

PubMed2001

Evidence for distinct conformations of the two alpha 1 subunits in diazepam-bound GABA(A) receptors.

Benzodiazepines allosterically modulate GABA(A) receptors to increase currents induced by submaximal GABA concentrations. Benzodiazepine-induced conformational changes in the transmembrane domain increase the reactivity of cysteines substituted for a subset of residues in the alpha(1) subunit M3 membrane-spanning segment. With the cysteine-substitution mutant alpha(1)F296Cbeta(1)gamma(2) we previously noted that p-chloromercuribenzenesulfonate (pCMBS(-)) modification in the presence of diazepam potentiated subsequent GABA-induced currents. In contrast, pCMBS(-) modification in the presence of GABA caused inhibition of subsequent responses. We now show that in the presence of diazepam, pCMBS(-) only reacts with the engineered cysteine in one of the two alpha subunits; whereas, in the presence of GABA, pCMBS(-) reacts with the cysteine in the other alpha subunit, or with both cysteines. This implies that the two alpha subunits have distinct conformations in the diazepam-bound state. Based on analysis of single channel kinetic data, others have hypothesized that diazepam only alters the GABA affinity of one of the two GABA binding sites. The results presented here provide structural evidence to support the hypothesis that diazepam binding only alters the conformation of one of the two alpha subunits in a GABA(A) receptor and provides new insights into the mechanism of allosteric potentiation by benzodiazepines.

Allosteric Regulation↗

PubMed1996

Direct evidence for diazepam modulation of GABAA receptor microscopic affinity.

Alteration of agonist affinity is a potential mechanism for pharmacological modulation of ligand-gated receptor channel function. The time course for receptor activation and current onset is determined by the combined rates for two kinetic transitions that underlie the protein confirmations for binding agonist and channel gating. Using ultrafast ligand exchange techniques, we distinguish between these previously difficult to separate events and demonstrate their independent pharmacological modulation. Diazepam, which increases apparent affinity of gamma-aminobutyric acid (GABA) to GABAA receptors, was used to examine its effects on GABA binding and ion channel gating of expressed alpha 2 beta 1 gamma 2 receptors from excised outside-out patches of acutely transfected HEK 293 cells. Diazepam increased rates of current onset evoked by low concentrations (< 1 mM) but not at saturating GABA concentrations. Furthermore, rates of current decay were not affected during brief applications of GABA, and thus, demonstrated a diazepam specific effect on ligand binding affinity and not channel gating kinetics. However, current decay during and following prolonged GABA applications were altered by diazepam in a fashion similar to that for higher concentrations of GABA which also increased receptor desensitization. These findings and analysis by computer modeling indicated that diazepam likely enhances GABA receptor currents primarily by accelerating GABA association to its receptor at the first agonist binding site. These results provide the first direct physiological evidence for pharmacological modulation of microscopic binding affinity of GABA receptors.

Cells, Cultured↗

PubMed1999

Pharmacological studies on synthetic flavonoids: comparison with diazepam.

The present experiments compared the central BZ-omega binding characteristics and pharmacological profiles of two synthetic flavonoids (6-bromoflavone and 6-bromo-3'-nitroflavone) with those of the benzodiazepine (BZ) diazepam. In vitro experiments showed that while diazepam displaced [3H]flumazenil binding to the GABA(A) receptor in membranes from rat cerebellum and spinal cord, two brain areas enriched in the BZ-omega1 and BZ-omega2 receptor subtypes, with nearly equivalent half maximally effective concentrations, 6-bromo-3'-nitroflavone was somewhat more potent in displacing [3H]flumazenil binding to membranes from rat cerebellum (IC50 = 31 nM) than from spinal cord (IC50 = 120 nM), indicating selectivity for the BZ-omega1 receptor subtype. 6-Bromoflavone displayed weak (IC50 = 970 nM) affinity for the BZ-omega1 and no affinity for the BZ-omega2 (IC50 > 1000 nM) receptor subtypes. Diazepam, but not the synthetic flavonoids increased the latency to clonic seizures produced by isoniazid, thereby indicating that neither 6-bromoflavone nor 6-bromo-3'-nitroflavone display detectable intrinsic activity at GABA(A) receptors in vivo. Results from two conflict tests in rats showed that 6-bromoflavone (3-10 mg/kg) and 6-bromo-3'-nitroflavone (0.3-1 mg/kg) elicited anxiolytic-like activity in the punished drinking test, while both drugs were inactive in the punished lever pressing test. The positive effects displayed by the synthetic flavonoids in the punished drinking procedure were smaller than that of diazepam and were not antagonized by the BZ receptor antagonist flumazenil. In two models of exploratory activity, 6-bromoflavone (3-30 mg/kg) and 6-bromo-3'-nitroflavone (0.3-1 mg/kg) produced anxiolytic-like effects in the rat elevated plus-maze test, whereas both compounds failed to modify the behavior of mice in the light/dark test over a wide dose-range. The effects in the elevated plus-maze were antagonized by flumazenil. In the mouse defense test battery, where mice were confronted with a natural threat (a rat), 6-bromoflavone and 6-bromo-3'-nitroflavone failed to decrease flight reactions after the rat was introduced into the test area and risk assessment behavior displayed when subjects were constrained in a straight alley, and only weakly affected risk assessment of mice chased by the rat and defensive biting upon forced contact with the threat stimulus. In a drug discrimination experiment 6-bromoflavone and 6-bromo-3'-nitroflavone up to 30 and 3 mg/kg, respectively, did not substitute for the BZ chlordiazepoxide. Taken together, these results failed to demonstrate that the synthetic flavonoids 6-bromoflavone and 6-bromo-3'-nitroflavone possess anxiolytic-like properties similar or superior to that of diazepam, as was suggested previously. Furthermore, they question the contribution of BZ-omega receptors to the behavioral effects of 6-bromoflavone and 6-bromo-3'-nitroflavone.

Animals↗

PubMed2001

Different effects of lorazepam and diazepam on perceptual integration.

Recent research has established the detrimental effect of lorazepam, a benzodiazepine, on both implicit and explicit memory. Furthermore, lorazepam is known to affect perceptual integration. Diazepam, on the other hand, though being a benzodiazepine too, only impairs explicit memory, leaving implicit memory fairly intact. Little is known about the effect of diazepam on perceptual integration. The present study aimed at filling in this gap, by comparing the effects of lorazepam and diazepam on the detection of discontinuities in random-shaped outlines. In line with previous findings, the results in a lorazepam-treated group were quite different from the results in a placebo-treated group. The results in a diazepam-treated group were analogous to the results in the placebo-treated group and different from the results in the lorazepam-treated group. This shows that lorazepam and diazepam differ, not only with respect to their effect on implicit memory, but also with respect to their effect on perceptual integration. It is argued that this bears important consequences for memory research that makes use of a pharmacological dissociation rationale.

Adult↗

PubMed2001

Diazepam fails to potentiate GABA-induced chloride uptake and to produce anxiolytic-like action in aged rats.

The pharmacological response to benzodiazepines has been demonstrated to be different in aged individuals in comparison to adults. We studied the age-dependent changes in some of the in vitro and behavioral effects of diazepam in aged (24 months old) rats, comparing them to adults (3 months old). We evaluated the in vitro gamma-aminobutyric acid (GABA)-induced 36Cl- uptake and the diazepam potentiation of GABA-stimulated 36Cl- uptake in microsacs from cerebral cortex of both groups of animals. We found no differences in the GABA-stimulated 36Cl- uptake between adult and aged animals, and diazepam failed to potentiate GABA-induced 36Cl- flux in the aged cortical microsacs. We also examined the effect of 0.03-10 mg of diazepam on locomotor activity in an open-field test and the anxiolytic-like action of diazepam in doses ranging from 0.03 to 1 in a dark-light transition test. We observed no anxiolytic-like action of the drug in the dark-light transition test in the aged rats, while there was a shift to the left in the diminution of locomotor activity evaluated by the open-field test. We conclude that the pharmacodynamic changes observed in cortical GABA(A) receptors in aged rats could partially explain the lack of anxiolytic-like action but not the oversedation evidenced in this group of animals.

Aging↗

PubMedDate not supplied

Different effects of anxiolytic agents, diazepam and 5-HT(1A) agonist tandospirone, on hippocampal long-term potentiation in vivo.

Benzodiazepines and 5-HT(1A) agonists have been widely used as anxiolytic agents. Some clinical reports document that 5-HT(1A) agonists induce memory impairment to a lesser degree than diazepam. In the present study, we compared the effects of diazepam and 5-HT(1A) agonist, tandospirone, on hippocampal long-term potentiation (LTP) in Schaffer collateral-CA1, mossy fiber-CA3 and perforant path-dentate gyrus synapses. In the diazepam-injected group, the reduction in LTP was observed in all three types of synapses, although the effective dose differed among these. In the tandospirone-injected group, no reduction in LTP was observed except in Schaffer-CA1 synapses. In addition, population spike amplitude was potentiated by tandospirone in mossy fiber-CA3 synapses in a dose-dependent manner. Thus, there was a discrepancy in the effects on hippocampal LTP between diazepam and tandospirone, possibly reflecting the reported clinical properties of these drugs, in that 5-HT(1A) partial agonists do not affect learning and memory, whereas diazepam impairs memory function.

Animals↗

PubMedDate not supplied

Different effects of diazepam in Fischer rats and two stocks of Wistar rats in tests of anxiety.

The behaviour of animals in tests of anxiety varies between strains, even in identical tests and surroundings. To evaluate the results obtained, a more detailed knowledge of the behaviour of different rat strains is indispensable. Identically raised Fischer 344 rats and two stocks of Wistar rats were examined in two animal tests of anxiety: the X-maze and a modified open-field test following diazepam treatment (0.5-4.0 mg/kg). Harlan-Wistar rats were the least 'anxious' when the behaviour of vehicle treated controls was compared. The largest effect of the anxiolytic diazepam, however, was observed in Harlan-Fischer rats. To determine possible reasons for strain and stock differences, plasma concentrations of diazepam and metabolites and concentrations of serotonin (5-HT) in the CNS were measured. Plasma concentrations of diazepam and metabolites differed between the strains with the Harlan-Fischer rats showing higher diazepam concentrations. 5-HT levels in discrete brain regions varied with Harlan-Fischer rats having higher 5-HT concentrations. Strain differences influence the anxiety-associated behaviour of untreated animals and the effect of anxiolytics.

Animals↗

PubMedDate not supplied

Propranolol and metoprolol enhance the anticonvulsant action of valproate and diazepam against maximal electroshock.

The anticonvulsive potential of classical antiepileptics co-administered with beta-adrenergic receptor antagonists against generalized tonic-clonic seizures was evaluated in the model of maximal electroshock (MES)-induced convulsions. Propranolol, acebutolol, metoprolol and atenolol were tested in the doses not affecting the electroconvulsive threshold. Propranolol and metoprolol lowered the ED(50) of valproate and diazepam. Acebutolol reduced valproate's but not diazepam's ED(50) value. In contrast, hydrophilic atenolol, not penetrating via blood-brain barrier, affected neither the action of valproate nor diazepam. None of the studied drugs changed the protective activity of carbamazepine and phenytoin against MES. beta-blockers per se did not alter the motor performance of mice. Moreover, propranolol and metoprolol did not influence diazepam-evoked impairment of locomotor activity. The free plasma and brain levels of antiepileptic drugs were not affected by beta-blockers. In conclusion, the use of certain beta-adrenoceptor antagonists, such as propranolol and metoprolol, might improve the antiepileptic potential of valproate and diazepam.

Adrenergic beta-Antagonists↗

PubMed2003

Differential effects of diazepam infused into the amygdala and hippocampus on negative contrast.

Behavioral suppression is observed when animals shift from a high to a lower magnitude of reward in comparison to animals that continuously receive the lower magnitude reward. As previously reported, systemic administration of benzodiazepines promotes recovery from this negative contrast. This study aimed to assess where the neural substrate(s) located in the limbic areas for diazepam to induce such recovery effects on negative contrast. With food-deprived rats, the negative contrast procedure was conducted by comparing a group consuming a 32% sucrose solution which was shifted to 4% with a group consuming only 4% sucrose throughout the experiment. Represented mainly by a decreased number of licks, the negative contrast effects were clearly shown in the control groups receiving the vehicle. Systemic injection of diazepam dose-dependently reduced this contrast. Further, this negative contrast effect was significantly attenuated by local infusion of diazepam (30 microg) into the amygdala, but no such effect was confirmed when diazepam was infused into the hippocampus. Together, the present study shows that a reliable anti-contrast effect can be induced by diazepam administration peripherally or locally infused into the amygdala. These data indicate that the amygdala is involved in the recovery effects of benzodiazepines on consummatory negative contrast.

Amygdala↗

PubMed2003

Orchidectomy sensitizes male rats to the action of diazepam on burying behavior latency: role of testosterone.

The anxiolytic-like effect of diazepam (0.0, 0.5, 1.0 mg/kg) on the cumulative burying behavior and the burying behavior latency were compared between intact and castrated male rats. In both groups a clear reduction in cumulative burying, denoting an anxiolytic-like response, was observed. However, castrated males were more sensitive to diazepam in the burying behavior latency, a parameter indicating reactivity. Thus, orchidectomized males showed an increase in burying behavior latency after 1.0 mg/kg diazepam treatment. This dose has no effect on burying behavior latency in intact animals. The higher sensitivity to diazepam on reactivity seems to be androgen dependent because it was reversed by chronic treatment with testosterone propionate (TP, 0.0625 mg/rat for 2 weeks). TP (0.0, 0.0625, 0.125, 0.25, 0.5 and 1.0 mg/rat) produced a dose-dependent reduction in burying behavior after chronic treatment (four injections separated 48 h). At no dose did TP affect burying behavior latency. These results indicate that some actions of diazepam vary in males depending upon the endocrine milieu. Results also support the idea of androgens possessing anxiolytic-like actions.

Animals↗