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PubMed2004

Diazepam-induced adaptive plasticity revealed by alpha1 GABAA receptor-specific expression profiling.

Benzodiazepines are in wide clinical use for their sedative and tranquilizing actions, the former being mediated via alpha1-containing GABAA receptors. The signal transduction pathways elicited beyond the receptor are only poorly understood. Changes of transcript levels in cerebral cortex induced by acute diazepam administration were therefore compared by microarray analysis between wild-type and point mutated alpha1(H101R) mice, in which the alpha1 GABAA receptor subunit had been rendered insensitive to diazepam. In wild-type animals, diazepam reduced the expression levels of the alpha subunit of the calcium/calmodulin-dependent protein kinase II, as well as brain-derived neurotrophic factor, MAP kinase phosphatase, transcription factor GIF, c-fos and nerve growth factor induced gene-A. None of these transcripts was changed in the alpha1(H101R) mice after treatment with diazepam. Thus, the sedative action of diazepam is correlated with a selective down-regulation of transcripts involved in the regulation of neuronal plasticity and neurotrophic responses. Most transcript changes were transient except for the decrease of the CaMKIIalpha transcript which persisted even 40 h after the single dose of diazepam. This long-term alteration is likely to contribute to the resetting of the neuronal responsiveness, which may be involved in rebound phenomena and, under chronic treatment, in the development of tolerance and dependence.

Animals↗
PubMed2003

The influence of diazepam on atropine reversal of behavioural impairment in dichlorvos-treated rats.

Acute effects on the behaviour of the organophosphate insecticide dichlorvos and its standard antidotes possessing behavioural activity, atropine and diazepam, were studied separately and in combinations in male Wistar rats. In the spontaneous locomotor activity test, dichlorvos and diazepam decreased, whereas atropine increased performance. The effect of dichlorvos was obtained at a dose (5 mg/kg) that induced overt intoxication, and could not be reversed during first half hour-period after administration of any combination of drugs. In the other two tests, active avoidance learning and rotarod performance, the effective dose of dichlorvos (2 mg/kg) was devoid of somatic signs of intoxication. In these more sensitive tests, the effective atropine dose (40 mg/kg) completely reversed dichlorvos-induced incapacitation. In the rotarod test, diazepam (0.5 mg/kg) contributed to the incapacitating effect of dichlorvos, and impeded desirable influence of atropine as well. In the active avoidance test, diazepam (2.5 mg/kg) contributed to failure to escape; it did not influence the dichlorvos-induced decrease of avoidance performance, nor did it impair the completely reversing effects of atropine. The results point to the possible summation of acute incapacitating effects of organophosphates and diazepam on motor performance, which seems to be, at least partly, antagonized by sufficiently high doses of atropine. However, taking into account the long-term neuroprotective role of the anticonvulsant diazepam, and hence its delayed beneficial influences on behaviour, the immediate testing of atropine/diazepam treatment of organophosphate intoxication in active avoidance paradigm could possess beside sensitivity the predictive value as well.

Animals↗
PubMedDate not supplied

Conditioned fear-induced changes in neuropeptide Y-like immunoreactivity in rats: the effect of diazepam and buspirone.

The study aimed to investigate the influence of conditioned fear, produced in the passive avoidance test, on neuropeptide Y-like immunoreactivity (NPY-LI) and the effect of anxiolytics on NPY-LI in frightened rats. Rats avoided the dark chamber, where they were previously subjected to electric footshock, and they exhibited increased numbers of defecations and gastric ulcers. Moreover, they showed increased NPY-LI in the amygdala, nucleus accumbens and hypothalamus, and decreased NPY-LI in the frontal cortex. Diazepam (1 or 3 mg/kg) and buspirone (1.5 or 5 mg/kg) dose-dependently inhibited passive avoidance and decreased the numbers of defecations, and they also decreased the number of gastric ulcers. Diazepam reversed while buspirone only attenuated the fear-induced changes in NPY-LI in all regions studied. In the amygdala, the effect of diazepam was dose-dependent. The effect of diazepam on both behaviour and NPY-LI was antagonized by flumazenil (15 mg/kg). Apart from supporting the role of the NPY system in fear and anxiety, the results of this study suggest that NPY is involved in the anxiolytic effects of diazepam and buspirone and that the effect of diazepam is mediated by benzodiazepine receptors.

Amygdala↗
PubMed1990

Preference for alprazolam as opposed to diazepam in benzodiazepine-dependent psychiatric inpatients.

Fourteen inpatients with long-term benzodiazepine (BDZ)-dependency were gradually withdrawn from their medication. During a four-day study period patients received 5 mg diazepam t.d.s. Under double-blind conditions the 5 mg diazepam was replaced twice, by either 0.5 mg or 0.37 mg alprazolam. When the hypothetically realistic alprazolam to diazepam equivalent ratio of 1:10 with regard to hypnosedative and anxiolytic properties was used, alprazolam was clearly preferred to diazepam in three sensitive tests. When alprazolam and diazepam were tested using the altered equivalent ratio of 1:14, "liking" and "seeking potentials" revealed no significant differences. However, also under these test conditions alprazolam tended to be preferred in a drug choice test. It is concluded that alprazolam appears to implicate somewhat higher reinforcing properties, possibly leading to a higher abuse liability in BDZ-dependent patients as compared to diazepam.

Adult↗
PubMed1982

[Psychological and physiological effects of cloxazolam and diazepam under anxiety-evoking and control conditions on healthy subjects (author's transl)].

The physical and psychophysiological effects of an orally administered single dose of 3 mg cloxazolam as compared to 5 mg diazepam and a placebo were investigated for 144 healthy male subjects using a double blind technique. In a pre-experimental test, the Ss were classified as either emotional stabiles or labiles, and in the experimental program of one four and half hour period were tested under either stress or control conditions. In order to create appropriate conditions for testing the tranquilizers, three stress situations that would induce anxiety were used: anticipation of an electric shock, preparation of a public speech and one due to failure in an achievement test. By combining these methods it was possible to sustain for 30 minutes in healthy Ss a state of anxiety or emotional activation which seemed suitable as a model for clinical anxiety. Under 5 mg diazepam rather week, but tranquilizer-typical effects were registered in both subjective and objective measures: an increase in self-confidence in emotional labiles, mood improvement, lower electrodermal responses and tranquilizer-typical EEG-pattern, but also subjective deactivating effects. The HR-increase elicited by anxiety induction was not influenced by Diazepam. Under 3 mg cloxazolam very similar effects to those under diazepam were apparent in the subjective measures; there was however, no mood improvement. Cloxazolam was judged as more strongly deactivating and fatigue inducing than diazepam. Cloxazolam was clearly different from diazepam with respect to its physiological effects, especially showing an obvious heart rate increase in the control group, which requires further investigation.

Adult↗
PubMed2002

Potentiation by saiboku-to of diazepam-induced decreases in hippocampal and striatal acetylcholine release in rats.

Effects of saiboku-to, a traditional oriental herbal medicine, on diazepam-induced changes in cerebral acetylcholine (ACh) were investigated in rat striatum and hippocampus. Diazepam (10 mg/kg, i.p.) increased tissue concentrations of the ACh in both regions. The increase was enhanced in rats subacutely treated with saiboku-to (2.0 g/kg, p.o., once a day) for 7 days. Diazepam also decreased release levels of ACh in both regions. The release levels were further decreased in saiboku-to-treated rats. On the other hand, no significant changes in ACh synthesizing and the hydrolyzing enzyme activities in either brain region were observed in saiboku-to-, diazepam- and combination-treated rats. These results suggest that not only is the diazepam-induced increase in tissue ACh due to the inhibition of ACh release but also that saiboku-to potentiates diazepam-induced inhibition of ACh release.

Acetylcholinesterase↗
PubMed1997

Diazepam usage in veterans with spinal cord injury.

Diazepam is widely prescribed for persons with spinal cord injury (SCI) to treat muscular spasticity. To assess the current usage of diazepam in those persons with SCI being followed by the Department of Veterans Affairs Medical Centers (DVAMCs), a survey was mailed to all 23 DVAMCs that have specialized SCI Services. We discovered that no policy regarding the prescription of benzodiazepines existed at 65 percent of the SCI Services. At 70 percent of the SCI Services, diazepam or another benzodiazepine was routinely prescribed. One-third of patients were estimated to have taken diazepam for greater than 10 years and an additional 37 percent for six to 10 years. Despite the potential for addiction, only 10 of the 23 SCI Services reported having a program to encourage discontinuation of diazepam use; a 20 percent success rate was reported in withdrawing this medication. A need for greater understanding with regard to the prescription of diazepam exists and strategies for its withdrawal should be considered. Appropriate guidelines for its use in patients with SCI and spasticity should be developed.

Baclofen↗
PubMedDate not supplied

Midazolam and diazepam for pediatric seizures in the prehospital setting.

OBJECTIVE: The objective of this study was to compare the efficacy and adverse events associated with the use of diazepam and midazolam for the treatment of pediatric seizures in the prehospital setting. METHODS: This was a retrospective cohort study of all patients younger than 18 years treated for a seizure with a benzodiazepine by emergency medical services in Multnomah County, Oregon, from 1998 to 2001. The emergency medical services system consists of a single private advanced life support transporting ambulance service with fire department first responders that are all advanced life support capable. The benzodiazepine used changed from diazepam to midazolam at the midpoint of this period. The primary outcomes were termination of the seizure by arrival to the emergency department (ED), recurrence of seizure while in the ED, or the requirement for active airway interventions including intubation. The two cohorts were also compared for demographics, past history of seizures, long-term use of seizure medications, response times, route of administration, use of second doses of benzodiazepines, and final disposition. RESULTS: Forty-five patients were treated with diazepam, and 48 were treated with midazolam. The two cohorts were comparable except the diazepam cohort had a significantly increased proportion of patients with previous afebrile seizures (53% vs. 25%; p = 0.005). The midazolam cohort had an increased use of nonintravenous route for initial dosing (65% vs. 42%; p = 0.02). The two cohorts were equivalent in rates of termination of seizures before to ED arrival, recurrence of seizures in the ED, requiring airway support or a second dose of benzodiazepine, and admission to the hospital. CONCLUSIONS: Diazepam and midazolam appear to be equivalent in treating seizures and causing adverse events. Paramedics appear to be administering midazolam intramuscularly more often than they use diazepam rectally.

Anticonvulsants↗
PubMed1979

Serum diazepam concentrations in overdose. Their significance.

Total serum benzodiazepine concentrations were correlated with clinical manifestations in 93 cases of diazepam overdose. Diazepam and nordiazepam were also each separately determined in 101 serum specimens from cases of diazepam overdose, including 27 cases from the aforementioned clinical correlation study. In addition, serum nordiazepam concentrations were measured in five cases of chlorazepate overdose. Concentrations of total benzodiazepine ranged from 1 to 22 microgram/ml. All patients survived with supportive therapy only. Each of the 25 patients who had ingested only diazepam was awake or in grade 0 coma, even when drug concentrations were ten-fold greater than the accepted upper limit of the therapeutic range. None of the patients who had ingested only diazepam needed hospitalization; all were discharged from acute medical care after a period of emergency room observation. The ratios of parent drug to N-desmethyl metabolite (nordiazepam) in those overdose specimens analyzed by gas chromatography averaged 3:1. This high ratio may be useful in differentiating acute overdose from high concentrations resulting from chronic therapy. Although determination of diazepam concentrations aid in establishing that an overdose has occurred, when more than grade I or II coma is present, other drugs or an alternative explanation should be sought, regardless of the drug concentration.

Alcohol Drinking↗
PubMed1975

Biliary excretion of diazepam in man.

In a study of diazepam metabolism, diazepam 10 mg was administered i.m. to four patients who had biliary T-tube drainage. Blood and bile diazepam metabolite concentrations were measured for 12 hr. The expected fluctuations in blood diazepam concentrations were seen, and conjugated diazepam metabolites were present in human bile. Bile diazepam concentrations were insufficient to account for an enterohepatic circulation.

Aged↗
PubMed1976

Diazepam in the prophylaxis of lignocaine seizures.

Diazepam 0.05-0.25 mg/kg increased the dose of lignocaine required to cause seizures in Rhesus monkeys by 24-34%. Spontaneous ventilation was maintained adequately during lignocaine administration following diazepam treatment and no adverse cardiovascular effects occurred. Before the onset of lignocaine-induced seizures in non-treated animals, the animals appeared to be drowsy. However, prior to administration of diazepam masked this effect. Convulsions were controlled by smaller doses of diazepam in non-treated animals than in diazepam-treated animals. Also, the animals that were pretreated with diazepam had a greater duration of depression after seizure.

Acid-Base Equilibrium↗
PubMed1983

Ro 15-1788 antagonizes the effects of diazepam in man without affecting its bioavailability.

In a double-blind, placebo-controlled three-way cross over study, the efficacy of Ro 15-1788 200 mg, a new benzodiazepine antagonist, in blocking the amnesic, cognitive, psychomotor and subjective effects of diazepam 20 mg, was investigated in a group of six healthy male volunteers. The amnesic effects of diazepam were markedly attenuated by the combined administration of Ro 15-1788. The psychomotor and subjective effects of diazepam by mouth were most pronounced 2.5 h after administration. Concurrent oral administration of Ro 15-1788 completely prevented these effects at 2.5 h. Plasma diazepam concentrations observed after administration of the combination of diazepam and the antagonist did not differ from those observed following diazepam alone.

Adolescent↗
PubMed1999

Detection of aneuploidy by multicolor FISH in mouse sperm after in vivo treatment with acrylamide, colchicine, diazepam or thiabendazole.

Multicolor fluorescence in situ hybridization (FISH) was used to investigate the induction of aneuploidy during meiosis in young adult male mice treated with chemicals chosen for the EU sponsored aneuploidy project (acrylamide, colchicine, diazepam and thiabendazole). The aim of the present study was to evaluate the frequency of aneuploid sperm induced by each of these chemicals by sperm FISH. Male (102/ElxC3H/El)F1 mice were treated with acrylamide (120 and 60 mg/kg single dose i.p.), colchicine (1.5 and 3 mg/kg single dose, i.p.), diazepam (300, 150 and 75 mg/kg single dose by oral intubation) or thiabendazole (100 and 300 mg/kg daily for 11 days by oral intubation). At 22 days after the last treatment, sperm were collected from the cauda epididymis. Three chromosome FISH was applied to determine hyperhaploid and diploid sperm with DNA probes specific for the chromosomes X, Y and 8. Five animals were treated per dose group and sperm aneuploidy was evaluated in 10,000 sperm per animal. We found significant increases in the frequency of total hyperhaploidy for the males treated with 3.0 mg/kg colchicine (0.092 versus 0.056%, P < 0.05) and with 1.5 mg/kg colchicine (0.082 versus 0.050%, P < 0.05), as well for the males treated with 300 mg/kg diazepam (0.081 versus 0.050%, P < 0.05), indicating that colchicine and diazepam each induced germ cell aneuploidy. We also found significant increases in the frequency of total diploidy for the males treated with 300 mg/kg diazepam (P < 0.05) and with 300 mg/kg thiabendazole (P < 0.05). No significant effects were found for 120 and 60 mg/kg acrylamide or for the other doses of diazepam and thiabendazole. These first results indicate that the multicolor FISH method is useful to determine aneuploidy induction in sperm of mice.

Acrylamide↗
PubMedDate not supplied

The effect of diazepam on voluntary ethanol intake in a rat model of alcoholism.

This paper reports the effects of a diazepam treatment on voluntary ethanol intake in rats included in an animal model of alcoholism. In a first dose-seeking experiment, rats had a choice between 10% (w/v) ethanol and water for 24 h each week. Single doses of diazepam between 2 and 20 mg/kg injected i.p. prior to the 24-h choice caused a dose-dependent decrease in voluntary ethanol intake from 3.2 +/- 0.4 g/kg/day down to 2.3 +/- 0.3 g/kg/day (P < 0.01) after a dose of 20 mg/kg. In a second experiment, psychological dependence was induced by a 1-year intermittent exposure to ethanol (a choice between 10% ethanol and water for 24 h each week, followed by an i.p. injection of 2.0 g/kg of ethanol). After this year, the rats were given a continuous choice between ethanol and water. A 3-week treatment with diazepam (20 mg/kg/day, i.p.) was started in week 68, during which period a choice of 10% (w/v) ethanol was available only on the first and the last days of treatment. On the first day of the diazepam treatment, ethanol intake was decreased from a pre-experimental value of 2.7 +/- 0.3 g/kg/day to 1.2 +/- 0.1 g/kg/day (P < 0.001). On the last day of the treatment, voluntary intake was higher than before the treatment (3.8 +/- 0.27 g/kg/day, P < 0.01). Ethanol intake remained elevated during the week after the end of the diazepam treatment (P < 0.05). When single doses of diazepam (20 mg/kg) were re-tested 10 and 19 weeks after the treatment, there was no decrease in ethanol intake, indicating that the initial effect had not been re-established.

Alcohol Drinking↗
PubMed1980

Respiratory depression by midazolam and diazepam.

The purpose of this study was to examine the respiratory depression produced by diazepam and by midazolam. Ventilatory and mouth occlusion pressure responses to CO2 were measured in eight healthy volunteers before and after the intravenous administration of 0.3 mg/kg of diazepam and 0.15 mg/kg of midazolam. The mean ventilatory response to CO2 (mean +/- SEM) decreased after administration of diazepam or midazolam from 2.0 +/- 0.2 to 1.3 +/- 0.1 1.min-1/torr or from 2.1 +/- 0.2 to 1.4 +/- 0.1 1.min-1/torr, respectively. In the same volunteers, the mouth occlusion pressure responses decreased from 0.54 +/- 0.05 to 0.30 +/- 0.04 cm H2O/torr after midazolam and from 0.67 +/- 0.12 to 0.28 +/- 0.07 cm H2O/torr after diazepam. When compared with the control slopes of the ventilatory and mouth occlusion pressure responses, the drug slopes were significantly different. Respiration was similarly depressed after diazepam and after midazolam. That both the ventilatory and mouth occlusion pressure responses to CO2 are equally depressed by intravenous injections of midazolam and of diazepam at equipotent doses suggests a direct depression of the central respiratory drive by these drugs.

Adult↗
PubMed1982

Cerebral metabolic, vascular and protective effects of midazolam maleate: comparison to diazepam.

The effects of midazolam maleate and diazepam on cerebral metabolism and circulation were examined for each drug in six dogs maintained on N2O 70 per cent and halothane less than 0.1 per cent. Midazolam maleate at 0.2 mg/kg and diazepam at 0.3 mg/kg (the ED 100 per cent for induction of anesthesia for each drug in humans) did not decrease metabolic rate for oxygen (CMRO2) but did decrease cerebral blood flow (CBF) to about 55 per cent of control. Additional drug administrations (2.0, 5.0, and 10.0 mg/kg midazolam maleate, and 3.0 and 7.5 mg/kg diazepam) resulted in dose-related decreases in CMRO2 to a maximum of 55 per cent of control after 10.0 mg/kg midazolam maleate. Concomitant with the initial decreases in CMRO2, there was a change in the EEG as reflected by a decrease in frequency and an increase in amplitude. This EEG change suggests that 2.0 mg/kg midazolam maleate and 3.0 mg/kg diazepam represent a comparable canine anesthetic dose. Each additional dose of midazolam maleate decreased CBF to a greater extent than did the added doses of diazepam. Brain biopsies taken at the end of the midazolam maleate studies revealed a normal cerebral energy state (phosphocreatine, ATP, ADP, and AMP) and normal glucose, lactate, and pyruvate concentrations. In a hypoxic mouse model (FIO2 = 0.05), midazolam maleate provided greater protection from hypoxia (2.8 x control survival time) than diazepam (1.6 x control survival time). By comparison barbiturates in this model provide a survival time which is 4.0 x control.

Anesthetics↗
PubMed1982

The influence of droperidol, diazepam, and physostigmine on ketamine-induced behavior and brain regional glucose utilization in rat.

Diazepam and droperidol are used clinically with ketamine anesthesia to reduce emergence hallucinations, vivid unpleasant dreams, and hyperexcitability. Also, there are reports that the recovery time from ketamine anesthesia is shortened after administration of physostigmine. The authors investigated the influence of diazepam, droperidol, and physostigmine pretreatment on ketamine anesthesia by measuring the brain local regional activity and behavioral responses in rat. The 2-deoxyglucose brain local metabolic mapping method was used to determine regional brain functional activity. The recovery of tail flick response and righting reflex from ketamine anesthesia were prolonged by diazepam and by droperidol pretreatment, but the duration of agitation was shortened; physostigmine caused no significant change in any of these responses. Ketamine alone caused a statistically significant (P less than 0.05) increase in the rate of glucose utilization along the hippocampal molecular layer (control 87 mumol . 100 g-1 . min-1; ketamine 166 mumol . 100 g-1 . min-1) and a decrease in medial geniculate (25%), inferior colliculus (37%), and lateral habenula (18%). Diazepam, droperidol, and physostigmine pretreatment did not significantly alter any ketamine-induced glucose use changes, except for a decreased activity in hippocampal molecular layer with diazepam pretreatment (20%) and an increased activity in the lateral habenula with droperidol pretreatment (94%, P less than 0.05). These findings corroborate the "epileptogenic" character of ketamine anesthesia and implicate the hippocampus as a major focus. The reduced activity in the hippocampus induced by diazepam retreatment and the increased activity in the lateral habenula induced by droperidol pretreatment may be factors in the clinical reduction of ketamine hyperexcitability and hallucination by these drugs.

Animals↗
PubMed2000

Diazepam in the ventral striatum dissociates dopamine-dependent and dopamine-independent place conditioning.

We have previously shown that diazepam blocks both the formation and the expression of amphetamine-induced conditioned place preference (CPP), but has no effect on the CPP induced by morphine. Because diazepam reduces dopamine activity in the nucleus accumbens, three experiments were conducted in order to investigate whether diazepam selectively blocks the expression of place conditioning dependent on mesolimbic dopamine. The first experiment found that systemic diazepam blocked the expression of conditioned place aversion induced by the kappa-receptor agonist U50-488. The second and third experiments demonstrated that intra-cranial injections of diazepam in the nucleus accumbens blocked the expression of amphetamine CPP but not of morphine CPP. It is concluded that diazepam interferes with mesolimbic dopamine-dependent motivational effects of drugs.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗