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PubMed1995

Conditioned fear-induced changes in behavior and in the expression of the immediate early gene c-fos: with and without diazepam pretreatment.

The synthesis of Fos, the protein product of the immediate early gene c-fos, was used to map metabolically some of the neural substrates of conditioned fear in the rat. Analysis of the behaviors emitted by the rats during the test session provided strong evidence that the conditioning procedure was effective. Exposure to the environment in which they had previously received footshock significantly increased the number of Fos-like immunoreactive neurons in nearly 50 brain regions, both cortical and subcortical. Among the structures showing the most dramatic increases in fear-induced c-fos expression were the cingulate, piriform, infralimbic, and retrosplenial cortices, the anterior olfactory nucleus, claustrum, endopiriform nucleus, nucleus accumbens shell, lateral septal nucleus, various amygdalar nuclei, paraventricular thalamic nucleus, ventral lateral geniculate nucleus, the ventromedial, lateral, and dorsal hypothalamic nuclei, the ventral tegmental area, and the supramammillary area. These data demonstrate that a relatively simple classical conditioning procedure activates a large number of widely dispersed cortical and subcortical structures. Some of the structures showing increased c-fos expression have important autonomic functions and may therefore have reflected centrally mediated changes in blood pressure and respiration produced by the anxiogenic stimuli. In a second experiment, the effects of pretreatment with the anxiolytic drug diazepam (2.5, 5.0, or 10 mg/kg) were evaluated. The benzodiazepine produced dose-related decreases in the frequency of crouching (freezing) elicited by the aversively conditioned contextual cues. Diazepam also produced dose-related decreases in conditioned stress-induced c-fos expression in all but one structure, the effects being statistically significant in 38 of 60 sampled structures. Diazepam dose dependently increased fear-induced c-fos expression in the central nucleus of the amygdala. There was considerable regional variability with respect to sensitivity to diazepam, the retrosplenial cortex and the supramammillary area being the only two structures to show decreases after the lowest dose of diazepam. In contrast, the entorhinal cortex, nucleus accumbens core, ventromedial and posterior hypothalamic nuclei, median raphe, and locus coeruleus were particularly resistant to diazepam, all failing to show statistically significant decreases in conditioned fear-induced c-fos expression even at the highest dose. The extent to which diazepam decreased conditioned stress-induced c-fos expression was unrelated to previous estimates of benzodiazepine receptor density in the sampled structures.

Animals↗
PubMed1994

Reversal of diazepam withdrawal induced hyperactivity in mice by BR 16-A (Mentat), a herbal preparation.

Abrupt cessation of chronic treatment of diazepam (20 mg/kg/day for 21 days) produced withdrawal reactions. BR 16-A, a multicomponent herbal preparation shown to reverse the withdrawal reactions to opiates was studied against diazepam induced withdrawal reactions in mice. Acute dose of diazepam (20 mg/kg) produced a decrease in the ambulatory and total activity. However, chronic administration for 21 days produced tolerance and no significant change in the ambulatory and total activity. On abrupt termination of diazepam treatment after 21 days, the animals showed anxiety and excitement as there was an increase in ambulatory and total activity. The withdrawal excitement was highest at 72 hr of the last dose of diazepam. Concomittant administration of BR 16-A (100 and 500 mg/kg) reversed the acute effect of diazepam in a dose dependent manner. Similarly, chronic administration of BR 16-A (100 and 500 mg/kg/day for 21 days) with diazepam (20 mg/kg/day for 21 days) also reversed the withdrawal induced hyperambulation and total activity. Chronic administration of BR 16-A per se had no significant effect on the ambulatory and total activity, however, in acute doses, BR 16-A (100 and 500 mg/kg) produced a dose dependent increase in the ambulatory and total activity. BR 16-A with its CNS profile of activity could be a useful preparation in the management of substances of abuse.

Animals↗
PubMed1993

Evidence that diazepam elicits alterations on rat renal function.

The effects of diazepam on rat renal function were investigated by means of clearance techniques in conscious animals. Different intravenous doses of diazepam were tested: 0.1, 0.3 and 10 mg/Kg body weight A marked increase in fractional water, sodium and potassium excretion was found in every group studied. This alteration was associated with a urine-to-plasma osmolality ratio diminution. On the other hand, no modifications in glomerular filtration rate or p-aminohippuric acid clearance were observed. The reabsorption of water in collecting tubule in diazepam treated rats was decreased as compared with control rats. To assess diazepam-effects on collecting tubule response to vasopressin, the effects of desmopressin on concentrating ability in control and diazepam-treated rats were tested. Desmopressin-treatment promoted a significantly lower free water reabsorption in diazepam-treated group as referred to control rats. This results indicate that diazepam may promote impairments on renal tubular ions reabsorption and that it modifies the collecting tubule response to desmopressin.

Animals↗
PubMed1996

Low level hyperbaric antagonism of diazepam's locomotor depressant and anticonvulsant properties in mice.

Exposure to 12 atmospheres absolute (12 ATA) helium oxygen gas (heliox) (low level hyperbaric exposure) antagonizes the behavioral effects of ethanol and n-propanol, but not morphine. These and other results indicate that the mechanism of the antagonism is direct (pharmacodynamic) and selective. Our study further investigates the selectivity of low level hyperbaric antagonism by testing its effectiveness against diazepam, a high affinity binding drug that acts via allosteric modulation of GABAA receptors. C57BL/6J mice received injections i.p. of vehicle or diazepam, and were then exposed to 1 ATA air, 1 ATA heliox or 12 ATA heliox. Exposure to 12 ATA heliox antagonized the locomotor depressant effect of 4 and 6 mg/kg, but not 8 mg/kg diazepam. Hyperbaric exposure also antagonized the anticonvulsant effect of 8 and 24 mg/kg, but not 4 mg/kg, diazepam vs. 300 mg/kg isoniazid. Exposure to 12 ATA heliox did not significantly affect blood concentrations of diazepam or its metabolite n-desmethyl diazepam. The pharmacological characteristics of the antagonism (direct, surmountable, rightward shift in diazepam's dose-response curve) closely matched those seen in previous studies for hyperbaric antagonism of ethanol. The results add to the evidence that low level hyperbaric exposure is a direct, mechanistic antagonist that selectively antagonizes drugs that act via perturbation or allosteric modulation of receptor function. Moreover, the results suggest that allosteric coupling pathways, which transduce binding events on ligand-gated ion channels, may represent initial sites of action for ethanol.

Animals↗
PubMed1996

Evidence against oppositional and pharmacokinetic mechanisms of tolerance to diazepam's sedative effects.

Acute administration of diazepam (2 mg/kg i.p.) to rats decreased the number of head-dips, locomotor activity and the number of rears made in the holeboard apparatus, indicating sedative effects. After daily treatment for 7 days with diazepam (2 mg/kg) tolerance developed to all these behavioural effects, despite serum concentrations of diazepam and N-desmethyldiazepam significantly higher than those following acute treatment. After 7 drug-free recovery days the rats were quite unresponsive to a probe dose of diazepam (2 mg/kg) and although there was a gradual recovery of responsiveness to diazepam, the reduction in rears still did not reach the level of the acute group even after 21 drug-free days. There was evidence for pharmacokinetic changes when probe doses of diazepam were given after 7, 14 or 21 recovery days. Lower levels of diazepam and higher levels of N-desmethyldiazepam than following an acute dose to the drug-naïve group were detected, indicating that the chronic treatment had resulted in a persistently enhanced rate of N-demethylation. It is argued that these changes do not fully account for the reduced responsiveness to the probe doses, and nor can they account for the gradual return of response over the 3-week recovery period. There were no detectable scrum concentrations of either compound 24 h after the end of the chronic treatment. However, no rebound increases in behavioural responses were detected at any time-point in withdrawal. Thus, the mechanism underlying this behavioural tolerance was not oppositional in nature. It is suggested that a situation-independent learned behavioural strategy is the most likely mechanism for the observed tolerance.

Animals↗
PubMed1996

Protracted treatment with diazepam reduces benzodiazepine1 receptor-mediated potentiation of gamma-aminobutyric acid-induced currents in dissociated rat hippocampal neurons.

Tolerance to benzodiazepines (BZs) is thought to involve alterations of the gamma-aminobutyric acid (GABA)A receptor as a result of the prolonged occupancy of its modulatory BZ recognition site. We used the whole-cell patch-clamp technique to compare the functional and pharmacological properties of GABAA receptors in acutely dissociated hippocampal neurons from the control or diazepam-tolerant rats. Administration of diazepam (15 mg/kg p.o.) twice a day for 10 days induced tolerance as demonstrated by the decreased potency of acute diazepam i.p. injections to protect against pentylenetetrazole-induced clonictonic convulsions (10.5% of tolerant rats protected by 0.1 mg/kg of diazepam against 55% of nontreated rats, 48 hr after the last dose of the chronic treatment). The specific current induced by 1 microM GABA in acutely dissociated hippocampal neurons 48 hr after withdrawal (10.5 +/- 1.3 microA/cm2) was similar to that observed in the control rats (8.7 +/- 0.8 microA/cm2). The EC50 value for GABA was unchanged by the chronic treatment [6.3 (5.4-7.1) and 7.5 (6.2-8.7) microM in neurons from the control and treated rats, respectively]. The potency of the nonselective allosteric modulator diazepam to stimulate Cl- currents was identical in cells from treated rats [EC50 values of 25 (20-30) and 34 (26-41) nM in the control and treated rats, respectively; P < .05], but the potency of the selective BZ1-site ligand zolpidem was decreased [EC50 values of 99 (88-111) and 267 (221-313) nM in the control and treated rats, respectively; P < .05]. The maximal potentiation of the GABA-induced current was significantly decreased with diazepam (maximal potentiation: 168.0 +/- 16.2 and 124.0 +/- 8.9% in the control and treated rats, respectively). These results suggest that tolerance to diazepam is accompanied in hippocampal neurons by a decrease in BZ1 binding sites and in the functional coupling of BZ/GABA recognition sites.

Allosteric Regulation↗
PubMed1998

Discriminative stimulus effects of diazepam, ketamine and their mixture: ethanol substitution patterns.

When ethanol is used as a training stimulus in drug discrimination experiments, benzodiazepines (such as diazepam) as well as non-competitive N-methyl-D-aspartate (NMDA) antagonists (such as ketamine) substitute for ethanol; in contrast, when a benzodiazepine or an NMDA antagonist is used as a training drug, ethanol does not substitute reliably. In the present experiments, we trained rats to discriminate a mixture of diazepam and ketamine, to test the hypothesis that ethanol would substitute for this drug combination. Using a two-lever choice procedure with food as a reinforcer, 22 rats were trained to discriminate a mixture of diazepam (5.6 mg/kg) and ketamine (10 mg/kg) from vehicle. When administered as a mixture, diazepam and ketamine substituted for the training mixture in a dose-dependent manner. When administered separately, diazepam or ketamine substituted for the mixture with full substitution occurring at 5.6 and 17.8 mg/kg, respectively. Ethanol almost completely substituted for the mixture at 1 g/kg. There was no cross-substitution between diazepam and ketamine in rats trained to discriminate diazepam (5.6 mg/kg, n = 10) or ketamine (10 mg/kg, n = 12) from vehicle. In addition, ethanol did not substitute for the training drug in either of these discriminations. These results suggest that the simultaneous action of GABAA agonist and NMDA antagonist mechanisms produce a greater ethanol-specific discriminative stimulus than activation of either component individually.

Animals↗
PubMed1998

Magnesium sulphate versus diazepam in the management of eclampsia.

This clinical trial was conducted to compare the anticonvulsant response of magnesium sulphate and diazepam in the management of eclampsia. The study was carried out at the eclampsia unit of Dhaka Medical College Hospital during the period from October, 1995 to January, 1996. Two hundred consecutive admitted patients were recruited for the study and randomly assigned to two treatment groups: magnesium sulphate and diazepam. One hundred patients received injection magnesium sulphate and another one hundred received injection diazepam. All patients of both the group were matched for baseline characteristics. Convulsion was controlled in 95% of the patients of magnesium sulphate group and 74% of the patients of diazepam group (p < .0005). The mean controlling time is also significantly lower in magnesium sulphate group than diazepam group (8.50 hours vs 9.39 hours). Patients of magnesium sulphate group regain consciousness much earlier (mean time 20.62 hrs.) than the patients of diazepam group (mean time 40.62 hrs.). No significant difference was observed in controlling blood pressure and foetal outcome. The study finding shows that magnesium sulphate has some advantage over diazepam in controlling convulsion and regaining consciousness. If magnesium sulphate can be made available in the market by local production it may be recommended to use this drug in the primary health care without any hazzard before referring to other hospital.

Adult↗
PubMed1993

Fentanyl antagonizes diazepam on carotid sinus baroreflex control of circulation in rabbits.

To investigate the effects of a combination of fentanyl and diazepam on carotid sinus baroreflex in conscious rabbits, we examined the responses of mean systemic arterial pressure (MAP), heart rate (HR) and total peripheral resistance (TPR) to bilateral carotid occlusion (BCO). Seven rabbits were given 0.5 mg.kg(-1) of diazepam i.v. followed by 10 mg.kg(-1) of fentanyl i.v. at 5 min intervals (group 1), and the drugs were given in the reverse order to 5 other rabbits (group 2). BCO was repeated in conscious state (control) and after each drug injection. MAP responses did not differ from control response in either group when both drugs were given. In group 1, however, diazepam decreased HR response to 71.4% of control, and increased TPR response by 36%. Fentanyl administration reversed diazepam-induced changes in BCO responses to the control level. In group 2, fentanyl decreased TPR response to 61.6% of control and increased HR response by 41.5%. Administration of diazepam following fentanyl restored HR and TPR responses to control levels. Carotid sinus baroreflex gain was 3.1 +/- 0.4 (mean +/- SEM) in control and 3.1 +/- 0.4 after administration of both drugs in 12 rabbits. The results suggest that a sedative dose of either fentanyl or diazepam antagonizes the other drug's action on the carotid sinus baroreflex. The combination of fentanyl and diazepam has little influence on carotid sinus baroreflex control of the circulation in rabbits.

Journal Article↗
PubMed1992

Discriminative stimulus effects of alprazolam and diazepam: generalization to benzodiazepines, antidepressants and buspirone.

Rats in one group were trained to discriminate alprazolam (1.0mg/kg, i.p.) and in another group diazepam (3.0mg/kg, i.p.) from saline in a two-lever drug discrimination procedure. Food presentation occurred after 10 consecutive responses on the lever associated either with the training drug or with saline. Alprazolam, diazepam, lorazepam and chlor diazepoxide increased responding on the drug-associated lever in a comparable dose-related manner in both groups of rats: the relative order of potency was lorazepam >/= alprazolam > diazepam >/= chlordiazepoxide. Flumazenil (10.0mg/kg, i.p.) attenuated the effects of the training drugs. A range of doses of buspirone and four drugs having antidepressant properties (amitriptyline, fluoxetine, cericlamine, imipramine) then were studied in both groups of rats. All five drugs caused approximately 40% increases (group mean) in drug-appropriate responding in alprazolam-trained rats whereas only amitriptyline partially substituted for diazepam. The results indicate that alprazolam has interoceptive stimulus effects that overlap with the stimulus effects of diazepam, yet the effects of alprazolam may not be identical to those of diazepam because the antidepressant drugs and buspirone substituted partially for alprazolam but generally not for diazepam.

Journal Article↗
PubMed1980

Withdrawal reaction from long-term, low-dosage administration of diazepam. A double-blind, placebo-controlled case study.

Symptoms of diazepam withdrawal developed in a young man who had been taking diazepam in dosages of 15 to 25 mg/day during a six-year period. This was verified in a study conducted under placebo-controlled, double blind conditions, with plasma levels of diazepam and its major metabolite, desmethyldiazepam, monitored throughout the course of the study. Severe symptoms of physiological withdrawal were observed within two days of replacement of diazepam with placebo capsules. The patient recovered promptly on reinstitution of diazepam administration, and relapsed during a second withdrawal phase. During an additional two week-period of placebo administration, the patient's condition first worsened, then gradually improved. Examination of plasma levels of diazepam and desmethyldiazepam indicated no obvious pharmacokinetic abnormalities. Thus, with long-term administration of diszepam, even in therapeutically accepted doses, withdrawal reactions can be encountered on abrupt termination.

Adult↗
PubMed1986

Diazepam-binding inhibitor. A brain neuropeptide present in human spinal fluid: studies in depression, schizophrenia, and Alzheimer's disease.

Diazepam-binding inhibitor is a novel peptide purified to homogeneity from rat and human brain. Diazepam-binding inhibitor is present, though not exclusively, in gamma-aminobutyric acid (GABA)-containing neurons where it is believed to inhibit GABAergic neurotransmission mediated by GABA by binding to the benzodiazepine-GABA receptor complex. Since an impairment of central GABAergic tone has been postulated to be associated with a number of neuropsychiatric disorders, we measured human diazepam-binding inhibitor immunoreactivity in the cerebrospinal fluid (CSF) of patients suffering from endogenous depression, schizophrenia, and dementia of the Alzheimer's type. Patients with major depression had significantly higher concentrations of human diazepam-binding inhibitor immunoreactivity in CSF when compared with age- and sex-matched normal volunteers, while no difference in CSF diazepam-binding inhibitor immunoreactivity was found in schizophrenics or patients with dementia of the Alzheimer's type when compared with controls. The possibility is discussed that the increased CSF human diazepam-binding inhibitor immunoreactivity observed in depressed patients may represent a functional disinhibition of GABAergic neurotransmission associated with depression.

Adult↗
PubMed2000

Magnesium sulphate versus diazepam for eclampsia.

BACKGROUND: A number of different anticonvulsants are used to control eclamptic fits and to prevent future seizures. OBJECTIVES: The objective of this review was to assess the effects of magnesium sulphate compared with diazepam when used for the care of women with eclampsia. Magnesium sulphate is compared with phenytoin and with lytic cocktail (in preparation) in other Cochrane reviews. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth trials register and the Cochrane Controlled Trials Register, 1999 Issue 3. SELECTION CRITERIA: Randomised trials comparing magnesium sulphate (intravenous or intramuscular administration) with diazepam for women with a clinical diagnosis of eclampsia. DATA COLLECTION AND ANALYSIS: Trial quality was assessed and data extraction was done by the two reviewers. MAIN RESULTS: Five trials involving 1236 women were included. Most of these trials were of good quality. Magnesium sulphate was associated with a substantial reduction in the recurrence of convulsions, when compared to diazepam (relative risk 0.45, 95% confidence interval 0.35 to 0.58). Maternal mortality was also reduced, although this difference was borderline for statistical significance (relative risk 0.60, 95% CI 0.36-1.00). There are no differences in any other measures of outcome, except for fewer Apgar scores <7 at five minutes (relative risk 0.72, 95% CI 0.55-0.94) and in length of stay in SCBU >7 days (relative risk 0. 66, 95% CI 0.46-0.95) associated with magnesium sulphate. REVIEWER'S CONCLUSIONS: Magnesium sulphate appears to be substantially more effective than diazepam for treatment of eclampsia.

Anticonvulsants↗
PubMed1989

Differential regulation of gamma-aminobutyric acid receptor channels by diazepam and phenobarbital.

The anticonvulsant activity of diazepam and phenobarbital may be mediated in part by enhancement of inhibition involving gamma-aminobutyric acid (GABA). While both diazepam and phenobarbital increase GABA receptor chloride current, they may have different mechanisms of action, since they bind to different sites on the GABA receptor-chloride channel complex. We used the patch clamp technique to compare the effects of diazepam and phenobarbital on single GABA receptor currents. Outside-out patches were obtained from mouse spinal cord neurons grown in cell culture for 2 to 4 weeks. GABA (2 microM) evoked single channel currents that occurred as single brief openings or in bursts of multiple openings. Diazepam (20 nM) and phenobarbital (500 microM) both increased the GABA receptor current by increasing mean open time without altering channel opening frequency. However, the temporal grouping of openings into bursts suggested that the enhancement occurred via different mechanisms. Diazepam increased the frequency of bursting GABA receptor currents with minimal effect on the duration of bursts. Phenobarbital increased the duration of bursting GABA receptor currents without altering the frequency of bursts. These results suggest that diazepam binds to a site that may enhance single channel burst frequency by increasing the affinity of GABA binding, while phenobarbital may stabilize the bursting open state of the channel by binding to a different modulatory site at or near the chloride channel.

Animals↗
PubMed1994

Lactate-induced anxiety after imipramine and diazepam treatment.

To examine the effect of treatment on lactate-induced anxiety in a controlled study, we infused 44 panic disorder patients with lactate and placebo before and after eight weeks of double-blind treatment with imipramine, diazepam, or placebo. During treatment, both imipramine and diazepam groups improved more than the placebo group. After treatment, patients in both the imipramine and diazepam groups had significantly less anxiety than the placebo patients when reinfused with lactate. In addition, imipramine decreased posttreatment panic attack frequency and diazepam decreased the perceived severity of posttreatment lactate-induced panic attacks. This study demonstrates that diazepam, like imipramine, is an effective treatment for panic disorder, and that both imipramine and diazepam blunt lactate-induced anxiety in a placebo controlled study.

Adolescent↗
PubMed1991

The pharmacokinetics of atropine and diazepam in sheep: intramuscular co-administration.

The purpose of this study was to determine whether the co-administration of atropine and diazepam affect the rate and extent of absorption of either drug. A triple crossover pharmacokinetic study using adult sheep was conducted. Each of nine animals received single injections of atropine (2 mg), diazepam (10 mg), and a combination of the two compounds weekly over a 3-week period. The combination of the drugs was injected into a single intramuscular site through a specially designed tandem syringe. Blood samples were obtained from time 0 to 300 min post-injection. Serum samples were analyzed for atropine by radioimmunoassay and for diazepam by gas chromatography/mass spectrometry. Pharmacokinetic parameters were evaluated by non-compartmental analysis. The co-administration of atropine and diazepam intramuscularly in sheep caused a delay in the time to reach maximal concentration of atropine. However, at the time when a single injection of atropine reached its maximum serum concentration, 92 per cent of that concentration was reached by atropine in the presence of diazepam. Additionally, no difference was detected in the rate or extent of diazepam absorption when administered intramuscularly in combination with atropine at the same site.

Animals↗
PubMed1976

Biliary elimination of diazepam in man.

The metabolism of 14C-5-diazepam has been studied in 5 patients with T tube biliary drainage. A single bolus of 40 to 50 muCi was given intravenously and blood, urine, and bile were analyzed from 5 to 14 days. The mean half-life of elimination from blood was 93.2 hr; the major metabolite noted in blood was N-desmethyl-diazepam. In urine the average recovery of radioactivity was 48.9% and consisted of 3 OH-diazepam, 4'OH-diazepam, and oxazepam. In bile the average recovery of radioactivity was 5.35% (corrected to a bile flow of 700 ml was 15.0%) and consisted of the same metabolites as in the urine. Essentially no diazepam or N-desmethyl-diazepam was found, and therefore an enterohepatic circulation cannot be held to account for the prolonged half-life of these substances in man.

Adult↗
PubMed1978

Relationship between diazepam dose, plasma level, age, and central nervous system depression.

Patients undergoing elective cardioversion for treatment of arrhythmias were premedicated with diazepam. The dose was individualized to achieve a degree of central nervous system CNS) depression characterized by response to painful but not vocal stimulation. Promptly following each cardioversion, blood was drawn and the plasma diazepam concentration was measured by gas chromatography. The plasma levels varied as widely as the diazepam doses so that there was no fixed plasma level of diazepam associated with the degree of CNS depression produced in these patients. However, both the dose of diazepam and the resulting plasma level were inversely correlated to age, indicating that age is a critical factor in the use of diazepam for cardioversion premedication; elderly are more sensitive to the depressant effects of this drug than the young.

Adult↗