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PubMed1982

The effect of prenatal exposure to diazepam on aspects of postnatal development and behavior in rats.

In the present study the effects of chronic treatment of pregnant rats with diazepam on the physical and behavioral development of their offspring were investigated. Rats that were diazepam-exposed prenatally were compared to age-matched controls in terms of the following: number of littermates; birth weight and weight gain until weaning: motor development and coordination; simple motor learning; open field activity; performance on learning tasks of varying complexity; retention of these tasks. Nulliparous Wistar rats were injected s.c. for 16 days of their pregnancy was either 2.5, 5, of 10 mg/kg diazepam or an equal volume of vehicle. Prenatal diazepam treatment did not alter litter size, birth weight, or the righting reflex, but seemed to retard early motor development transiently. Diazepam pups showed longer latencies and less rearing in the open field. There were no differences between animals exposed to drug and vehicle in simple motor learning or in acquiring a simple successive discrimination task. However, there were significant dose-dependent differences on a complex six-choice simultaneous discrimination learning task, the diazepam-exposed rats making more errors and taking more time to reach the goal. A significant difference was seen again between diazepam- and vehicle-exposed rats on the retention test 10 days later. The results indicate that diazepam administered to pregnant rats has long-range effects on the behavior of the offspring, some becoming manifest even in maturity.

Animals↗
PubMed1985

The reinforcing properties of diazepam under several conditions in the rhesus monkey.

Diazepam self-administration was studied in rhesus monkeys under several conditions of availability. Lever-press responding was maintained in twelve monkeys under a fixed-ratio 10 (FR 10) schedule of IV cocaine or pentobarbital delivery in daily sessions of 1-3 h duration. Each of several doses of diazepam (0.012-0.4 mg/kg/infusion) or vehicle was periodically substituted for 5-14 consecutive sessions. Between each substitution, responding was maintained by the baseline drug (cocaine or pentobarbital). Another procedure was to decrease the response requirement for drug delivery to a fixed-ratio one (FR 1). In three of eleven monkeys studied under conditions of a cocaine baseline and the FR 10 schedule, responding was maintained by diazepam and was inversely related to dose. In each of five monkeys tested in a similar manner but with a pentobarbital baseline, at least one dose of diazepam maintained responding above vehicle levels. Three of these monkeys had previously failed to self-administer diazepam under the cocaine baseline condition. Subsequently when two of these monkeys were returned to the cocaine baseline, diazepam was not self-administered above vehicle levels. Under FR 1 conditions of substitution, vehicle and pentobarbital intake increased in each monkey tested and cocaine intake increased in two of four monkeys. Diazepam self-administration also increased but did not exceed vehicle levels under the FR 1 schedule. However, in two monkeys the number of diazepam infusions was increased compared to the FR 10 substitution condition. These results emphasize the importance of testing drugs under several conditions to determine their relative dependence potential.

Animals↗
PubMed1985

Diazepam-induced place preference conditioning: appetitive and antiaversive properties.

The place conditioning paradigm was used to examine the reinforcing properties of diazepam. Rats were injected with diazepam (0.5-5.0 mg/kg, IP) and 30 min later were confined for 30 min to one side of a shuttle box, in which each of the two compartments had distinctive features. On alternate (control) days they received vehicle injections and were confined for 30 min to the opposite side. At almost all doses tested, diazepam produced place preference for the distinctive compartment that had been previously associated with the drug. Preference for the drug side developed regardless of whether diazepam was paired or unpaired with the least-preferred side, and regardless of whether testing was carried out in the undrugged or in the drugged state. The rats preferred the drug side over a novel compartment, but they did not change their initial preference for the side when diazepam was given after removal from the training box. Animals injected with meprobamate (70 mg/kg, PO), a non-benzodiazepine anxiolytic, also developed conditioned preference for the drug side, comparable to that seen following cocaine hydrochloride (10 mg/kg, IP). The diazepam (2.5 mg/kg)-induced place preference was antagonized by CGS 8216 (3 mg/kg, IP), picrotoxin (2 mg/kg, IP) and naloxone (0.8 mg/kg, SC), injected 3 min before and 15 and 20 min after diazepam respectively. Sodium valproate (200 mg/kg, IP) did not influence diazepam (1 mg/kg)-induced place preference. Sodium valproate by itself had marginal effects on place conditioning. Picrotoxin and naloxone, but not CGS 8816, produced place aversion which, in the case of picrotoxin, was due to state dependent learning.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Mechanisms of the initial treatment phenomenon to diazepam in the rat.

The initial treatment phenomenon (ITP) to diazepam was investigated using a conditioned suppression of drinking (CSD) paradigm. Female Sprague-Dawley rats were trained to a stable baseline of punished and unpunished responses in the CSD paradigm. In Experiment 1, a control group (1) received vehicle after the CSD session on each of seven drug test days, while group 2 was treated with 3.0 mg/kg diazepam IP after each of these sessions. On drug test days 8-12, diazepam was administered to both groups before the CSD session. Drug test days were separated by 2-3 days when the animals were untreated but performed in the CSD. Prior exposure to diazepam in group 2 after sessions 1-7 conditioned the animals so that a greater release in punished behavior was seen during sessions 8-12 than in the control group (1). In Experiment 2, one group (3) of rats was administered diazepam vehicle after the CSD session for 4 drug test days and another group (4) was injected with 5.6 mg/kg diazepam after the CSD session on these same days. On the next 4 drug test days both groups received diazepam before they performed in the CSD. An ITP was observed in both the control (3) and the drug-conditioned (4) group, although the ITP was less obvious in the conditioned group. After a 28-day period of CSD exposure without vehicle or drug treatments, 5.6 mg/kg diazepam was administered to both groups before the CSD session for an additional 8 drug test days.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1980

Drug preference and mood in humans: diazepam.

A group of ten normal human volunteers participated in choice experiments comparing d-amphetamine or diazepam with placebo and with each other. Although amphetamine was preferred to placebo by most subjects, 2 mg diazepam and placebo were chosen equally. However, placebo was chosen over higher doses (5 and 10 mg) of diazepam and 5 mg d-amphetamine was preferred to 2 mg diazepam. Subjective effects were assessed using the Profile of Mood States (POMS) before drug was taken and 1, 3, and 6 h later. Compared to placebo, amphetamine produced changes in mood on the POMS including increases in Vigor and Arousal. Doses of 5 and 10 mg diazepam produced decreases in Vigor and Arousal and increases in Fatigue and Confusion. The effects of diazepam were most pronounced 1 h after ingestion and appeared dose-dependent. For one subject who consistently chose diazepam, its subjective effects were similar to placebo and he stated that he could not distinguish them. These results are discussed in terms of the abuse liability of diazepam.

Choice Behavior↗
PubMed1983

High doses of diazepam improve neuroleptic-resistant chronic schizophrenic patients.

According to the two currently most popular biological hypotheses, schizophrenic symptoms result from a hyperactivity in dopaminergic neurotransmission or from a hypoactivity in GABAergic neurotransmission. Since diazepam is known to reduce dopamine release and to potentiate GABA, the possible beneficial effects of diazepam were tested in ten hospitalized chronic schizophrenic patients who were resistant to standard neuroleptic treatment. High doses of diazepam, up to 200 mg/day initially, but smaller maintenance doses (less than 55 mg/day diazepam in eight of the ten patients) were added to the previous neuroleptic medication of these patients. The diazepam dose was adjusted daily to avoid oversedation. The effects of diazepam treatment on the mental status were assessed weekly for 12 weeks by the Brief Psychiatric Rating Scale (BPRS), the physician's Clinical Global Impressions Scale (CGI), and the Psychotic Inpatient Profile Scale (PIP). For additional documentation, videotapes of mental status interviews were obtained at baseline and during diazepam treatment. These videotapes were rated blind by an independent psychiatrist. The addition of diazepam produced a marked improvement in three, a moderate improvement in four, a mild improvement in one and no change in two of the ten patients. Four of the ten patients were so much improved that they were discharged from the hospital. No side effects were noted, except for one patient who became confused and disoriented on 160mg diazepam/day.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1977

Convulsions induced by hyperbaric oxygen: inhibition by phenobarbital, diazepam and baclofen.

1. The anticonvulsive potencies of diazepam, phenobarbital and baclofen against convulsions induced by oxygen under high pressure (OHP), by isoniazid and by strychnine were investigated in mice and rats. 2. The anticonvulsive potency of diazepam was much higher than that of phenobarbital and baclofen against all three types of convulsions. 3. The selective activity of diazepam against isoniazid induced convulsions in rats (dose ratio ED50 phenobarbital/ED50 diazepam: 400) could not be confirmed in mice (dose ratio ED50 phenobarbital/ED50 diazepam: 20-40), where diazepam was equipotent against all three types of convulsions. 4. Baclofen which does not inhibit strychnine induced convulsions was equipotent in inhibiting convulsions evoked by isoniazid and OHP in mice. 5. The results are in agreement with the postulated GABA-inhibitory mechanism of OHP induced convulsions, whereas they make a glycine inhibitory mechanism very unlikely. Although the results do not allow further conclusions about the mode of action of diazepam, a clinical trial of diazepam in OHP-induced convulsions should be considered.

Aminobutyrates↗
PubMed1983

Differential transplacental binding of diazepam: causes and implications.

Diazepam plasma binding was determined in 17 matched pairs of maternal and foetal plasma, collected at delivery. Diazepam % free was higher (p less than 0.001) in maternal (mean 3.24%) than in either umbilical venous (mean 1.50%) or umbilical arterial (mean 1.24%) plasma. The data from in vitro dialysis studies were consistent with the reported higher diazepam concentrations in infants than in mothers at delivery. Plasma nonesterified fatty acids (NEFA) concentrations were higher (p less than 0.001) in maternal (mean = 643 microM) than in matched umbilical venous plasma (means = 211 microM) and there was a significant correlation (p less than 0.01) between diazepam % free and corresponding plasma NEFA concentration for pooled data (r = 0.871, n = 34). Multiple and partial regression analysis indicates that transplacental differences in albumin, bilirubin and total protein concentrations made a minimal contribution to diazepam binding differences between mother and foetus and that approximately 76% of the variability in diazepam % free was accounted for by plasma NEFA concentration. The binding of diazepam to human serum albumin (HSA) was markedly perturbed by the presence of NEFA but not by bilirubin and there was no apparent cooperativity between bilirubin and NEFA on diazepam-HSA binding. Moreover, our findings provide further evidence that substantial differences in binding affinities exist between foetal and maternal plasma albumins.

Adult↗
PubMed1983

Pharmacodynamic and pharmacokinetic interactions between ketamine and diazepam.

Anaesthesia with continuous i.v. ketamine and 65% nitrous oxide in oxygen was given to a total of 49 patients undergoing major abdominal surgery. A control group was premedicated with atropine and other groups received in addition rectal diazepam or clorazepate i.v. For further patients had been on oral diazepam or barbiturates for 1-14 years; as premedication they received atropine alone. The anaesthetic technique gave good operative conditions in the 4 groups of patients. The haemodynamic stimulation of ketamine was significantly reduced in patients premedicated with diazepam. Psychotomimetic side effects were not prominent in any of the groups. Patients premedicated with diazepam required a lower rate of ketamine infusion as compared to controls during the initial 30 min of anaesthesia. The patients in the other groups did not differ from the control group in this respect. There were large differences in metabolic pattern between the groups. As compared to the controls, the patients on long-term diazepam or barbiturates had high concentrations of hydroxylated metabolites, with levels higher than that of norketamine. The patients pretreated with diazepam had very low plasma levels of hydroxylated metabolites. Clorazepate premedication did not significantly affect the metabolism of ketamine. The biological half-life of ketamine was significantly increased in the diazepam-treated group, and it was shortened in those on long term treatment with barbiturates or diazepam.

Aged↗
PubMed1988

A role for the mesolimbic dopamine system in the reinforcing properties of diazepam.

The conditioned place preference paradigm was used to investigate the neurochemical and neuroanatomical substrates which mediate the rewarding properties of diazepam. The results confirmed that diazepam (1 and 2.5 mg/kg, IP) produced place preference for a distinctive environment that had previously been paired with injections of the drug. Pretreatment with haloperidol (0.1 mg/kg) antagonised the place preference induced by diazepam (1 mg/kg). Pretreatment with domperidone (2 mg/kg) failed to influence this effect of diazepam. Haloperidol (0.1 mg/kg) and domperidone (2 mg/kg) alone did not produce place aversion. In separate experiments the diazepam-induced place preference was examined in rats having 6-hydroxydopamine (6-OHDA) lesions of the nucleus accumbens. These animals did not show preference for the compartment associated with diazepam. Depletion of central noradrenaline produced by systemic injections of DSP4 did not affect diazepam-induced place preference conditioning. These findings suggest that dopamine-containing neurons of the mesolimbic system are a component of the neural circuitry that mediates the reinforcing properties of diazepam.

Animals↗
PubMed1994

Characterization of diazepam-insensitive [3H]Ro 15-4513 binding in rodent brain and cultured cerebellar neuronal cells.

Experiments were performed to characterize diazepam-insensitive [3H]Ro 15-4513 binding sites in discrete regions of rodent brain and cultured rat cerebellar granule cells. Scatchard analysis of [3H]Ro 15-4513 binding in the presence of 10 microM diazepam revealed that diazepam-insensitive binding sites in the rat brain were most abundant in the cerebellum, followed by the hippocampus, cerebral cortex and olfactory bulb. Diazepam-insensitive sites represented approximately 80% of the total [3H]Ro 15-4513 binding sites in the membranes of cultured rat cerebellar granule cells. The Bmax values for total [3H]Ro 15-4513 and [35S]TBPS are almost identical, and 5-6 times larger than that for [3H]diazepam in this preparation. Although some annelated [1,5-a]benzodiazepine analogues such as Ro 15-4513, ro 16-6028, flumazenil and Ro 15-3505, and an imidazothieno-diazepine, Ro 19-4603, showed high affinity for cortical and cerebellar diazepam-insensitive sites, all the annelated benzodiazepine compounds tested showed higher affinity for cerebellar diazepam-insensitive sites than cortical ones. In contrast, a pyrazoloquinoline compound, CGS 8216, and beta-carboline analogues such as beta-carboline-3-carboxylate ethyl ester (beta-CCE) and beta-carboline-3-carboxylate methyl ester (beta-CCM) exhibited higher affinity for cortical than cerebellar sites. These results suggest that diazepam-insensitive sites are heterogeneous in brain areas with respect to ligand specificity.

Affinity Labels↗
PubMed1983

Prediction of diazepam disposition in the rat and man by a physiologically based pharmacokinetic model.

A physiologically based pharmacokinetic model for diazepam disposition was developed in the rat, incorporating anatomical, physiological, and biochemical parameters, i.e., tissue volume, blood flow rate, serum free fraction, distribution of diazepam into red blood cells, drug metabolism and tissue-to-blood distribution ratio. The serum free fraction of diazepam was determined by equilibrium dialysis at 37 degrees C and was constant over a wide concentration range. Partition of diazepam between plasma and erythrocytes was determined in vitro at 37 degrees C, and the resultant blood-to-plasma concentration ratio was constant over a wide concentration range. The enzymatic parameters (Km, Vmax) of the eliminating organs, i.e., liver, kidney, and lung, previously determined using microsomes, were used for the prediction. The tissue-to-blood distribution ratios inferred by inspection of the data when pseudoequilibrium is reached after i.v. bolus injection of 1.2 mg/kg diazepam were corrected according to the method of Chen and Gross. Predicted diazepam concentration time-course profiles in plasma and various organs or tissues, using an 11-compartmental model, were compared with those observed. Prediction was successful in all compartments including brain, the target organ of diazepam. Scale-up of the disposition kinetics of diazepam from rat to man was also successful.

Animals↗
PubMed1983

Diazepam potentiates the effect of neuroleptics on behavioural activity as well as dopamine and norepinephrine turnover: Do benzodiazepines have antipsychotic potency?

A single injection of diazepam (10 mg/kg, s.c.), haloperidol (2 mg/kg, i.p.) or chlorpromazine (10 mg/kg, i.p.) decreased the ambulatory as well as sniffing behaviour of rats. These behavioural responses were further decreased when diazepam was administered concurrently with the neuroleptic. Acute haloperidol or chlorpromazine treatment increased striatal dopamine as well as cerebro-cortical norepinephrine turnover. In contrast, diazepam diminished the release of both of these catecholamines. When diazepam was administered together with haloperidol or chlorpromazine, a further decrease particularly in dopamine release was seen in striatum. This effect of diazepam on norepinephrine and dopamine turnover persisted even after 21 days of daily treatment, Similarly, the sedative effect of diazepam elicited in the form of depressed locomotor activity was also apparent after long-term administration of this benzodiazepine. However, chronic administration of neuroleptics enhanced the spontaneous locomotor activity and sniffing behaviour by about 25%. Furthermore, repeated neuroleptic treatment decreased the synthesis and turnover of dopamine and norepinephrine. This was reflected in decreased tyrosine hydroxylase and homovanillic acid level in striatum as well as by low concentration of 3-methoxy-4-hydroxyphenylethylene glycol in the cerebral cortex. When diazepam was administered together with haloperidol or chlorpromazine for 21 days, behavioural activity remained elevated and was comparable to groups of rats receiving neuroleptics alone. The cocomitant injection of diazepam and neuroleptics for 21 days elicited a synergistic effect on decreased synthesis and release of dopamine as well as norepinephrine. These data provide neurochemical evidence for potentiation of the neuroleptic effects by a benzodiazepine.

Animals↗
PubMed1982

Diazepam absorption: effects of age, sex, and Billroth gastrectomy.

The kinetics of diazepam absorption were assessed in 37 healthy volunteers, aged 19--79 years, who ingested a single 5-mg tablet in the fasting state. Diazepam plasma concentrations were measured by gas chromatography in multiple samples drawn over the next 72 hr. After a lag time averaging 12 min elapsed between tablet ingestion and the start of absorption, first-order absorption proceeded with a mean half-life of 19 min (range: 0--96 min), with peak plasma concentrations reached 0.9 hr after dosage (range: 0.25--2.5 hr). Age and sex did not influence absorption kinetics. Peak plasma concentrations averaged 157 ng/ml, and tended to be higher in women than in men because of lower body weights in women. Peak levels also declined with age, probably due to increased volume of distribution of diazepam in the elderly. Absolute systemic availability of oral diazepam was evaluated in seven of the subjects who received intravenous diazepam on another occasion. Based on areas under the oral versus intravenous plasma concentration curve, bioavailability of diazepam averaged 97%. Six male patients, at least 2 years after undergoing Billroth gastrectomy, also participated in the diazepam absorption study. Absorption kinetic parameters were nearly identical to those in six healthy age-matched male volunteers without gastrointestinal disease. Thus absorption of oral diazepam in the fasting state is rapid and nearly complete, and is minimally influenced by age, sex, or Billroth gastrectomy.

Administration, Oral↗
PubMed1991

A comparative study of diazepam levels in bone marrow versus serum, saliva and brain tissue.

The distribution of diazepam in biological fluids and tissues of rats was examined 1, 2, 4 and 8 h after intraperitoneal administration by using a radioimmunoassay with specific anti-diazepam antibody. The diazepam levels in serum, saliva, brain and bone marrow decreased over a period of 2 h and levelled off 4 h after administration. The diazepam concentration in bone marrow was much higher than in serum, saliva and brain, suggesting an accumulation of diazepam in this tissue. This indicates that bone marrow could be a very useful material for the detection of diazepam in skeletonized remains. The diazepam concentrations in bone marrow, serum, saliva and brain showed a linear relationship (r = 0.860-0.997), indicating that a valid estimate of diazepam concentration in blood can be made from bone marrow samples.

Animals↗
PubMed1991

Diazepam withdrawal responses measured in the social interaction test of anxiety and their reversal by baclofen.

After 21 days of treatment with diazepam (0.5 or 2 mg/kg/day) rats were tolerant to the effects of diazepam to increase social interaction in the low light unfamiliar test condition of the social interaction test of anxiety. When they were tested 24 h after the last of 21 injections they showed significant decreases in social interaction, indicating an anxiogenic withdrawal response. However, the social interaction scores of rats tested 48 h after withdrawal from diazepam treatment were no longer different from those of the control group. The decreased social interaction, indicating increased anxiety, detected 24 h after withdrawal of diazepam (21 daily injections of 0.5 or 2 mg/kg), could be reversed by the usual daily diazepam dose (0.5 or 2 mg/kg, respectively) or by baclofen (0.5 or 1 mg/kg). Baclofen (2 mg/kg) was sedative in both control treated and diazepam-dependent rats, but was ineffective at reversing the decrease in social interaction seen after diazepam withdrawal. Possible sites of action mediating these effects of baclofen are discussed, and it is suggested that either post-synaptic GABAB sites in the hippocampus are involved or that the reversal of the decreased social interaction detected on withdrawal of diazepam treatment is due to a baclofen-mediated inhibition of 5-HT release in the hippocampus.

Animals↗
PubMed1993

Pharmacodynamic interactions of diazepam and intravenous alcohol at pseudo steady state.

Pharmacodynamic interactions of low doses of diazepam and alcohol were investigated in a double blind, randomised, 2 x 2 factorial, cross-over study in eight healthy volunteers. Alcohol or glucose 5% were administered intravenously at rates calculated to maintain breath alcohol levels of 0.5 g/l from 1.5 to 5.5 h after starting the alcohol infusion. Diazepam 5 mg or placebo were administered orally at 1.5 h. Evaluation of pharmacodynamic interactions was performed for the average results of tests performed at 2, 3.5 and 5 h. Plasma concentrations of (desmethyl-) diazepam and breath alcohol levels were measured for pharmacokinetic analysis. Breath alcohol reached pseudo steady state levels of 0.38 g/l (range: 0.24-0.57) after alcohol alone and 0.37 g/l (range: 0.27-0.52) in combination with diazepam. Alcohol effects were demonstrated for latency of saccadic eye movements, smooth pursuit eye movements and subjective drug effects. Diazepam impaired smooth pursuit and saccadic eye movements, adaptive tracking, digit symbol substitution and body sway. The effects of combined alcohol and diazepam were mostly additive without significant synergistic interactions. However, in two subjects large supra-additive effects occurred at 3.5 h following alcohol+diazepam, which were not explained by increased drug levels. The design and methods used in this study proved advantageous in evaluating low dose pharmacodynamic interactions. Despite the absence of significant synergistic interactions, unanticipated impairment of performance may occur in susceptible individuals when taking combined low doses of alcohol and diazepam.

Adult↗
PubMed1996

Comparative absorption kinetics of intramuscular midazolam and diazepam.

PURPOSE: This study investigates the rate and extent of absorption following intramuscular injection of midazolam and diazepam. METHODS: Four healthy male volunteers were recruited in this randomized three-way cross-over study. On one occasion each subject received simultaneous im injections of 5 mg midazolam and 10 mg diazepam in separate deltoid muscles. On two other separate occasions each subject received an iv infusion of 7.5 mg midazolam and 30 mg diazepam over five minutes. Frequent arterial blood samples were collected for up to two hours and venous blood samples were collected for up to 24 hours for midazolam and ten days for diazepam. A gas chromatography assay was used to determine the plasma concentrations of midazolam and diazepam. The im absorption profiles were estimated using constrained least-squares deconvolution. RESULTS: There were substantial intersubject variabilities in the estimated pharmacokinetic parameters (volume and clearances) of intravenous midazolam and diazepam. The mean (+/-sd) time to peak plasma concentration (Cmax) was shorter for im midazolam (17.5 +/- 6.5 min) relative to diazepam (33.8 +/- 7.5 min). The mean (+sd) time to peak absorption rate was also shorter for midazolam (9 +/- 2 vs 13.8 +/- 7.5 min). The peak rate of absorption was identical (0.18 mg. min-1) and bioavailability was 1.0 for both drugs. CONCLUSIONS: We conclude that midazolam has more rapid absorption than diazepam following im administration.

Absorption↗