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PubMed1989

Conditioned emotional responding under diazepam: a psychophysiological study of state dependent learning.

An experimental study on 34 healthy male volunteers demonstrated that a therapeutic dose of diazepam (15 mg PO) influenced the reproduction of a conditioned emotional response (skin conductance activity) on subsequent test days. This effect depended upon the pharmacological state present at acquisition, and was in accordance with a drug-dissociation interpretation of diazepam's amnesic effect. The results are interpreted as an example of diazepam state-dependency effects upon development of behavioral tolerance to stress. The clinical consequence of the results indicates that patients under diazepam medication will to a certain degree be deprived of the ability to develop appropriate coping strategies. It is concluded that combining psychotherapy with diazepam treatment may have the opposite effects to those intended.

Adult↗

PubMed1982

Changes in ambulatory activities and muscle relaxation in rats after repeated doses of diazepam.

Changes in rat ambulatory activity and muscle tone after diazepam treatments (2.5, 5, 10, and 20 mg/kg orally) were compared under single and repeated (for 2, 4, 7, and 14 days) administration schedules. Ambulatory activity in the open field test was enhanced by a single dose of 2.5 mg/kg and reduced by 20 mg/kg. However, after all repeated treatment schedules, diazepam resulted in dose-dependent elevations of activity. Even with a treatment period of only 2 days, 20 mg/kg diazepam produced a marked increase in ambulation, which became more conspicuous with increases in the treatment periods. Acutely administered diazepam produced a dose-dependent reduction in muscle tone, but tolerance was noted to this effect during repeated administrations. Thus, time- and dose-dependent increases in ambulation during repeated treatments with diazepam can be partially explained by time-dependent tolerance development to its muscle relaxant effects. The enhancement in ambulation after short-term repetitive dosings of benzodiazepines can be used as a simple indicator for detecting their disinhibitory potentials.

Animals↗

PubMed1986

Diazepam attenuates the antagonism of haloperidol against apomorphine-induced stereotypic behavior after subchronic but not acute treatment in rats.

Apomorphine-induced stereotypic behavior was investigated in rats treated with diazepam or haloperidol and with the combination of both drugs in a one day trial or subchronically. The drugs were administered via the drinking water. Diazepam dose-dependently reduced apomorphine stereotypies after the subchronic (6 days) but not after the acute treatment. Haloperidol suppressed apomorphine-induced stereotypic behavior dose-dependently after acute as well as after subchronic administration apparently without the development of tolerance. This discrepancy to other studies may be explained by the concomitant increase in maximum number of D2-receptors in the striatum. The apomorphine antagonistic effect of haloperidol was attenuated when the neuroleptic was administered subchronically in combination with the benzodiazepine. This finding was unexpected since both drugs reduced apomorphine-induced stereotypic behavior when administered alone. The further increase in maximum number of D2-receptors due to combined treatment with low doses of diazepam, suggesting a sort of "over adaptation", possibly explains the haloperidol-antagonistic action of diazepam in the behavioral experiments. Binding studies on dopamine (D1), 5-hydroxytryptamine (5-HT2) and benzodiazepine receptors revealed that modification of the apomorphine-induced stereotypies by the combined treatment with haloperidol and diazepam cannot be explained by interactions of the drugs at the level of the D1, 5-HT2 or benzodiazepine-receptors.

Animals↗

PubMed1987

Differences in diazepam pharmacokinetics in Chinese and white Caucasians--relation to body lipid stores.

We have compared diazepam pharmacokinetics in 16 Chinese and 18 white Caucasian healthy male volunteers, resident in Hong Kong and have correlated them with physical attributes. Serum concentrations of diazepam and desmethyldiazepam were measured in venous blood by an enzyme-linked immunoassay (0-3 h samples) and HPLC (3-72 h samples). Pharmacokinetic parameters were derived assuming a two compartment model, distribution phase less than 6 h, and 100% oral systemic availability. Compared with the Chinese the white Caucasians were older, heavier, taller, and fatter, as judged by skin fold thickness (SFT) and total body weight to 'Ideal' body weight (TBW/IBW) ratio; respective mean differences being 16%, 27%, 4%, 26%, and 15% (p less than 0.05). Mean diazepam apparent volume of distribution (V) and V/IBW were larger in the white Caucasians (52% & 39% respectively, p = 0.002). SFT and TBW/IBW ratio yielded the best correlations with V, V/TBW and V/IBW (0.50-0.75, p less than 0.05). Obesity indices contributed most to the overall regressions (R2 up to 0.52), and for V there was a further small effect (2%, partial F test) due to ethnic group, possibly reflecting stature. Mean peak diazepam concentration (Cmax) was similar in both ethnic groups. Time to Cmax (tmax) was more often prolonged in the Chinese (chi 2 test, p = 0.01). Body fat and stature may thus account for these inter-ethnic differences in the apparent volume of distribution of diazepam, a highly lipid-soluble drug.

Adult↗

PubMed1984

Chronic diazepam administration and appetitive discrimination learning: acquisition versus steady-state performance in pigeons.

Chronic injections of 2 mg/kg diazepam disrupted both steady-state performance and new discrimination learning in pigeons. However, the time course of disruption differed for each of the two tasks, i.e., steady-state performance was briefly disrupted early, whereas acquisition showed a more persistent delayed disruption. The difference was interpreted as resulting from a dual effect of diazepam on behavior. The early performance disruption was thought to reflect a general nonspecific sedative action of the drug, while the delayed disruption of learning was interpreted as the result of diazepam's selective interference with acquisition processes. Some support for rapid adjustment to the sedative effects of diazepam was found, but there was no evidence for the development of physiological tolerance to diazepam-induced acquisition deficits.

Animals↗

PubMed1982

Interaction between phenytoin and diazepam in mutant Han-Wistar rats with progressive spastic paresis.

The muscle relaxant (antispastic) effect of diazepam, alone or in combination with phenytoin, was studied in mutant Han-Wistar rats with progressive spastic paresis. Alone, phenytoin did not alter the spontaneous activity in the electromyogram (EMG) of the gastrocnemius soleus (GS) muscle of mutant rats, but strongly enhanced the depressant action of diazepam on the spontaneous EMG activity. Picrotoxin reduced the antispastic effect of diazepam alone and partially reversed the antispastic effect of combined treatment. Therefore, the antagonistic effect of picrotoxin on the reduction of the spontaneous activity in the EMG produced by the combination of both drugs hardly suggests an interaction of picrotoxin with phenytoin, but rather indicates an interaction with the effect of diazepam. Phenytoin enhancement of the depressant action of diazepam on the spontaneous EMG activity of mutant rats strongly suggests the potential therapeutic usefulness of the combined treatment with both drugs.

Animals↗

PubMed1978

Effect of diazepam on the gamma motor system indicated by the responses of the muscle spindle of the triceps surae muscle of the decerebrate cat to the muscle stretch.

The experiments were performed on 37 intercollicularly decerebrate cats. The triceps surae muscle was subjected to trapezoidal stretches of 10 mm/s or 2 mm/s over a length of 14 mm. The reflex arc was left partially or fully intact. The effect of diazepam given intravenously on the discharge frequencies of group Ia afferent fibres from muscle spindles in the belly of the triceps surae muscle was studied. Diazepam depressed both the dynamic and the static gamma motor responses. When gamma motor fibres were selectively blocked by procaine a parallel shift of the tension-extension curve was observed. From comparison of the effect of procaine and diazepam on the phasic and static responses of the muscle spindle it was concluded that directly after the injection of diazepam the gamma motor activity was completely abolished at a dose as low as 0.1 mg/kg whereas the alpha motor system was only partly depressed even at higher doses. Differences in the effect of diazepam on the dynamic and static gamma system respectively, could not be found.

Action Potentials↗

PubMed1985

Famotidine, a new H2-receptor antagonist, does not affect hepatic elimination of diazepam or tubular secretion of procainamide.

In 8 healthy male volunteers the pharmacodynamic responses to a single dose of diazepam and a single dose of procainamide were assessed before and after pre-treatment with the H2-receptor antagonist famotidine in a randomized crossover study. The pharmacokinetics of diazepam and procainamide were also studied, and the binding of famotidine to human liver microsomes was also measured. Cimetidine induced binding changes with a spectral dissociation constant (Ks) of 0.87 mM, whereas famotidine produced no measurable spectral alteration in concentrations up to 4 mM. The elimination half-life (t1/2: 45.6 h) and total plasma clearance (CL: 0.28 ml/min/kg) of diazepam were not significantly altered by famotidine (t1/2 = 39.0 +/- 11.4 h; CL = 0.31 +/- 0.08 ml/min/kg). Similarly, there was no enhancement of the sedative effect of diazepam by famotidine. The pharmacodynamics and pharmacokinetics of procainamide and N-acetylprocainamide (NAPA), too, were not significantly changed by famotidine: procainamide t1/2 2.9 vs 3.0 h under famotidine and renal clearance (CLR) 436 vs 443 ml/min; and NAPA CLR 195 vs 212 ml/min under famotidine. The data suggest that famotidine, in contrast to cimetidine, does not affect the pharmacokinetics of diazepam (hepatic elimination) or procainamide (tubular secretion). This new H2-receptor antagonist appears to be devoid of an interaction potential for either type of drug elimination.

Adult↗

PubMed1989

Interaction between diazepam and oral antidiabetic agents on serum glucose, insulin and chromium levels in rats.

This study was undertaken to investigate the effect of diazepam in the presence and absence of glibenclamide, metformin or their combination on serum levels of glucose, insulin and chromium in rats. Results indicated that diazepam (10 mg/kg i.p.) induced marked hyperglycaemic effects in hyperglycaemic rats. This effect was associated with significant reductions in serum chromium levels and insignificant reduction in serum insulin levels. Diazepam-induced hyperglycaemia was counteracted by concurrent administration of glibenclamide (5 mg/kg orally), metformin (500 mg/kg orally) or their combination. The effect of diazepam on serum chromium level was counteracted partially by administration of glibenclamide and augmented in the presence of metformin or its combination with glibenclamide. It is concluded that the diazepam-induced hyperglycaemia, as well as the hypoglycaemic effect of glibenclamide, might be related to changes in serum chromium levels.

Animals↗

PubMed1995

Toxicological analysis of the psychotropic drugs chlorpromazine and diazepam using chemically fixed organ tissues.

Toxicological analysis for chlorpromazine and diazepam was performed using chemically fixed organ tissue specimens. After chlorpromazine and diazepam had been injected into rabbits, organ tissues (brain, lung, liver, kidney and skeletal muscle) were collected and fixed in 3 fixative solutions: buffered 10% formalin solution (pH 7.4, 10% BF), non-buffered 10% formalin solution (pH 5.1, 10% non-BF), buffered 4% paraformaldehyde solution (pH 7.4, 4% BPA). Chlorpromazine and diazepam were determined by GC-MS (gas chromatography-mass spectrometry) after 5 different fixation periods, and were detected even after 28 days of fixation. Recoveries of chlorpromazine and diazepam in 10% BF were within the range 48-86% and 68-171%, respectively after 28-day fixation, those in 10% non-BF were 22-54% and 48-78%, respectively, and those in 4% BPA solution were 13-59% and 14-50%, respectively. Thus, 10% BF was found to be the most suitable fixation medium for analysis of chlorpromazine and diazepam.

Animals↗

PubMed1978

[Occurrence of diazepam in blood samples of drivers under the influence of alcohol (author's transl)].

Diazepam was determined by radioimmunoassay and gas chromatography in 2050 unselected blood or serum specimens of subjects, who were sus,ected of driving under the influence of alcohol in the years 1974 and 1976. A "cut-off" limit of 20 ng/ml was selected. Diazepam was found in 46 samples corresponding to 2.24%, 27 samples (1.3%) exhibited concentrations of 20--100 ng/ml, 14 samples (0.7%) of 100--500 ng/ml, 1 sample (0.05%) of 500--1000 ng/ml and 4 samples (0.2%, as related to the total of 2050 samples) of more than 1000 ng/ml. Furthermore, 44 blood specimens of subjects were analyzed, who had claimed diazepam intake before the blood sample was withdrawn. Diazepam was found in 27 cases corresponding to 61%. Finally, blood specimens of 219 unselected inpatients of a surgical ward were investigated; 59 of these (27%) were found to be diazepam-positive.

Alcoholic Intoxication↗

PubMed1990

A comparison of the effects of scopolamine and diazepam on acquisition and retention of inhibitory avoidance in mice.

Administration of either the muscarinic antagonist scopolamine or the benzodiazepine diazepam prior to training produced a dose-dependent impairment in the retention of one-trial inhibitory avoidance training in mice. To investigate the nature of this drug effect, the effects of scopolamine and diazepam were subsequently assessed on both acquisition and retention of inhibitory avoidance using a multiple-trial, training-to-criterion procedure. The training was conducted using either continuous trials in which the mouse was free to shuttle back and forth between shock and safe compartments or discrete trials in which the mouse was moved from the shock compartment of the safe compartment at the start of each trial. In either case, training continued until the mouse refrained from crossing into the shock compartment for a specified length of time on a single trial. Scopolamine (1.0 mg/kg) administered before training significantly increased the number of trials required to attain criterion, but did not affect retention when these mice were tested 2, 16, or 28 days later. In contrast, diazepam (1.0 mg/kg) did not significantly alter the number of trials necessary to reach criterion, but impaired retention of the inhibitory response in mice trained using discrete trials. The differences in the amnestic effects of scopolamine and diazepam revealed by this detailed analysis suggest that diazepam does not impair inhibitory avoidance performance through an effect on cholinergic function.

Animals↗

PubMed1990

Antagonism of the anti-conflict effects of phenobarbital, but not diazepam, by the A-1 adenosine agonist l-PIA.

The present study examined the effects of the anxiolytics diazepam and phenobarbital, the A-1 adenosine agonist N6-R-phenylisopropyladenosine (l-PIA), and the A-2 adenosine agonist 5'-N-ethylcarboxamidoadenosine (NECA) on conflict behavior. Water-restricted rats were trained to drink from a tube that was electrified (0.5 mA intensity) on a FI-29s schedule, electrification being signaled by a tone. After 3 weeks of daily 10-min sessions, the animals accepted a stable number of shocks (punished responding) and consumed a consistent volume of water (unpunished responding) per session. Different doses of l-PIA and NECA were then tested separately at weekly intervals. In addition, the effects of diazepam and phenobarbital were determined in animals pretreated with saline, l-PIA, or NECA. Neither l-PIA (15-250 nmole/kg) nor NECA (2.5-20 nmole/kg) produced a significant anti-conflict effect when administered alone. Diazepam (1.25-10 mg/kg) or phenobarbital (10-40 mg/kg) administration to saline-pretreated rats resulted in a dose-dependent increase in punished responding (shocks received) with minimal effects on unpunished responding (water intake). Neither l-PIA nor NECA pretreatment reliably altered the effects of diazepam on conflict behavior. Pretreatment with l-PIA, but not NECA, significantly reduced the anti-conflict effects of phenobarbital on conflict behavior. These data suggest that phenobarbital, but not diazepam, anti-conflict responses may involve interactions with A-1 adenosine receptors.

Adenosine↗

PubMed1990

Benzodiazepine concentrations in brain directly reflect receptor occupancy: studies of diazepam, lorazepam, and oxazepam.

Groups of male CF-1 mice received 3 and 10 mumol/kg diazepam, lorazepam, and oxazepam intravenously. Between 1 min and 24 h after injection, benzodiazepine concentrations were determined by gas chromatography (GLC) in plasma and in one brain hemisphere; in the other hemisphere, ex vivo benzodiazepine receptor occupancy was measured using 3H-flunitrazepam displacement. Based on GLC data, diazepam entered brain rapidly, and was also cleared rapidly, yielding desmethyldiazepam and oxazepam as metabolites in plasma and brain. However, lorazepam and oxazepam entered brain slowly, with brain:plasma equilibrium achieved at 30-60 min; thereafter, the drugs were eliminated from plasma and brain in parallel. The time course and extent of ex vivo occupancy were highly consistent with GLC data (for diazepam, GLC levels were expressed as the sum of diazepam, desmethyldiazepam, and oxazepam, with metabolite concentrations, normalized for molecular weight and for in vitro benzodiazepine receptor affinity.) Between-method correlations were 0.95 or higher. Thus benzodiazepine receptor occupancy is highly dependent on benzodiazepine concentrations in brain. Differences in the time-course of onset and duration of pharmacologic activity between the highly lipophilic benzodiazepine diazepam and the less lipophilic hydroxylated derivatives lorazepam and oxazepam are largely explained by differences in systemic kinetics and in the rate of uptake into brain.

Animals↗

PubMed1990

Diazepam changes risk assessment in an anxiety/defense test battery.

An anxiety/defense test battery was designed to assess defensive reactions of laboratory rats to situations associated with nonpainful threat (exposure to a cat). The battery measured three defense patterns, movement inhibition, risk assessment behaviors, and inhibition of nondefensive behaviors, in two tasks. Diazepam (4.0 mg/kg) altered four of five risk assessment measures, but failed to show an anxiolytic effect on movement inhibition, and had minimal and inconsistent effects on inhibition of nondefensive behaviors. The risk assessment changes with diazepam were all consistent with an anxiolytic action of diazepam. These results provide a partial contrast to the general lack of anxiolytic action of diazepam in a fear/defense test battery designed to measure reactions to a discrete, present, threat stimulus, and suggest a greater diazepam effect on risk assessment than on other aspects of defensive responding. Sex differences indicating higher defensiveness for female than male rats were obtained on many of these measures.

Animals↗

PubMed1990

Effects of acute administration of diazepam and d-amphetamine on aggressive and escape responding of normal male subjects.

Normal males participated in sessions providing two operant response options and were administered either diazepam (study I and II) or d-amphetamine (study II). The acute effects of diazepam on human aggressive responding, which ostensibly subtracted points from another person, were determined in study I. Study II was conducted to determine the extent to which social context and response consequence influenced diazepam (study I) and d-amphetamine (previous research) effects on aggressive responding. In study II, the other response option was escape responding which protected the subject's counter from point losses. Aggressive and escape responding were engendered by subtracting points from the subject's counter, and maintained by initiation of intervals free of point loss. Point subtractions were attributed to the other person (study I) or to a machine (study II). Responding to accumulate points exchangeable for money was available in both studies. Acute diazepam administration decreased aggressive responding in most subjects (study I), slightly increased escape responding (study II), and decreased responding to accumulate points. In study II, d-amphetamine increased both escape responding and responding to accumulate points. The effects of d-amphetamine and diazepam were altered by the instructed source of point loss.

Aggression↗

PubMed1993

Effect of diazepam on cortical 5-HT release and behaviour in the guinea-pig on exposure to the elevated plus maze.

Previous studies have used the elevated plus maze to test for "anxiolytic" drugs in rats. The present study demonstrates that guinea-pigs handled daily from birth exhibit similar behaviour to rats on the plus maze. Pretreatment with diazepam (1.0 mg/kg) significantly increased the time the animals spent in the open arms and amount of entries into the open arms. Using intra-cortical microdialysis on exposure of the guinea-pig to the elevated plus maze resulted in increased extracellular 5-HT in the frontal cortex. Diazepam reduced, but not significantly, the increase in extracellular 5-HT and produced an "anxiolytic" profile of behaviour. Pretreatment with the benzodiazepine antagonist flumazenil (10.0 mg/kg) fully antagonised the behavioural effects of diazepam. Flumazenil also reduced the effect of diazepam on the increase in extracellular 5-HT observed on exposure of the guinea-pig to the elevated plus maze. Flumazenil alone decreased basal extracellular cortical 5-HT but had no effect on behaviour in the elevated plus maze. The results show that an increase in extracellular 5-HT occurs in the guinea-pig exposed to aversive conditions. While it remains to be determined whether the "anxiolytic" effects of diazepam in the guinea-pig are causally associated with decreased extracellular 5-HT, it is of interest that the selective benzodiazepine antagonist also prevented the increase in basal extracellular 5-HT produced by the exposure to the elevated plus maze but had no effect on behaviour. Results indicate that there is no simple relationship between inhibition of 5-HT release and the "anxiolytic" action of benzodiazepines.

Animals↗

PubMed1992

Locomotor responses to benzodiazepines, barbiturates and ethanol in diazepam-sensitive (DS) and -resistant (DR) mice.

Diazepam-sensitive (DS) and -resistant (DR) mice were selectively bred for increased and reduced sensitivity to the ataxic effects of diazepam (40 mg/kg). Other response differences between DS and DR mice may reflect pleiotropic effects of the genes fixed during their selection. These mice were tested for their sensitivity to the locomotor stimulant effects of several doses of diazepam, flunitrazepam, pentobarbital, phenobarbital, and ethanol. DR mice were more sensitive than DS mice to the locomotor stimulant effects of all drugs except phenobarbital. These results largely support the hypothesis that a common biological mechanism mediates sensitivity to the stimulant effects of sedative-hypnotic drugs. Receptor mediation of the benzodiazepine effects was examined by administering the benzodiazepine receptor antagonist, RO15-1788. Locomotor depression produced by diazepam and flunitrazepam in DS mice was blocked by RO15-1788. However, while the locomotor stimulation produced by diazepam in DR mice was antagonized, the stimulant effect of flunitrazepam was not. This suggests that binding of flunitrazepam to the GABAA-benzodiazepine receptor is not necessary for production of locomotor stimulation.

Analysis of Variance↗