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At least 595 records · Page 33Linked to original sources
PubMed1994

Using a computer model to explore impairments of acquisition processes following ingestion of diazepam.

Hypotheses about the information processes impaired in diazepam-induced amnesia were tested by fitting the output from a computer simulation of list learning to observed serial position curves and to overt rehearsal protocols. Twenty-four subjects received an average weight-relative dosage of 0.18 mg/kg oral diazepam; 24 subjects received placebo. Immediate free recall of 16-word lists was examined at 2- and 8-s presentation times. Subjects receiving diazepam recalled significantly fewer words than placebo subjects (diazepam = 6.77 +/- 2.39 words; placebo = 9.29 +/- 1.42 words); their memory impairment was greater at the 8-s than 2-s presentation time. Tests of nonlinear regression models based on computer simulations of list learning performance were consistent with the hypothesis that diazepam reduces rehearsal capacity and disrupts the formation or utilization of contextual and inter-item associations. Among these causes of diazepam-induced amnesia, the disruption of contextual associations appears most important. The results further suggest that quantitative modeling of memory data may complement traditional methods of inferring relationships between brain processes and cognitive dysfunction in amnesic states.

Adult↗
PubMed1995

Diazepam prevents progression of kindled alcohol withdrawal behaviour.

The purpose of the present experiment was to study the "kindling" hypothesis of alcohol withdrawal stating that exposure to repeated episodes of alcohol withdrawal results in an increased severity of subsequent withdrawal reactions. Two groups of male Wistar rats were subjected to 13 episodes of 2 days severe alcohol intoxication and 5 days alcohol withdrawal. Animals in the control group (n = 80) developed clinical withdrawal signs following each intoxication episode. In the diazepam group (n = 80) the withdrawal reactions during episodes 1-9 were blocked by intraperitoneal diazepam administration (0-30 mg/kg) 8, 11 and 15 h into withdrawal. During episode 10-13 diazepam treatment was terminated and convulsive withdrawal behaviour was observed 9-15 h after last alcohol dose. The probability of seizure activity during these four withdrawal episodes was calculated as 0.239 and 0.066 in the control and the diazepam groups, respectively. Based on Monte Carlo simulation techniques, this difference was found to be statistically significant (P < 0.05). No differences in the non-convulsive alcohol withdrawal symptoms tremor, hyperactivity and rigidity were detected between controls and diazepam animals after diazepam treatment. It was concluded that the increased convulsive behaviour in the control group was caused by cumulated kindling-like cerebral alterations during the previous repeated alcohol withdrawal phases.

Animals↗
PubMed1993

Automatic quantification of withdrawal from 5-day diazepam in rats: ultrasonic distress vocalizations and hyperreflexia to acoustic startle stimuli.

The purpose of the present work was to develop an objective and precise method to quantify withdrawal responses from anxiolytics relying on ethologically valid responses. Behavioral effects of diazepam withdrawal in rats are automatically measured that appear to correspond to clinically relevant disturbances in affective and sensory-motor functions. Ultrasonic vocalizations and startle reflexes in response to acoustic stimuli were measured as indices of withdrawal 24 h after 5 days of 2.5, 5 or 10 mg/kg diazepam, b.i.d., IP in male Long-Evans rats. About 60% of male rats emit 22-26 kHz ultrasonic calls when exposed to acoustic startle stimuli (18 presentations, 9 at 105 dB and 9 at 115 dB, each 30 s apart on average). Diazepam-withdrawn rats exhibited startle responses with larger maximal and average amplitude and emitted more frequent 22-26 kHz ultrasonic vocalizations than vehicle-treated control animals. The magnitude of the withdrawal changes in ultrasonic calls and in startle reflex amplitude increased significantly already at the low 2.5 mg/kg diazepam dose in spite of considerable individual variability. The increased ultrasound rates during diazepam withdrawal contrast with the suppressive effects of acutely administered diazepam in drug-naive rats. The current methodology offers the opportunity to more adequately characterize withdrawal from anxiolytic substances in a quantitative, objective and automated manner.

Acoustic Stimulation↗
PubMed1997

125I-iomazenil binding shows stress- and/or diazepam-induced reductions in mouse brain: supporting data for 123I-iomazenil SPECT study of anxiety disorders.

Effects of repeated swim stress on the binding of 125I-iomazenil were examined in the brains of diazepam-treated and non-treated mice. The mice were orally administered diazepam or vehicle (0.5% ethylene glycol) and subjected to daily swim stress (at 20 degrees C for 10 min) for seven consecutive days. The distribution and the amount of 125I-iomazenil binding were analyzed autoradiographically after in vivo and in vitro binding experiments. Repeated swim stress decreased the in vivo binding in the hippocampus (p < 0.05) and cerebral cortex (p < 0.05) of vehicle-treated mice but caused no significant changes in diazepam-treated mice. Subchronic treatment with diazepam decreased the in vivo binding approximately 50% in all brain regions examined (p < 0.01). The in vitro experiment, however, revealed no significant changes except in the hippocampus, where a small but significant decrease in the binding was observed after subchronic treatment with diazepam (p < 0.01). The stress- or diazepam-induced reductions seem to represent alterations in the in vivo environment related to 125I-iomazenil binding. These results suggest that we can investigate the pathophysiology of stress and anxiety with 123I-iomazenil SPECT. Care must be taken concerning the effects of benzodiazepines.

Animals↗
PubMed1998

Buspirone is differentiated from diazepam in humans using a three-response drug discrimination procedure.

The discriminative stimulus effects of buspirone and diazepam were examined in 12 healthy volunteers using a three-response drug discrimination procedure and a within-subject design. During an initial sampling phase, the training drug conditions (placebo, 15 mg/70 kg buspirone, and 10 mg/70 kg diazepam) were identified to subjects by letter codes before oral drug administration. During a subsequent training phase, subjects earned money for correct drug identifications made two hours after drug administration. Ten out of 12 subjects acquired the three-response discrimination. When lower doses of buspirone (3.75 and 7.5 mg/70 kg) and diazepam (2.5 and 5.0 mg/70 kg) were tested in a subsequent generalization testing phase, both buspirone and diazepam produced dose-related increases in appropriate drug identifications, without significant cross-generalization. Analyses of standardized and unstructured self report questionnaires revealed that buspirone and diazepam produced different profiles of effects, and that buspirone was associated with a number of "negative" subject-rated effects including tension, nausea, and dizziness. These results demonstrate a distinct profile of discriminative stimulus and subjective effects for buspirone relative to diazepam which is consistent with its distinct pharmacological profile, and provide evidence for the sensitivity of the three-response drug discrimination procedure.

Adult↗
PubMed1991

Effect of beta-carboline derivatives on the binding of L-tryptophan and diazepam to bovine and human albumin.

The effects of 12 beta-carboline derivatives on the binding of L-tryptophan and diazepam to bovine and human albumin have been investigated to seek similarities between the indole binding site on albumin and the benzodiazepine receptor in the brain. The binding of L-tryptophan and diazepam was measured at 37 degrees and pH 7.4 by equilibrium dialysis. Norharmane was the most potent inhibitor of the binding of L-tryptophan and diazepam to both bovine and human albumin. The kinetics of the inhibitory effects of several of the beta-carbolines were studied. Norharmane decreased the value (n) for the number of binding sites for the binding of L-tryptophan to both bovine and human albumin. Norharmane and harmane decreased the apparent association (Ka) but increased n for the interaction of diazepam with bovine albumin. Norharmane also had a similar effect on the binding of diazepam to human albumin. The similarities between the inhibitory effects of the beta-carbolines on the binding of L-tryptophan and diazepam to albumin and the affinity of the beta-carbolines for the central benzodiazepine receptor point to some common structural requirements for binding to the receptor and to albumin.

Albumins↗
PubMed1992

Lateralized effects of diazepam on frontal brain electrical asymmetries in rhesus monkeys.

A growing body of literature has documented the differential role of the frontal regions of the two cerebral hemispheres in certain positive and negative affective processes. This corpus of evidence has led to the hypothesis of a possible differential effect of diazepam on asymmetry of frontal activation. To examine this question, nine infant rhesus monkeys were tested on two occasions during which brain electrical activity was recorded from left and right frontal and parietal scalp regions. During one session, recordings were obtained under a baseline restraint condition and then after an injection of diazepam (1 mg/kg). In the other session, following the same baseline restraint condition, a vehicle injection was given. In response to diazepam, the animals showed an asymmetrical decrease in power in the 4-8 Hz frequency band, which was most pronounced in the left frontal region. No change in electroencephalogram (EEG) activity was observed in response to vehicle. Asymmetry in parietal EEG activity was also unchanged by diazepam. Diazepam also produced overall reductions in power across different frequency bands in both frontal and parietal regions. Good test-retest stability of EEG measures of activation asymmetry was also found between the two testing sessions separated by three months. The possible proximal cause of the asymmetrical change in frontal brain electrical activity in response to diazepam, as well as the implications of these findings for understanding the mechanism of action of benzodiazepines are discussed.

Animals↗
PubMed1984

Diazepam and its anomalous p-chloro-derivative Ro 5-4864: comparative effects on mouse neurons in cell culture.

The actions of diazepam and its p-chloro-derivative Ro 5-4864 were compared on mouse spinal cord and dorsal root ganglion neurons in cell culture. Diazepam enhanced but Ro 5-4864 reduced iontophoretic GABA responses in a concentration-dependent manner. Both diazepam and Ro 5-4864 limited sustained, high frequency repetitive firing of spinal cord neurons but diazepam was more potent. Ro 5-4864 was, however, more potent than diazepam in inhibiting spontaneous neuronal activity of spinal cord neurons and reducing the duration of calcium-dependent action potentials of dorsal root ganglion neurons. The differing actions of diazepam and Ro 5-4864 may account for the contrasting pharmacological spectra of the two benzodiazepines.

Animals↗
PubMed1984

Chronic administration of diazepam to rats causes changes in EEG patterns and in coupling between GABA receptors and benzodiazepine binding sites in vitro.

The daily administration of diazepam (10 mg/kg i.v.) in rats elicited tolerance to the sedative effect within 2-3 days, parallel to the emerging of a stimulatory syndrome. In the EEG, the latter was accompanied by a progressive replacement of the trains of spindles with 25-30 Hz low amplitude waves. No clear signs of tolerance to the myorelaxant effect of diazepam were observed. After 10 days of treatment, the drug was discontinued. Thereafter, a single administration of diazepam elicited a stimulatory syndrome and EEG desynchronization throughout the 15 days of withdrawal. [3H]diazepam binding studies, performed in frozen-thawed membrane preparations incubated at 37 degrees C for 30 min, showed a decrease of KD values in tolerant rats up to 7 days after discontinuation of the drug. In parallel, a reduction in the ability of GABA to enhance [3H]diazepam binding, as well as to protect [3H]diazepam recognition sites from thermoinactivation at 60 degrees C, were found in tolerant rats up to 15 days after drug termination. These data suggest that a modification in the regulatory activity of GABA on benzodiazepine recognition sites might underlie the tolerance to the sedative effects and EEG changes of benzodiazepines.

Animals↗
PubMed1990

Benzodiazepine receptors modulating serotonergic neurotransmission in rat hippocampus do not desensitize after long-term diazepam treatment.

Previous studies have shown in the rat that long-term diazepam treatment induces a desensitization of gamma-aminobutyric acid (GABA) benzodiazepine receptors which modulate serotonergic (5-HT) neuron firing activity in the dorsal raphe. We have examined the effect of a 21-day treatment with diazepam (5 mg/kg/day, i.p.) on the benzodiazepine receptors (BZR) which modulate the efficacy of the electrical stimulation of the ascending 5-HT pathway in suppressing the firing activity of rat dorsal hippocampus pyramidal neurons. The efficacy of the stimulation was not modified 24 h after the last dose of diazepam. Moreover, the potentiating effect of acute diazepam (1 mg/kg, i.v.) on the efficacy of the stimulation was similar in diazepam- and vehicle-treated rats. These results indicate that GABA-benzodiazepine receptors that modulate the release of 5-HT in the rat dorsal hippocampus are not desensitized by long-term diazepam treatment.

Animals↗
PubMed1991

Action of diazepam on the voltage-dependent Na+ current. Comparison with the effects of phenytoin, carbamazepine, lidocaine and flumazenil.

The influence of diazepam, an agonist, and flumazenil (Ro 15-1788), an antagonist of the benzodiazepine receptor, on repetitive firing of action potentials in cultured spinal neurons and on voltage-dependent Na+ currents in cultured N2A neuroblastoma cells was examined. The effects were compared to those of the antiepileptics phenytoin and carbamazepine and the local anesthetic lidocaine. The whole-cell configuration of the patch-clamp technique was used for potential and current recording. Diazepam (10 microM) or phenytoin (10 microM) reduced the duration of repetitive action potential discharges in 50 or 67% of the spinal neurons, respectively. At a concentration of 100 microM repetitive firing was completely blocked. Flumazenil (100 microM) had no effect. In N2A neuroblastoma cells diazepam, phenytoin, carbamazepine and lidocaine, but not flumazenil, at a concentration of 100 microM reduced the Na+ current to 60-67% of control. At 10 microM no or only a weak depression was seen with any drug. In the presence of diazepam (100 microM) the Na+ channel inactivation curve was shifted in the hyperpolarizing direction by -4.8 +/- 0.5 mV. Phenytoin, carbamazepine and lidocaine (all 100 microM) caused stronger shifts of -17.4 +/- 2.1, -10.6 +/- 0.9 and -17.0 +/- 2.1 mV, respectively. Inhibition of the Na+ current by diazepam increased use-dependently over 9 depolarizing pulses repeated at high frequency (200 Hz), whereas use-dependent effects of the other compounds developed less rapidly. At a low stimulation rate (7 Hz) use-dependent block was pronounced with lidocaine, but weak or absent with diazepam and carbamazepine.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1980

The effect of diazepam on tension and electrolyte distribution in frog muscle.

The effect of diazepam on sartorius muscles of the frog was evaluated. Resting tension in sartorius muscle was not affected by diazepam (5 x 10(-5)M) but twitch tension was increased and tetanus tension decreased. The kinetics of 45Ca efflux were altered by diazepam. The calcium content of the intermediate pool was increased by diazepam (5 x 10(-6)M). When the diazepam concentration was increased (5 x 10(-5)M), the time constant of the slow pool decreased and the 45Ca content of the intermediate pool increased further. It is suggested that diazepam interferes with the calcium sequestering system of the sarcoplasmic reticulum (slow pool) and causes an increase of the calcium content of the myofibrillar space (intermediate pool).

Animals↗
PubMed1982

Differential actions of diazepam on the release of [3H]5-hydroxytryptamine from cortical and midbrain raphe slices in the rat.

The possible interaction of the benzodiazepine diazepam with synaptic mechanisms of the central neurotransmitter 5-hydroxytryptamine (5-HT) has been studied in the rat using the superfusion in vitro release technique. The effect of diazepam (1-100 microM) on the spontaneous and potassium-induced release of radioactivity from superfused slices preloaded with [3H]5-HT prepared from cerebral cortex (fronto-parietal) and midbrain raphe region was monitored and compared. The results demonstrate a differential action of diazepam on the release of cortical and raphe 5-HT. In cerebral cortex diazepam significantly reduces both spontaneous and potassium-evoked release of [3H]5-HT. Conversely in raphe slices diazepam significantly enhances both spontaneous and potassium-evoked release of [3H]5-HT. In both tissues the effect of diazepam on K+-stimulated neurotransmitter release was abolished in the presence of picrotoxin. The experiments suggest that the effects of benzodiazepines on 5-HT mechanisms may be manifested at least in part through gamma-aminobutyric acid receptors.

Animals↗
PubMed1985

Possible mechanism of action of diazepam as an adenosine potentiator.

Diazepam (10(-5)-3 X 10(-4) M) selectively enhanced the negative inotropic responses of guinea-pig atria and the relaxation of guinea-pig taenia coli caused by adenosine and ATP. In the atria, the effect of 2-chloroadenosine, a stable analog of adenosine, was not affected by diazepam. Segments of guinea-pig atria or taenia coli took up 3H-activity during incubation with [3H]adenosine but did not take up 32P-activity from [32P]ATP. Diazepam at concentrations sufficient to enhance the in vitro responses reduced by half the uptake of 3H-activity into the preparations. Adenosine (10(-6) M) and ATP (10(-6) M) were degraded to inactive inosine during incubation with atrial segments and their degradation was inhibited by diazepam. In contrast, in rat atria, diazepam did not enhance the negative inotropic effects of adenosine and ATP, and did not prevent the uptake of adenosine. These results suggest that in guinea-pig atria and taenia coli, diazepam like dipyridamole, acts as an adenosine potentiator by preventing the uptake and degradation of adenosine.

2-Chloroadenosine↗
PubMed1987

Attenuation of cerebral glucose use in kainic acid-treated rats by diazepam.

Diazepam's impact on kainic acid seizure-induced local cerebral glucose utilization (LCGU) was assessed by a quantitative [14C]2-deoxyglucose method. Male rats were injected i.p. with either kainic acid (12 mg/kg) or its vehicle, 3 or 48 h before LCGU determination. Diazepam (3.2 mg/kg) or its vehicle were injected i.m. 15 min before, 1 and 2.5 h after kainic acid. Diazepam blocked kainic acid-induced overt convulsions, attenuated LCGU increases at 3 h and prevented 48 h LCGU decreases in piriform cortex and amygdala. LCGU in (% of vehicle): CA3 (438%), CA4 (537%) and CA1-ventral (340%) of hippocampus, interpeduncular nucleus (200%) and lateral lemniscus (213%) were still significantly above vehicle levels in the 3 h diazepam-kainic acid group. These results suggest that diazepam suppresses the spread of kainic acid-induced seizure activity from the proposed CA3 epileptogenic focus. In addition, diazepam reduces, but does not abolish, hypermetabolic activity at the foci itself.

Animals↗
PubMed1988

Continuous slow release of low levels of diazepam produces tolerance to its depressant and anxiolytic effects on the startle reflex.

Development of tolerance to the depressant effects of diazepam on the acoustic startle reflex and to the blockade of fear-potentiated startle, a measure of fear or anxiety in rodents, was evaluated after chronic administration via continuous release from implanted diazepam-filled silastic capsules or daily intraperitoneal (i.p.) injections. After continuous exposure to diazepam via capsule implants, complete tolerance occurred to the depressant effects of diazepam on startle and partial tolerance occurred to the antifear effects. In contrast, no tolerance was observed after daily i.p. injection with comparable amounts of diazepam (5 mg/kg) although tolerance could be produced by daily i.p. injections of a much higher dose of diazepam (20 mg/kg). These data suggest that tolerance to at least some behavioral effects may be much easier to produce with continuous rather than intermittent occupation of benzodiazepine receptors.

Animals↗
PubMed1989

Diazepam enhances the inhibitory action of adenosine on transmission at the frog neuromuscular junction.

The effect of diazepam and its interaction with adenosine on evoked endplate potentials (e.p.p.s) and on twitch tension were investigated in innervated sartorius muscles of the frog. Diazepam (100 microM) reversibly decreased the amplitude of the e.p.p.s and the twitch responses evoked by indirect stimulation, and reversibly increased the resting membrane potential recorded from the endplates. In a concentration (30 microM) virtually devoid of an effect on the e.p.p.s, twitch responses, or resting membrane potential of the muscle fibres, diazepam potentiated the inhibitory action of adenosine on neuromuscular transmission, but not that induced by the stable analogue of adenosine 5'-N-ethylcarboxamide adenosine (NECA), which is not a substrate for the adenosine uptake system. The potentiating effect of diazepam was not observed in the presence of dipyridamole, an adenosine uptake blocker which potentiated the effect of adenosine on neuromuscular transmission. Diazepam shifted to the left the concentration-response curve obtained for adenosine in the presence of the adenosine receptor antagonist 8-phenyltheophylline (8-PT). The results suggest that diazepam acts at the frog neuromuscular junction by increasing the level of adenosine at the junction level; this increase probably results from inhibition in the uptake of the nucleoside.

Adenosine↗
PubMed1990

Behavioural changes in the offspring of rats exposed to diazepam during gestation.

Primiparous pregnant Sprague-Dawley dams were administered a single daily s.c. injection of diazepam (0.1 and 1 mg/kg) or vehicle over gestation days 14-20. No differences in neonatal mortality and weight gain were found between the control and diazepam-exposed pups. Conversely, male pups prenatally treated with this benzodiazepine exhibited subtle behavioural alterations either during early postnatal life or during adulthood. In particular, a significant decrease in the locomotor activity of the diazepam-treated groups was found at the end of the second postnatal week (14-16 days). Furthermore, the administration of diazepam during gestation produced marked changes in the length of ultrasonic calls of rat pups removed from their nest. Finally, adult male rats (120 days of age) prenatally exposed to diazepam showed a notable impairment in copulatory activity as well as a significant decrease in the duration of ultrasonic (22 kHz) post-ejaculatory calls emitted during sexual behaviour. These findings suggest that late gestational exposure to diazepam induces both short- and long-term behavioural changes in rat offspring, changes characterized by altered activity patterns and emotional-motivational responsiveness to environmental challenges.

Animals↗