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PubMed1991

Teratogenic effect of cocaine and diazepam in CF1 mice.

This study was conducted to determine the teratogenic effect of cocaine hydrochloride, alone or in combination with diazepam. Pregnant mice were administered cocaine hydrochloride at 10 and 20 mg/kg body weight intravenously (tail), and/or diazepam at 20 or 40 mg/kg b.w. by gavage. Combinations of diazepam and cocaine (20/10 and 40/20, respectively) were used. Significant reductions of fetal weight and length were found in the group treated with diazepam and cocaine (40/20). The incidences of incomplete ossification of sternebrae and skull bones, as well as delayed ossification of the paws, were significantly increased in the combination groups. Hydronephrosis and cryptorchidism were observed in the cocaine-treated groups, with the incidence of these malformations increasing significantly when diazepam was co-administered.

Abnormalities, Drug-Induced↗

PubMed1990

The novel anticonvulsant loreclezole (R 72063) does not produce diazepam-like anterograde amnesia in a passive avoidance test in rats.

Rats were injected intraperitoneally with loreclezole (R 72063), diazepam, or scopolamine 60 min prior to acquisition of a passive avoidance task and tested 18 h later for retention of the learned (passive) behavior. The known impairment of performance produced by diazepam in this test is believed to be a model for the clinically observed diazepam-induced anterograde amnesia in humans. We report in this study that (1) consistent with the literature, pretreatment with diazepam (2.0-16.0 mg/kg i.p.) or scopolamine (3.0 mg/kg i.p.) produced impairment in passive avoidance performance of rats (anterograde amnesia), but (2) pretreatment with loreclezole (R 72063) (2.0-80.0 mg/kg i.p.) did not impair the acquisition, retention, or the retrieval (tested 18 h later) of passive avoidance behavior by rats at any dose. The results suggest that the anticonvulsant activity of loreclezole is mediated by a mechanism distinct from the one coupled to diazepam-like disruption of cognitive functions involved in the acquisition or posttraining information processing of passive avoidance behavior.

Amnesia↗

PubMed1988

Effects on memory following a single oral dose of diazepam.

The effects of diazepam on learning and memory were investigated in a double-blind study of 28 Uruguayan university women who were randomly assigned to four treatments, seven subjects each: placebo, 0.1, 0.2, and 0.3 mg/kg diazepam orally. Subjects were presented with five uncategorized and categorized word lists, a 12-digit number list, and a tonal discrimination test, before and up to 200 min after treatment. Immediate and delayed recall were tested. Performance of the 0.1 mg/kg diazepam group did not show significant differences from placebo in any of the tests. For the 0.2 dose group, marginal impairments were noted at 60 min followed by full recovery at 190 min. On the contrary, 0.3 mg/kg diazepam produced significant impairments on immediate and delayed recall, with marginal impairments still evident at 190 min. The finding that diazepam did not impair performance on a tonal discrimination test provided some evidence that memory impairments did not result from failures in general alertness.

Acoustic Stimulation↗

PubMed1988

The effects on memory of pipequaline, alone or in combination with diazepam.

Pipequaline (PK 8165) is a putative mixed agonist/antagonist at benzodiazepine receptors. The effects of pipequaline and diazepam on memory were assessed in 12 normal volunteers. Diazepam 10 mg or placebo was added to two doses of pipequaline, 50 and 150 mg, or to placebo in a double-blind crossover design. Diazepam produced impairments of episodic memory. In contrast, the effects of pipequaline were minor. Addition diazepam to pipequaline increased drowsiness and general lethargy, with a less marked effect occurring for the higher dose of pipequaline alone. Pipequaline did not antagonise any of the effects of diazepam.

Adult↗

PubMed1987

Diazepam, behavior, and aging: increased sensitivity or lower baseline performance?

Cognitive performance, psychomotor skills, and subjective reactions to diazepam and placebo were compared in 12 healthy, well-educated subjects in three age groups: 19-28, 40-45, and 61-73 years old. With only minor exceptions, the changes in performance caused by diazepam and age differences were statistically additive and noninteracting. Diazepam did not act synergistically in older individuals; the decrements in performance were about the same in all age groups. Baseline performance decreased with increasing age; middle-aged subjects performed more like older than younger subjects. A variety of tasks exhibited similar effects of aging and diazepam, i.e., when performance declined with increasing age, it was also reduced by diazepam.

Adult↗

PubMed1975

The effect of diazepam and fentanyl on mental, psychomotor and electroencephalographic functions and their rate of recovery.

Ten healthy male subjects received diazepam (10 or 20 mg), fentanyl (0.1 or 0.2 mg) or a placebo intravenously at weekly intervals according to a latin square design. They were tested on a battery of psychological and electroencephalographic tests at 0.5, 2, 6, and 8 hrs following injection. Fentanyl had little effect on memory while diazepam reduced the ability to learn without increasing forgetting of material alread acquired. By the 2nd hour post injection, only the low dose of fentanyl had no residual effect. Recovery was complete by the 6th hour for all treatments according to the psychological tests except for the lagging effect of high dose of diazepam on memory. The electroencephalographic effects of diazepam persisted beyond the end of the testing sessions while those of the high dose of fentanyl recovered by the 8th hour. Thus in the dosages tested, diazepam had more intense and prolonged effects than fentanyl.

Adult↗

PubMed1975

Clinical and experimental comparison of diazepam, chlorazepate and placebo.

A double blind clinical evaluation of chlorazepate (dipotassium-7-chloro-5-phenyl-2,2-dihydroxy-3-carboxy-1,2-dihydro-2H-1,4-benzodiazepine), diazepam and placebo on a patient group of young students, mean age 25 years, is reported. Both drugs were significantly better than placebo and according to global assessment chlorazepate was superior to diazepam. An analysis of the main target symptom revealed better effects of chlorazepate on the following items: anxiety, feeling of muscular tension and gastro-intestinal disturbances. With respect to irritability and sleep disturbances both drugs were found to be equally effective. In patients' self-ratings chlorazepate was considered superior to diazepam in giving more alertness and less drowsiness during day time. The results are discussed with reference to EEG-studies and pharmaco-kinetic properties of chlorazepate and diazepam. Performance tests in simulated car-driving by healthy volunteers did not demonstrate any significant difference as compared with placebo. The psychophysiological eeffects, however, are more pronounced after diazepam than after chlorazepate medication.

Adult↗

PubMed1984

Methylphenidate, apomorphine, THIP, and diazepam in monkeys: dopamine-GABA behavior related to psychoses and tardive dyskinesia.

In eight monkeys (Cercopithecus aethiops), previously treated with haloperidol for 4-14 months, we have examined the behavioral effect of: (1) methylphenidate vs apomorphine; (2) 4,5,6,7-tetrahydroisoxazolo-(5,4-c)-pyridin-3-ol(THIP, a GABA agonist) vs diazepam; and (3) THIP and diazepam in methylphenidate-induced behavior. Methylphenidate (0.5-5.0 mg/kg) and apomorphine (0.1-0.5 mg/kg) both increased locomotion, but otherwise exhibited different behavioral profiles. Methylphenidate induced repetitive movements of head, limbs, and trunk, and hallucinatory-like behavior, but not oral hyperkinesia (licking and gnawing), whereas apomorphine preferentially caused oral hyperkinesia. THIP produced a syndrome of bradykinesia, dystonia, ataxia, myoclonus, sedation, and decreased responsiveness, whereas diazepam produced only bradykinesia, ataxia, sedation, and decreased responsiveness, but not dystonia and myoclonus. Methylphenidate-induced locomotion and repetitive movements were reduced by THIP and diazepam, whereas hallucinatory-like behavior was markedly aggravated by THIP, but not by diazepam.

Animals↗

PubMed1977

Studies on human memory: the interactions of diazepam, scopolamine, and physostigmine.

Seventy volunteers were injected with diazepam (0.3 mg/kg), scopolamine (8 mug/kg), or placebo, followed 70 min later by another injection of physostigmine, physostigmine and methscopolamine (in case of diazepam treatment), or placebo. Physostigmine was given in two doses, 16 and 32 mug/kg; methscopolamine, 8 and 16 mug/kg. Subjects (Ss) were tested in groups of 5 in a double blind procedure with treatments distributed according to a Latin square design. Prior to treatment, Ss heard a series of lists of words, followed by an immediate recall test. Following the first injection, delayed free recall and recognition tests were given. The second drug was then injected, followed by a presentation of another two sets of lists which were tested similarly. Subjective feelings were also evaluated with a rating questionnaire. Diazepam and scopolamine did not affect recall of information which had been learned prior to drug injection. However, both drugs impaired the learning or acquisition of new information. Physostigmine, especially in its high dose, antagonized most of the memory deficits produced by scopolamine while those of diazepam remained. This is a strong indication that scopolamine acts centrally through an anticholinergic mechanism while diazepam may act through a different system.

Adult↗

PubMed1976

Fear-dependent variations in continuous avoidance behavior of pigs. II. Effects of diazepam on acquisition and performance of Pavlovian fear conditioning and plasma corticosteroid levels.

Previously acquired continuous avoidance performance of pigs in a shuttle-box was modified by a Pavlovian fear-conditioning procedure. Diazepam (1 mg/kg) given before the Pavlovian conditioning session prevented the increase in corticosteroids and the impairment of performance in the subsequent test session before the presentation of the fear signal. Diazepam given before the Pavlovian conditioning session and/or the test session did not prevent the increase of response to the CS presentation; however, the temporal pattern of increase differed according to the drug condition: the diazepam treatment on the day of the test significantly delayed the peak of responding to the CS; in pigs treated with diazepam on the day of Pavlovian conditioning and with saline on the day of test, the increase of response was diffuse instead of being localized to the CS presentation period. Pigs treated with diazepam both during learning and performance of fear conditioning showed some evidence of performance facilitation. Usual unitary interpretations cannot account for such results which would appear to be the net result of several intermingled effects among which state-dependent learning, acquisition deficit, and performance facilitation seem to be of importance.

Adrenal Cortex Hormones↗

PubMed1984

High dose diazepam treatment and its effect on prolactin secretion in adolescent schizophrenic patients.

Thirteen acute schizophrenic patients aged 14-18 years were treated with gradually increasing doses of diazepam to a maximum of 100-400 mg/day/p.o. with a total duration of treatment of 4 weeks. The clinical antipsychotic effect was evaluated by the Brief Psychiatric Rating Scale (BPRS), while the impact on the hypothalamic hypophyseal pathway was evaluated by monitoring the serum prolactin levels (SPL) determined by a highly sensitive homologous radioimmunoassay (RIA). High diazepam doses (100-400 mg/day) caused sedation but no clinical antipsychotic effect was observed. Diazepam treatment with doses up to 250 mg/day caused no significant rise in SPL, while the treatment with doses of higher than 250 mg/day resulted in a mild but still significant increase in SPL. The clinical and laboratory data suggest that diazepam has no direct antidopaminergic activity. The mild hyperprolactinemia achieved with the extremely high doses of diazepam (greater than 250 mg/day) is possibly due to activation of the GABA system which stimulates prolactin release directly or by inhibiting the dopaminergic neurons or alternatively to activation of the endorphinergic system.

Adolescent↗

PubMed1982

Lack of evidence for a role of endorphinergic mechanisms in mediating a discriminative stimulus produced by diazepam in rats.

Male Sprague-Dawley rats were trained in a two-lever food-reinforced procedure to discriminate between the effect of saline and diazepam (2.5 mg/kg). After acquisition of this discrimination, the ability of morphine to generalize, and naloxone to antagonize the diazepam discriminative stimulus was tested. The rats did not generalize the effect of morphine, and naloxone did not antagonize the diazepam discriminative stimulus whether it was given prior or subsequent to diazepam. These data suggest a lack of involvement of endorphins in mediating the discriminative stimulus property of diazepam.

Animals↗

PubMed1975

Effects of diazepam on photosynthesis, respiration, rubidium uptake, and finestructure of Scenedesmus obliquus in synchronous cultures.

Effects of diazepam (Valium) on photosynthesis, chlorophyll/photosynthesis ratios, respiration, uptake of rubidium ions, and ultrastructure of Scenedesmus obliquus synchronized by a light-dark regimen of 14:10 hrs were determined. 80 and 160 muM diazepam, added to the nutrient medium at the start of the light-dark change (i.e., start of the cell cycle) gradually reduced rates of photosynthesis, below the initial rates from the beginning of the experiment. Contents of chlorophyll, however, remained nearly unaffected. Consequently, the diazepam-treated cells had a higher chlorophyll/photosynthesis ratio--also with regard to respiration in order to calculate the gross photosynthesis. The occurrence of photorespiration cannot be assumed. The net influx of rubidium was slightly reduced by 100 muM diazepam 0.5 and 2.0 hrs after the start of the cell cycle and was strongly inhibited after 5 to 14 hrs. 80 and 160 muM diazepam caused separation of thylakoids, formation of giant mitochondria and enlargement of vacuoles.

Adenosine Triphosphate↗

PubMed1981

Memory and performance effects of single and 3-week administration of diazepam.

The effects of diazepam of several cognitive and performance tasks were investigated in 30 healthy volunteers randomly assigned to three groups: A chronic group received diazepam for 21 days; an acute group received placebo during the same period, except at session 4 when they received diazepam; and a third group received placebo only at the sessions. Diazepam was given orally in a dose of about 0.2 mg/kg. Behavioral sessions were conducted before treatment (practice), after one administration (session 2), after 19 days (session 3), after 20 days (session 4), and 7 days following withdrawal (session 5). A single administration of diazepam produced significant memory impairment in both immediate and delayed free recall. Reduced memory performance was the result of impaired acquisition rather than reduced retention. Comparison of the chronic and acute groups in sessions 3 and 4 and analysis of the performance of the chronic group over sessions indicated the development of some tolerance to the memory impairment with continued administration. No residual memory effects were apparent following withdrawal. No other cognitive or psychomotor functions differed among the three treatment groups.

Diazepam↗

PubMed1985

Effects of diazepam and triazolam on auditory and visual thresholds and reaction times in the baboon.

Adult male baboons were trained on a psychophysical procedure that measured detection thresholds and reaction times for pure tone and white light stimuli. Intramuscular injections of diazepam or triazolam were given 30 min before session onset; stimulus intensity was randomly varied from trial to trial, and four to five estimates of sensory thresholds and reaction times were obtained throughout each session. Diazepam produced dose-related elevations of both auditory and visual thresholds and reaction times. Effects of a single high dose of diazepam were apparent 4-5 days after administration. Triazolam was approximately 100 times more potent than diazepam in elevating reaction times and visual thresholds, but did not elevate auditory thresholds. There were no residual effects of triazolam on the day after dosing. These results suggest that diazepam and triazolam produce qualitatively similar effects on basic psychophysical function, but that they can be differentiated on the basis of sensory modality changes and post-drug recovery time.

Animals↗

PubMed1982

Lack of central 5-hydroxytryptamine influence on the anticonflict activity of diazepam.

This study examined the effects of various drug treatments (IP injections) proposed to modify central 5-hydroxytryptamine (5-HT) activity on a conditioned suppression of drinking behavior in water-deprived rats. The subjects were trained to drink their daily water requirement during a 10-min session. Intermittent tone periods of 7 s were then introduced, the last 5 s of which the drinking tube was electrified. The animals gradually suppressed tube contacts during the tone to a low constant level within 2 weeks of training. Diazepam increased punished responding dramatically. The 5-HT antagonists methysergide (1 - 18 mg/kg), cyproheptadine (1 - 18 mg/kg), metergoline (0.25 - 2.0 mg/kg) and cinanserin (10 - mg/kg) failed to induce large, reliable increases in punished responding. When a low dose of diazepam was combined with 5-HT antagonists, only one treatment, methysergide at 3 mg/kg, potentiated the anticonflict activity of diazepam. Acute or chronic treatment with PCPA increased behavior suppressed by punishment, but this effect was weak, brief, and poorly related to the depletion of brain 5-HT. LSD (0.3 - 100 microgram/kg) administered 1, 10, or 30 min before the test was ineffective in overcoming suppression by punishment. Mescaline (6 - 30 mg/kg) had no significant effect on punished responding. 5-HTP (18 mg/kg) decreased the number of shocks accepted, but not after pretreating with carbidopa. Pretreatment with carbidopa plus 5-HTP potentiated the anticonflict effect of diazepam. The 5-HT agonist mCPP (0.25 - 2.0 mg/kg) enhanced suppression due to punishment, but only in doses that interfered with unpunished responding. The 5-HT-releasing agent fenfluramine (0.25 - 1.0 mg/kg) did not affect this behavior. Amitriptyline pretreatment in a dose not affecting unpunished behavior (5.6 mg/kg) potentiated the diazepam-induced increase in punished responding. These results are difficult to reconcile with the proposal that suppression of behavior consequent to punishment is related to brain 5-HT activity.

Animals↗

PubMed1981

Pre-exposure effects of morphine, diazepam and delta 9-THC on the formation of conditioned taste aversions.

Prior to taste aversion conditioning with morphine, diazepam or delta 9-tetrahydrocannabinol (delta 9-THC), rats received pre-exposures to the vehicle or one of the three drugs. Morphine pre-exposures blocked the aversion normally induced by morphine, but not by delta 9-THC or diazepam. Diazepam pre-exposures attenuated both the morphine- and diazepam-induced taste aversions to a significantly greater degree than the taste aversion induced by delta 9-THC. As a result of delta 9-THC pre-exposures, the aversions induced by diazepam and delta 9-THC were attenuated as well as the morphine-induced aversion, which was the most greatly attenuated. These results demonstrate that pre-exposure effects are not necessarily bi-directional and, moreover, they are inconsistent with current hypotheses which attempt to account for the attenuating effect of drug pre-exposures on taste-aversion conditioning.

Animals↗

PubMed1980

Effect of p-chlorophenylalanine on diazepam withdrawal signs in rats.

The effect of p-chlorophenylalanine (PCPA), a specific serotonin (5-HT) depleter, on diazepam withdrawal signs was studied. Rats were made dependent on diazepam by the chronic administration of this drug in the diet. At the time of diazepam withdrawal, the animals were treated with PCPA (200 mg/kg, IP) or the corresponding vehicle (control). After diazepam withdrawal, the maximal body weight losses of control and PCPA-treated animals were 4.1% and 9.0%, respectively. In naive animals, PCPA did not cause any change in body weight. These results suggest that depletion of central 5-HT by PCPA may potentiate the severity of diazepam withdrawal signs.

Animals↗