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At least 973 records · Page 54Linked to original sources

PubMed1994

Quantification of the depressive effects of diazepam on the guinea pig righting reflex.

The effects of 5 mg/kg/day diazepam (IP for 21-39 days) on righting reflex latency (RRL) and neuronal activity in the medial vestibular nucleus (MVN) were investigated in guinea pigs. Diazepam treatment increased the RRL relative to vehicle-injected controls (p < 0.05, ANOVA); although the average RRL in the diazepam-treated animals did decrease over time, this decrease was not statistically significant and therefore evidence of tolerance was not obtained. MVN slices were removed from diazepam-treated animals and recordings were made from MVN neurons in vitro. The average resting activities for MVN neurons in slices from diazepam-treated animals and uninjected animals from a previous study were not significantly different.

Animals↗

PubMed1995

Relationship between histamine receptors in the brain and diazepam-induced hyperphagia in rats.

We investigated whether histaminergic neurons in the brain are involved in diazepam-induced hyperphagia in rats. Pretreatment with intracerebroventricular (ICV) injection of either histamine H1-receptor antagonist, pyrilamine (10 and 30 micrograms) or histamine H2-receptor antagonist, famotidine (3 and 10 micrograms) did not affect only diazepam (1 mg/kg, subcutaneous, SC)-induced hyperphagia in nondeprived rats, but also spontaneous feeding in food-deprived rats. In addition, pretreatment with ICV injection of histamine H3-receptor antagonist, thioperamide, and histamine H3-receptor agonist, (R) alpha methylhistamine, enhanced and inhibited diazepam-induced hyperphagia (1 mg/kg, SC) in nondeprived rats, respectively. However, thioperamide and (R) alpha methylhistamine did not affect spontaneous feeding in food-deprived rats. These findings suggest that histaminergic neurons are not directly involved in diazepam-induced hyperphagia in rats. Furthermore, enhancement or inhibition of diazepam-induced hyperphagia by histamine H3-receptor antagonist or agonist may occur via histamine H3-receptors localized in the other neurons in the rat brain.

Animals↗

PubMed1996

Diazepam modulates the period of locomotor rhythm in mice (Mus booduga) and attenuates light-induced phase advances.

Experiments were carried out on the continuous action of diazepam (benzodiazepine) offered through drinking water in 2% ethanol on psi and tau of the activity rhythms under LD (12:12) and DD conditions. Under entraining conditions diazepam failed to evoke striking changes in psi. On the other hand, under free-running conditions period-lengthening and period-shortening effects were observed. Further experiments conducted on the continuous effect of diazepam on light pulse evoked phase shifts revealed that phase advances were attenuated significantly in diazepam-treated animals at CT 20 and 24. These results were discussed with regard to the action of diazepam on the light sensitivity of the circadian pacemaker.

Animals↗

PubMed1996

"Anxiolytic" action of diazepam and abecarnil in a modified open field test.

The effects of acutely administered diazepam and the beta-carboline abecarnil were examined in two animal models of anxiety in rats, and for their effects on food intake and locomotor activity. In the elevated x-maze diazepam (0.6-2.5 mg/kg) and abecarnil (0.03-0.3 mg/kg) induced anxiolytic-like effects. The second paradigm is based upon the suppression of feeding by exposure to a novel environment, adapted from Bodnoff et al. (1989). Food-deprived rats were placed in a corner of the open field containing food in the centre. The number of rats beginning to eat in the first 5 min was recorded. Diazepam (2.5-5.0 mg/kg) and abecarnil (0.01-0.3 mg/kg) increased the number of rats eating. Flumazenil, the benzodiazepine antagonist, was without effect, but antagonised the effects of diazepam and abecarnil. In a seperate series of experiments the effects of diazepam and abecarnil on feeding and locomotor activity were excluded as having influenced the the anxiolytic effects of these compounds in the animal models of anxiety.

Animals↗

PubMedDate not supplied

Interactions between angiotensin II, GABA and diazepam in convulsive seizures.

In experiments on male mice, we studied the effects of gamma-aminobutyric acid (GABA), angiotensin II (AT II), administered intracerebroventricularly, diazepam, injected intraperitoneally, and combinations of GABA + AT II and diazepam + AT II on convulsive seizures induced by pentylenetetrazol (PTZ) (80 mg/kg subcutaneously) and 3-mercaptopropionic acid (3-MPA) (40 mg/kg intraperitoneally). The anticonvulsant effects of GABA and diazepam on PTZ-induced seizures were increased by AT II in doses which did not significantly influence seizures. AT II applied together with GABA or diazepam in ineffective doses provoked a strong anticonvulsant effect on both PTZ- and 3-MPA-induced seizures. These results indicate that the anticonvulsant effects of GABA and diazepam on PTZ- and 3-MPA-induced seizures might effectively be potentiated by the octapeptide AT II. It is suggested that AT II operates as an endocoid acting on GABA, respectively benzodiazepine recognition sites in the CNS.

3-Mercaptopropionic Acid↗

PubMed1983

Structure-activity relationships in kynurenine, diazepam and some putative endogenous ligands of the benzodiazepine receptors.

Kynurenine, an endogenous cerebral and peripheral neuroactive metabolite of 1-tryptophan, exerts stimulant and convulsant effects in mice, rats and frogs. In mice it (intracerebroventricularly, ICV) antagonized the anticaffeine effect of diazepam and in smaller doses potentiated its sedative action. In rats 1-kynurenine (ICV) potentiated the convulsant action of caffeine. The effect of pentylenetetrazol was not altered in either species. The convulsant effect of 1-kynurenine is the most resistant among various convulsants towards the protective action of diazepam. The structure of 1-kynurenine is similar to benzophenones, metabolites of diazepam, and has four structural fragments common with diazepam. Putative endogenous and non-endogenous ligands of the benzodiazepine receptors have from one to three of these common fragments. Among the antagonists of diazepam exhibiting stimulant and convulsant action ethyl-beta-carboline-3-carboxylate has the same four fragments, Ro 5-3663 and Ro 15-1788 have three and caffeine two. The most striking dissimilarity is a diazo-moiety (N-C-C-N or N-C=C-C=N) absent in the structure of 1-kynurenine. This moiety seems to be the most important for the binding to the benzodiazepine receptors. A role of each fragment and their combinations as well as the stereoconfiguration for the pharmacological activity is considered. It is suggested that 1-kynurenine is a putative endogenous modulator or, less probably, ligand of the benzodiazepine receptor of either type (most probably that which mediates anxiolytic action of benzodiazepines) or a part of this receptor. The benzodiazepine receptor might be a phylogenetically transformed kynurenine receptor. Highly selective antagonism of purines to 1-kynurenine suggests that it can modulate the function of the benzodiazepine receptors via purinergic mechanisms. Stimulant and convulsant action of 1-kynurenine can be related to a moiety of succinic acid (O=C-C-C-C=O) which is typical of quinolinic acid, the strongest endogenous convulsant among kynurenines, and aspartic acid, an excitatory amino acid. 1-Kynurenine is suggested to be an anxiogenic and convulsigenic endogenous factor.

Animals↗

PubMed1996

Social isolation increases aggressive behaviour and alters the effects of diazepam in the rat social interaction test.

Isolation rearing in the early stages of life has been shown to modify a variety of behaviours in many animals and the responsitivity to psychotropic drugs. The aims of the present study were to investigate the effects of isolation rearing on anxiety using the social interaction paradigm and to compare the effects of diazepam on social interaction behaviours in isolation and socially reared rats. Male Lister hooded rats were reared from weaning either alone (isolation reared) or in groups of four (socially reared) for 6 weeks and then were tested for social interaction. Both isolation and socially reared rats were exposed to the social interaction test either without drug treatment or following saline or diazepam (1 and 2.5 mg/kg, i.p., 30 min before testing). The results demonstrate that under high light in an unfamiliar arena, the isolation compared to the socially reared rats showed a significantly (P < 0.01) higher level of social interaction, manifested as increases in aggressive and avoidance behaviours, and that this interaction occur for a greater length of time during the test period (10 min). However, when the light level was decreased or when the arena was familiar, active social interaction of isolation reared rats decreased but increased in the socially reared rats. In both conditions the isolation reared rats displayed more aggressive behaviours, in particular biting and boxing the partners which did not occur with the socially reared rats. Pretreatment of diazepam (1 and 2.5 mg/kg., i.p.) caused a dose-related reduction in aggressive behaviours in rats reared under both conditions but increased passive interactions in the socially reared rats. In contrast diazepam (2.5 mg/kg) reduced active interaction in the isolation reared rats but had no effect on passive interaction. These results indicate that isolation rearing increases aggressive behaviours and alters the effects of diazepam.

Aggression↗

PubMed1987

The effect of diazepam and Ro 15-1788 on extracellular ascorbic acid, DOPAC and 5-HIAA in the striatum of anaesthetized and conscious freely moving rats, as measured by differential pulse voltammetry.

The effects of diazepam (10 mg/kg i.p.) and the central benzodiazepine receptor antagonist, Ro 15-1788 (30 mg/kg i.p.), on extracellular ascorbate, 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindoleacetic acid (5-HIAA) were examined using differential pulse voltammetry in anaesthetized and freely moving rats. In anaesthetized animals, diazepam did not significantly alter the heights of peak 1 (ascorbate) or peak 3 (5-HIAA), but significantly reduced that of peak 2 (DOPAC). In freely moving rats, diazepam greatly reduced the heights of all 3 peaks. Ro 15-1788, injected 2 h after diazepam, reversed the effect of diazepam on peak 3, but not on peaks 1 and 2.

3,4-Dihydroxyphenylacetic Acid↗

PubMedDate not supplied

Impaired host resistance to Trichinella spiralis as a consequence of prenatal treatment of rats with diazepam.

In utero exposure of Long Evans rats to low dosages of diazepam has previously been found to result in depression of cellular and humoral immune responses until adulthood, with marked changes in cytokine release by splenocytes and splenic macrophages. In order to assess the significance of these alterations in immune cells with regard to host resistance, we investigated the resistance of adult offspring towards Trichinella spiralis. Time-pregnant rats were treated with diazepam (1.25 mg/kg/day) or vehicle from gestational day 14 to 20. Male offspring were infected with T. spiralis at 2 months of age. This infection model tests the participation of T- and B-cell populations and of macrophages. Prenatally diazepam-exposed animals exhibited an impaired defence towards T. spiralis. The number of muscle larvae was increased as determined in digested carcasses and by morphometric analysis of the tongue. Moreover, antibody titers were altered, i.e., IgG was decreased and IgA was elevated in the prenatally diazepam-exposed group. These results demonstrate an impaired defense towards T. spiralis in adult rats after prenatal exposure to diazepam.

Animals↗

PubMed1980

The influence of diazepam on the activity of secondary vestibular neurons in the rabbit.

We have studied the influence of intravenously administered diazepam on the activity of single secondary vestibular neurons in unanesthetized, paralyzed rabbits evoked by sinusoidal angular accelerations about the vertical and longitudinal axes. Intravenous injections of diazepam (20-100 micrograms/kg) caused a decreased sensitivity of all secondary vestibular neurons which were tested. The reduction in sensitivity was sometimes preceded by a transient increase in excitability which lasted 10-40 sec. The duration of the decreased sensitivity to vestibular stimulation following intravenous injections of diazepam was dose-dependent, lasting 15-60 min. These data suggest that the diazepam-induced reduction of vestibuloocular reflexes is caused, at least in part, by the depressant action of diazepam upon secondary vestibular neurons.

Animals↗

PubMed1988

The abstinence syndrome in diazepam-dependent cats is precipitated by Ro 15-1788 and Ro 15-4513 but not by the benzodiazepine receptor antagonist ZK 93426.

Diazepam-dependent cats were challenged with different benzodiazepine recognition site ligands 24 h after the last dose of chronic treatment with diazepam (7 mg/kg, i.p. at 08.00 and 20.00 h, for 21 consecutive days). The benzodiazepine derivatives Ro 15-4513 (a partial inverse agonist) and Ro 15-1788 (a pure antagonist), precipitated an abstinence syndrome within minutes after i.p. administration. Abstinence signs included tremors, increased muscle tone, irritability, fear, pupillary dilation and vocalizations. On the contrary, the beta-carboline derivatives ZK 93426 (an antagonist) and FG 7142 (a partial inverse agonist) failed to precipitate abstinence signs in diazepam-dependent cats when given at doses that prevented the acute effects of diazepam. Our results demonstrate that the ability to induce withdrawal signs in diazepam-dependent cats strongly depends on the benzodiazepine structure of the challenge drug since beta-carboline antagonist and partial inverse agonists lack this property.

Animals↗

PubMed1990

Diazepam enhances bicuculline-induced increase of t-[35S]butylbicyclophosphorothionate binding in unwashed membrane preparations from rat cerebral cortex.

The effect of diazepam on t-[35S]butylbicyclophosphorothionate ([35S]TBPS) binding to membrane preparations from rat cerebral cortex was examined in the presence or absence of GABA. The in vitro addition of diazepam to unwashed membranes preparations (rich in endogenous GABA) decreased [35S]TBPS binding by 41%. On the contrary, diazepam produced an opposite effect (+28%) when GABA had been removed by extensive washes of membranes. Moreover, diazepam increased by 26% [35S]TBPS binding also in unwashed membrane preparations previously incubated with bicuculline. These results suggest that, in absence of gamma-aminobutyric acid (GABA), diazepam may have a paradoxical negative modulatory action on the function of the GABAA receptor-coupled chloride channels.

Animals↗

PubMed1982

Comparison of growth hormone stimulation induced by desimipramine, diazepam and metaclazepam in man.

A comparison of the effect on growth hormone (GH) stimulation in men (n = 6) of desimipramine (DMI), a tricyclic antidepressant, and of the benzodiazepine derivatives diazepam and metaclazepam with that of a placebo, showed that only DMI caused a significant (p less than 0.01) GH stimulation. After DMI, all six subjects showed a GH stimulation greater than 7.5 ng/ml, whereas after diazepam or metaclazepam, only three of the six subjects showed GH stimulation greater than 7.5 ng/ml, and the other three showed only a very small change, or no change at all in GH secretion. Higher GH stimulation occurred after diazepam (10 mg i.v.) than after diazepam (10 mg p.o.). No dose-dependent difference in GH stimulation after metaclazepam (10 and 30 mg p.o.) was apparent. No side effects appeared after administration of DMI during the test period (180 min); however, after administration of the benzodiazepine derivatives, sedative effects were clearly noted. DMI thus causes reliable GH stimulation in healthy male subjects, whereas GH stimulation could only be measured in some of the subjects after diazepam and metaclazepam.

Adult↗

PubMed1981

Diazepam use among methadone maintenance patients: patterns and dosages.

Methadone maintenance patients who use benzodiazepine drugs were interviewed about the dosage levels, patterns, frequency and motives for their use of these drugs. The sample was drawn from two treatment clinics, one in Baltimore (N = 12) and one in Philadelphia (N = 17). Benzodiazepine use was prevalent at both of these clinics - 65 -70% of maintenance patients had positive urinalysis tests during a single month. Ninety-three per cent of survey participants identified diazepam as the drug which they used most often. The median value of the usual daily dose was 40 - 45 mg; 31% reported usual daily doses between 70 and 300 mg and 62% had experience with doses of 100 mg and higher. The majority of the sample reported taking diazepam in a single daily dose within one hour of the time that they ingested their daily methadone; 72% of the sample indicated that diazepam boosts the effects obtained from the daily methadone dose. Another sample of addicts who reported extensive experience with both benzodiazepines and barbiturates indicated that diazepam increases the effects of methadone while barbiturates produce no change in the effects of methadone. Results of this study suggest that patterns and dosages of diazepam use among methadone maintenance patients are primarily abusive rather than therapeutic.

Adult↗

PubMed1986

Benzodiazepine antagonist, CGS-8216, in diazepam- or pentobarbital-dependent and non-dependent rats.

CGS-8216, a benzodiazepine antagonist, was administered to rats acutely dosed with diazepam, and to rats chronically dosed with diazepam or pentobarbital. The effects of an acute dose of diazepam were antagonized by CGS-8216 but signs of precipitated abstinence were not observed. An apparent arousing effect was seen in non-dependent rats when CGS-8216 was administered after placebo, but no arousal was observed when Ro15-1788 was administered after placebo in non-dependent rats. A precipitated abstinence syndrome was elicited with CGS-8216 in rats chronically dosed with diazepam and was very similar to the abstinence syndrome precipitated by Ro15-1788 in diazepam-dependent rats. Like Ro15-1788, CGS-8216 elevated Precipitated Abstinence Scale (PAS) scores in a dose-related manner until a plateau was reached with 5 mg/kg. No signs of precipitated abstinence were observed when CGS-8216 was administered to rats dependent on phenobarbital.

Animals↗

PubMed1988

Relative abuse liability of lorazepam and diazepam: an evaluation in 'recreational' drug users.

The subjective, psychomotor and cognitive effects of oral doses of lorazepam (0, 1.5, 3 and 6 mg) and diazepam (0, 10, 20 and 40 mg) were studied under double-blind conditions in 14 volunteers with histories of 'recreational' benzodiazepine use/abuse. For each subject, drug was administered over 4 test days in a 2 (drug) by 4 (dose level) mixed design. Drug was the between-groups factor while dose was the within-subjects factor. Test days were separated by at least 1 week. The results showed that subjective ratings of drug 'liking' and the psychomotor and cognitive effects of lorazepam were generally similar to those of diazepam over the range of doses studied. Lorazepam, however, tended to produce effects of longer duration than diazepam. Since previous studies have shown that diazepam has a relatively high abuse liability among the benzodiazepines, the present findings suggest that lorazepam shares this property with diazepam is subjects with a history of 'recreational' drug use/abuse.

Adult↗

PubMed1991

Chronic administration of and dependence on halazepam, diazepam, and nordiazepam in the dog.

Halazepam administered chronically to dogs in oral doses of 180 and 450 mg/kg/day produced physical dependence which was revealed by a flumazenil precipitated abstinence syndrome and measured by the Nordiazepam Precipitated Abstinence Scale score (NPAS) (McNicholas et al., 1988; Sloan et al., 1990). This abstinence as measured by the NPAS score was more severe in diazepam- and halazepam-dependent than in nordiazepam-dependent dogs whereas the incidence of precipitated clonic seizures was greater in the diazepam- and nordiazepam-dependent than in the halazepam-dependent dogs. Pharmacokinetic studies showed that in the dog the major conversion of halazepam, like diazepam, was to nordiazepam and an oxazepam conjugate. Appreciable quantities of oxazepam, 3-OH halazepam and its conjugated metabolite were also identified in plasma. The NPAS score obtained in the halazepam-dependent dogs, however, was greater than the NPAS score obtained in nordiazepam-dependent dogs who had nordiazepam plasma levels over three times higher than those obtained in the halazepam-dependent dogs. Further, the precipitated abstinence observed in the halazepam-, diazepam- and nordiazepam-dependent dogs differed in qualitative as well as in quantitative aspects including marked differences in the time course of abstinence signs. These data argue that the different dependencies produced by halazepam, diazepam and nordiazepam are not due solely to either the parent compound or to a single metabolite but most likely to their combined effects.

Administration, Oral↗

PubMed1987

Determination of diazepam and its metabolites by high-performance liquid chromatography and thin-layer chromatography.

A sensitive, simple high-performance liquid chromatographic assay, capable of simultaneously measuring diazepam, its active metabolites oxazepam, temazepam and N-desmethyldiazepam and two phenyl hydroxylated metabolites, 4'-hydroxy-N-desmethyldiazepam and 4'-hydroxydiazepam, is described. The assay is easily modified to include separation of additional metabolite(s), e.g. oxazepam glucuronide(s). A thin-layer chromatographic assay, which resolves diazepam, the active metabolites and the two phenyl hydroxylated derivatives in one solvent system, is also reported. Application of these procedures to the quantitation of diazepam and its metabolites was shown, after delivery of diazepam (5 micrograms/ml or 16 microM) at a constant flow-rate (10 ml/min per liver) through the single-pass perfused rat liver preparation. Blood perfusion medium and bile were analysed for parent drug and metabolites before and after enzyme hydrolysis. These assay methods are found to be particularly pertinent and useful in providing a more comprehensive metabolic profile of diazepam metabolism, especially when aromatic hydroxylation pathways predominate.

Animals↗