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PubMed1989

Involvement of GABAA receptor sites in diazepam hypothermia.

1. Intraperitoneal (i.p.) injection of diazepam (1.5-6 mg/kg) decreased the core body temperature (BT) of the rats. The effect was dose-dependent. 2. The hypothermia produced by diazepam (6 mg/kg, i.p.) was decreased in animals pretreated with high doses of bicuculline (BIC, 3 mg/kg, i.p.), while low doses of BIC (1.5 mg/kg, i.p.) potentiated the hypothermia. 3. Picrotoxin (PIC, 1 and 2 mg/kg, i.p.) pretreatment also decreased the hypothermic effect of diazepam. 4. Pretreatment of animals with atropine (AT, 10 mg/kg, i.p.) or propranolol (PRO, 10 mg/kg, i.p.) potentiated the hypothermic response of diazepam. Phenoxybenzamine (PHEN, 0.5 mg/kg, i.p.), methergoline (METH, 0.5 mg/kg, i.p.) or pimozide (PIM, 0.5 mg/kg, i.p.) did not change the diazepam hypothermia. 5. Single administration of BIC, PIC, PRO, PIM or METH also induced hypothermia. 6. One can postulate that diazepam hypothermia may be induced through GABAA receptor sites. However, further studies will clarify this hypothesis.

Adrenergic alpha-Antagonists↗
PubMed1995

Increased dopamine and norepinephrine release in medial prefrontal cortex induced by acute and chronic stress: effects of diazepam.

We have examined the effects of diazepam on the stress-induced increase in extracellular dopamine and norepinephrine in the medial prefrontal cortex using in vivo microdialysis. In naive rats, acute tail pressure (30 min) elicited an increase in the concentrations of dopamine and norepinephrine in extracellular fluid of medial prefrontal cortex (+54 and +50%, respectively). Diazepam (2.5 mg/kg, i.p.) decreased the basal concentration of extracellular dopamine and norepinephrine. Diazepam also attenuated the stress-evoked increase in the absolute concentrations of extracellular dopamine (+17%), but did not alter the stress-induced increase in norepinephrine (+41%). However, when the drug-induced decrease in basal dopamine and norepinephrine concentration was taken into account, the stress-induced net increase in dopamine above the new baseline was equivalent to that obtained in vehicle pretreated rats, whereas the net increase in norepinephrine was almost twice that obtained in control subjects. In rats previously exposed to chronic cold (three to four weeks at 5 degrees C), tail pressure again produced an increase in the concentrations of dopamine and norepinephrine in the medial prefrontal cortex (+42% and +92%, respectively). However, in these chronically stressed rats, diazepam no longer decreased basal dopamine or norepinephrine in extracellular fluid, nor did it affect the stress-induced increase in the concentrations of these catecholamines. These data indicate that diazepam has complex effects on the extracellular concentrations of dopamine and norepinephrine which vary depending upon whether the rat is undisturbed or stressed during the period of drug exposure as well as the rat's prior history of exposure to stress. Moreover, these data raise questions regarding the role of catecholamines in the mechanism by which diazepam exerts its anxiolytic properties.

3,4-Dihydroxyphenylacetic Acid↗
PubMedDate not supplied

Diazepam and caffeine administration during the first week of life: changes in neonatal and adolescent behavior.

The male offspring of hooded Lister rats were fostered at birth into 23 experimental litters. One pup in each litter was allocated to each of the following treatment groups: vehicle control; caffeine (15 or 30 mg/kg); diazepam (10 mg/kg, alone or plus caffeine 15 or 30 mg/kg). Pups were given daily injections on neonatal days 1-7 and were observed for 15 min following each injection. Diazepam significantly increased paddling and forward walking, particularly on days 5 and 7; caffeine also increased these behaviors, but less markedly. Diazepam increased the incidence of clonic jerks, particularly on day 7 and increased the spontaneous loss of righting reflex. The pups were then left undisturbed until weaning at day 21 and testing from days 35-42. There were no lasting effects of the neonatal treatments in two tests of anxiety, or in passive avoidance performance. Rats that had been treated neonatally with diazepam had significantly lower motor activity scores and reared less in the holeboard than did controls, and neonatal treatment with caffeine also resulted in lower motor activity scores. Neonatal treatment with caffeine made rats more aggressive (increased kicking and pushing) when they were intruding into another rat's territory. Neonatal treatment with diazepam increased aggression in resident rats, and this was counteracted by neonatal treatment with caffeine. Neonatal caffeine treatment enhanced rats' unconditioned preference for the black chamber in a black-white preference test and neonatal diazepam treatment reduced it.

Aggression↗
PubMed1990

Anticonvulsant effects of diazepam and MK-801 in soman poisoning.

An animal model was developed to evaluate the anticonvulsant effects of diazepam and MK-801 in soman poisoning and to examine the possible mechanism of soman-induced convulsions. The oxime HI-6 (125 mg/kg, i.p.) was given to male rats, to increase survival, 30 min prior to 180 micrograms/kg, s.c. (equivalent to 1.6 x LD50) of soman, which produced 100% occurrence of convulsions. Initially, diazepam was studied with or without the concomitant administration of various doses of atropine sulfate 30 min prior to soman challenge. Diazepam (1.25-10.0 mg/kg, i.m.) alone did not prevent soman-induced convulsions. In the presence of 2, 4, 8, and 16 mg/kg of atropine, the anticonvulsant ED50 doses of diazepam were 0.490, 0.257, 0.132 and 0.136 mg/kg, respectively. Atropine sulfate at a dose of 16 mg/kg prevented the soman-induced hypersecretion, showed some anticonvulsant activity and provided a good motor recovery. MK-801 by itself, at or above 1 mg/kg, prevented convulsions, but markedly potentiated the lethal effects produced by soman. With atropine (16 mg/kg), the anticonvulsant ED50 for MK-801 was 0.037 mg/kg, which indicated that MK-801 was about 4 times as potent as diazepam, and the lethal interactions between MK-801 and soman were suppressed. The findings indicate that, in soman poisoning, diazepam and MK-801 are effective anticonvulsants in the presence of the anticholinergic atropine sulfate. The possible sequence of events and neuropharmacological mechanism of soman-induced convulsions are discussed.

Animals↗
PubMed1993

Triazolam is more efficacious than diazepam in a broad spectrum of recombinant GABAA receptors.

Benzodiazepine-induced modifications of GABA (gamma-aminobutyric acid) activated Cl- currents were studied in native GABAA receptors expressed in neonatal rat brain cortical neurons in primary cultures and in recombinant GABAA receptors expressed in transformed human embryonic kidney cells (293) after a transient transfection with cDNAs encoding for different molecular forms of alpha, beta, and gamma subunits of GABAA receptors. The efficacy of triazolam in cortical neurons was higher than that of diazepam. In transfected cells, triazolam showed a greater efficacy as a positive modulator of GABA-elicited Cl- currents in alpha 1 beta 1 gamma 1, alpha 1 beta 1 gamma 2, alpha 1 beta 1 gamma 3, alpha 6 beta 1 gamma 2 and alpha 1 beta 3 gamma 2 receptors than diazepam, except in alpha 3 beta 1 gamma 2 receptors where diazepam was more efficacious. When triazolam and diazepam were applied together to GABAA receptors assembled by transfecting cDNAs encoding for alpha 1 beta 1 gamma 1 subunits, the action of triazolam was curtailed in a manner related to the dose of diazepam. In recombinant receptors assembled with alpha 1 beta 1 gamma 1 receptors, maximally active doses of triazolam were more efficacious than those of clonazepam, alpidem, zolpidem, diazepam or bretazenil.

Animals↗
PubMed1993

Improvement by diazepam of neuromuscular transmission blocked by anticholinesterase agents in mouse diaphragms.

Effects of diazepam on the neuromuscular transmission blocked by neostigmine were studied in isolated mouse phrenic nerve-diaphragm preparations. Diazepam, in the absence of neostigmine, had no significant effect on the neuromuscular transmission at concentrations lower than 100 microM, except to enhance muscle contractility. Single and train pulses-evoked endplate potentials (e.p.p.s) and miniature e.p.p.s (m.e.p.p.s) were also unaffected. At concentrations of 175 microM or higher, diazepam caused an axonal conduction block. However, neostigmine-induced twitch potentiation, spontaneous fasciculation and tetanic fade were antagonized by diazepam at 3.5-35 microM. Diazepam did not decrease the amplitude of neostigmine-augmented e.p.p.s and m.e.p.p.s but slightly reduced their decay time. The incidence of regenerative depolarization of endplates induced by repetitive stimulation in the presence of neostigmine, was decreased from 92% to 35% junctions and the duration shortened from 650 ms to 230 ms. The amplitude of train e.p.p.s was increased. It is suggested that diazepam reverses the muscle paralysis induced by anticholinesterase agents by inhibiting the regenerative release of acetylcholine.

Animals↗
PubMed1993

Diazepam's effect on systemic vascular resistance during cardiopulmonary bypass is not caused by its vehicle (alcohol-propylene glycol).

Control of hemodynamic parameters during cardiopulmonary bypass (CPB) is a desirable goal of the anesthesiologist. Diazepam is known to reduce systemic vascular resistance (SVR) during CPB. This study tested the hypothesis that diazepam reduces SVR during CPB through the action of its vehicle, alcohol-propylene glycol (APG). The study protocol was approved by the Institution's Human Experimentation Review Board and all patients gave informed consent. Premedication, induction, and maintenance of anesthesia were standardized. Thirty consecutive patients undergoing nonemergent cardiac surgical procedures were randomized to receive a standardized amount of diazepam, diazemuls, or alcohol-propylene glycol during stable CPB. SVR in the diazepam group decreased significantly (1,242 to 968 dyne.s.cm-5, P < 0.05) compared to baseline; whereas there was no significant change in SVR in the diazemul group, and a statistically significant increase in SVR (1,217 to 1,537 dyne.s.cm-5, P < 0.05) in the APG group. It is concluded that diazepam reduces SVR during CPB. Diazepam's vehicle does not reduce SVR during CPB, and is in fact associated with an increase in SVR.

Aged↗
PubMed2006

Baclofen in the treatment of alcohol withdrawal syndrome: a comparative study vs diazepam.

PURPOSE: Benzodiazepines are the drugs of choice in the treatment of alcohol withdrawal syndrome (AWS). Recent data have shown that baclofen may reduce AWS symptoms. At present, no comparative studies between baclofen and any benzodiazepine used in AWS treatment are available. Accordingly, the present study was designed to compare efficacy, tolerability and safety of baclofen versus diazepam in the treatment of AWS. SUBJECTS AND METHODS: Thirty-seven patients with AWS were enrolled in the study and randomly divided into 2 groups. Baclofen (30 mg/day for 10 consecutive days) was orally administered to 18 patients (15 males, 3 females; median age: 46.5 years). Diazepam (0.5-0.75 mg/kg/day for 6 consecutive days, tapering the dose by 25% daily from day 7 to day 10) was orally administered to 19 patients (17 men, 2 women; median age: 42.0 years). The Clinical Institute Withdrawal Assessment (CIWA-Ar) was used to evaluate physical symptoms of AWS. RESULTS: Both baclofen and diazepam significantly decreased CIWA-Ar score, without significant differences between the 2 treatments. When CIWA-Ar subscales for sweating, tremors, anxiety and agitation were evaluated singly, treatment with baclofen and diazepam resulted in a significant decrease in sweating, tremors and anxiety score, without significant differences between the 2 drug treatments. Both treatments decreased the agitation score, although diazepam was slightly more rapid than baclofen. CONCLUSION: The efficacy of baclofen in treatment of uncomplicated AWS is comparable to that of the "gold standard" diazepam. These results suggest that baclofen may be considered as a new drug for treatment of uncomplicated AWS.

Adult↗
PubMed2004

Effects of modulators of N-methyl-D-aspartate receptor-mediated neurotransmission on diazepam discrimination in rats.

N-methyl-D-aspartate (NMDA) antagonists share a number of pharmacological effects with GABA(A) agonists, including anxiolytic and anticonvulsant effects. This study evaluated the effects of site-selective NMDA antagonists in rats trained to discriminate the benzodiazepine diazepam from vehicle. As expected, diazepam produced robust discriminative stimulus effects and dose-dependently substituted for the training dose. Mixed results were obtained with competitive NMDA antagonists: whereas NPC 17742 partially substituted for diazepam, SDZ EAA 494 did not elicit responding on the diazepam-associated lever. Other site-selective NMDA antagonists, including the open channel blocker phencyclidine, the glycine-site antagonists ACEA 1021 and MDL 102,288, the polyamine-site antagonist arcaine, and the glutamate release inhibitor riluzole, failed to substitute for diazepam. Agonists at nonbenzodiazepine sites of the GABA(A) receptor complex were also tested for comparison purposes. The barbiturate pentobarbital and the neurosteroid Co 2-1068 partially substituted for diazepam. In contrast, the anticonvulsant carbamazepine failed to substitute even at a dose that substantially reduced response rates. These results suggest that substitution of NMDA antagonists for GABA(A) agonists is dependent upon the site at which the NMDA antagonist binds. Further, they suggest that similarities between the stimulus properties of GABA(A) agonists and NMDA antagonists are at least as strong as similarities among agonists acting at different sites on GABA(A) receptors.

Amino Acids↗
PubMed2004

Diazepam reduces brain lesion size in a photothrombotic model of focal ischemia in rats.

The neuroprotective effect of diazepam has been demonstrated in global ischemia models in vivo and in vitro [Neuroscience (2000) 471]. We studied the effect of diazepam on lesion volume in a photothrombotic model of focal brain ischemia in the rat, and the relation of such effect to time of drug administration. For this purpose we induced photochemically a focal brain lesion, and added diazepam 10 mg/kg intraperitoneally just before, at 1 and 4 h after lesion induction. After 24 h the rats were decapitated, and lesion volumes of 27 diazepam-treated rats were compared with that of 12 controls. Treated animals had a significant smaller lesion volume than controls, except those who received diazepam before induction of the lesion. We conclude that diazepam is neuroprotective in focal brain ischemia even when administered up to 4 h after ischemia onset.

Animals↗
PubMed2004

Anxiolytic effects of diazepam and ethanol in two behavioral models: comparison of males and females.

The present study compared the anxiolytic effects of the benzodiazepine agonist diazepam and ethanol in adult male and female rats. Varying doses of diazepam (1-3 mg/kg) or ethanol (0.5-2.0 g/kg) were tested using both the elevated plus maze and defensive prod-burying models. Two time points following ethanol administration (10 and 30 min) were tested in the plus maze. Sex differences were seen in some anxiety-related behaviors, with females showing greater open arm time and reduced burying behavior than males. Although this suggests females displayed less anxiety-like behavior than males, the differences in the plus maze were not observed in all testing situations. Both diazepam and ethanol dose-dependently increased open arm times in the plus maze and reduced burying behavior in the defensive prod-burying task. The parallel nature of the dose-response curves suggests that both diazepam and ethanol have similar anxiolytic effects in males and females. No sex differences were seen in the brain levels of diazepam-like activity or blood alcohol levels with these treatments. A greater corticosterone response was observed in females than males with these two behavioral tests, but neither diazepam nor ethanol decreased this response. These results suggest a dissociation between the anxiety-reducing influences of these compounds and the changes in stress-related endocrine responses.

Animals↗
PubMed2004

Prevention of diazepam withdrawal syndrome by nifedipine-behavioural and neurochemical studies.

Our studies aimed at investigating whether the dihydropyridine calcium antagonist, nifedipine, could prevent anxiogenic-like consequences of diazepam withdrawal in rats. Animals withdrawn from chronic diazepam (2 mg/kg/day i.p. for 2 weeks) drank significantly less water than did control rats in the unfamiliar arm of a Y maze. This anxiogenic-like effect could be prevented by acute administration of nifedipine (at 10 mg/kg i.p., but not at lower doses), which, on its own, did not change water intake in naive rats. Given chronically in combination with diazepam for the second half of a 2-week treatment with this drug, nifedipine (at the daily dose of 5 mg/kg i.p.) also suppressed the reduction of water intake normally observed on diazepam withdrawal. Biochemical measurements showed that acutely, as well as chronically, administered nifedipine increased 5-HT turnover in the hippocampus of diazepam-treated rats, thereby suggesting that the prevention of diazepam withdrawal-induced anxiogenic behaviour by the calcium antagonist might be underlain by serotoninergic mechanisms.

Animals↗
PubMed2005

Rectal diazepam gel in the home management of seizures in children.

This study assessed the utility of rectal diazepam gel in the home management of prolonged or repetitive seizures in children. Thirty-eight children being prescribed rectal diazepam gel by their clinician were prospectively recruited. Seizures, rectal diazepam use, emergency department visits, and quality of life data before and after study entry were recorded. The 38 children included 14 (37%) with complex febrile seizures, and 24 with epilepsy (n = 22) or a single seizure (n = 2). There were 23 (61%) children with prolonged seizures and 15 (39%) with repetitive seizures. During the 6-month follow-up period, 12 children experienced 26 seizures which met the criteria for rectal diazepam administration. Rectal diazepam gel was administered to 8 children on 19 occasions. In 16 (84%) of these episodes, seizures stopped and no emergency department visit was required. Parental stress was decreased between baseline and 6 months in both the overall group and in all the subgroups. Home use of rectal diazepam gel is effective in aborting seizure activity, often avoiding an emergency department visit. Its use reduces morbidity and costs associated with hospital visits and provides parents a treatment option for home management of prolonged or repetitive seizures.

Administration, Rectal↗
PubMed2004

Comparison of intranasal midazolam with intravenous diazepam for treating acute seizures in children.

Midazolam, a water-soluble benzodiazepine, is usually given intravenously in status epilepticus. The aim of this study was to determine whether intranasal midazolam is as safe and effective as intravenous diazepam in the treatment of acute childhood seizures. Seventy children aged 2 months to 15 years with acute seizures (febrile or afebrile) admitted to the pediatric emergency department of a general hospital during a 14-month period were eligible for inclusion. Intranasal midazolam 0.2 mg/kg and intravenous diazepam 0.2 mg/kg were administered after intravenous lines were established. Intranasal midazolam and intravenous diazepam were equally effective. The mean time to control of seizures was 3.58 (SD 1.68) minutes in the midazolam group and 2.94 (SD 2.62) in the diazepam group, not counting the time required to insert the intravenous line. No significant side effects were observed in either group. Although intranasal midazolam was as safe and effective as diazepam, seizures were controlled more quickly with intravenous diazepam than with intranasal midazolam. Intranasal midazolam can possibly be used not only in medical centers, but also in general practice and at home after appropriate instructions are given to families of children with recurrent seizures.

Administration, Intranasal↗
PubMed2001

Synergistic interaction of diazepam with 3',5'-cyclic adenosine monophosphate-elevating agents on rat aortic rings.

We investigated the effect of the phosphodiesterase type 4 (PDE4) inhibitory activity of diazepam on the arterial wall. To this purpose, we examined the interaction of diazepam with 3',5'-cyclic adenosine monophosphate (cyclic AMP)-elevating agents on vasodilatation and cyclic AMP levels in rat aortic rings precontracted with phenylephrine. The involvement of benzodiazepine receptors was also studied. Diazepam (5-100 microM) produced a relaxation of this preparation which was neither mimicked by gamma-aminobutyric acid (GABA), nor antagonized by flumazenil and 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide (PK 11195), inhibitors of central or peripheral type benzodiazepine receptors, respectively. The diazepam-induced relaxation was potentiated by the presence of isoprenaline (10 nM), forskolin (50 nM) or milrinone (0.1 microM). Furthermore, diazepam increased the enhancement of cyclic AMP levels induced by these three agents in this tissue. Our results demonstrate a functional and biochemical synergistic interaction of diazepam with cyclic AMP-elevating agents on rat aortic rings.

Animals↗
PubMed1996

Flunarizine but not theophylline modulates inotropic responses of the isolated rat heart to diazepam.

Diazepam (2 x 10(-5)-6 x 10(-4) M) induced a concentration-dependent positive inotropic effect on the perfused rat heart which was preceded by a transient concentration-dependent negative inotropic response. The influence of the Ca(2+)-entry blocking drug, flunarizine, and the adenosine receptor blocking drug, theophylline on these inotropic responses was studied. Flunarizine in concentrations of 10(-9)-10(-6) M antagonized the positive inotropic response to diazepam significantly; the negative inotropic response was reduced as well. At the lower concentrations of diazepam the negative inotropic response was completely abolished in the presence of flunarizine. The actions of the Ca(2+)-entry blocker were related to the concentrations used. Theophylline in concentrations up to 5 x 10(-5) M did not interfere with either inotropic response to diazepam. The results suggest that Ca2+ currents in the myocardium are involved with the response of the isolated heart to diazepam. It is concluded that the finding that the negative inotropic effect of diazepam was almost abolished by flunarizine suggests that the site of this response most be associated with Ca(2+)-current mechanisms.

Animals↗
PubMed1999

Role of metabotropic glutamate receptors in the hypersusceptibility to pentylenetetrazole-induced seizure during diazepam withdrawal.

To clarify the contribution of metabotropic glutamate (mGlu) receptors in brain to benzodiazepine withdrawal signs, we now examine the effects in mice of selective ligands for three subgroups of mGlu receptor on the hypersusceptibility to pentylenetetrazole-induced seizure during diazepam withdrawal. The seizure threshold for pentylenetetrazole was significantly decreased by the discontinuation of chronic diazepam treatment. The decrease in the seizure threshold for pentylenetetrazole during diazepam withdrawal was significantly suppressed by intracerebroventricular (i.c.v.) pretreatment with the group 1 mGlu receptor antagonist, (S)-4-carboxyphenylglycine ((S)-4CPG: 56 and 100 nmol). These doses of (S)-4CPG did not alter the seizure threshold in chronically vehicle-treated (control) mice. Pretreatment i.c.v. with a presynaptic mGlu receptor agonist (the group 2 mGlu receptor agonist (2S,1'S,2'S)-2-(carboxycyclopropyl)-glycine (L-CCG-I: 3.0 and 5.6 nmol) and the group 3 mGlu receptor agonist, L-amino-4-phosphonobutyric acid (L-AP4: 3.0 and 5.6 nmol)) failed to suppress the decrease in seizure threshold in diazepam-withdrawn mice, but increased the seizure threshold in control mice. Pretreatment i.c.v. with the group 1 mGlu receptor antagonist/group 2 mGlu receptor agonist, (S)-4-carboxy-3-hydroxyphenylglycine ((S)-4C3HPG: 56 and 100 nmol), significantly increased the seizure threshold in control mice and suppressed the decrease in seizure threshold in diazepam-withdrawn mice. These findings suggest that enhancement of group 1 mGlu receptor function and a decline in both group 2 and group 3 mGlu receptor functions may play an important role in the hypersusceptibility to pentylenetetrazole-induced seizure during diazepam withdrawal.

Animals↗
PubMed1999

Specificity of chronic effects of diazepam on responding of rats under fixed-ratio schedules.

Behavioral effects of diazepam were studied in rats responding in different daily sessions using different operant chambers and manipulanda. In one experiment, key pressing was maintained in a first session under a 40-response fixed-ratio schedule; lever pressing was maintained in a second session under a 40-response fixed-ratio schedule; and a third session consisted of a multiple schedule comprising both key and lever pressing maintained under a 40-response fixed-ratio schedule. In a second experiment, the first session consisted of a multiple schedule with both key and lever pressing maintained under a 40-response fixed-ratio schedule and the second session consisted of lever pressing maintained under a 40-response fixed-ratio schedule. After studying effects of widely spaced injections of diazepam (0.3-3.0 mg/kg) on responding for each separate schedule, animals received 1.7 mg/kg/day diazepam in order to study chronic effects of the diazepam on behavior among the different schedule-conditions. In both experiments, tolerance to rate-decreasing effects of diazepam in a particular schedule component did not extend to any other schedule component when the manipulandum or chamber was different, but did extend to other schedule components when the manipulandum or chamber was the same. These results suggest that behavioral effects of chronically administered diazepam were influenced not only by pharmacologic processes, but also by learned relationships among its interoceptive effects, reinforcement contingencies, and particular behavioral environments.

Animals↗