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PubMed1979

GABA receptor-mediated modulation of 3H-diazepam binding in rat cortex.

Three membrane preparations of rat cortex were used to examine the effects of GABA, bicuculline and bicucine on specific 3H-diazepam binding. In the crude synaptosomal fraction, GABA had no effect on either the maximal binding capacity (Bmax) or dissociation constant (KD) of 3H-diazepam binding. Bicuculline and bicucine both decreased binding affinity. This was antagonized by adding GABA. In the repeatedly washed membrane preparation, and in the washed, frozen and thawed preparation, GABA increased binding affinity and, at high concentrations, increased Bmax. Increased binding affinity was observed with as little as 10(-8) M GABA in the washed, frozen and thawed preparation. Bicuculline inhibited the effect of GABA on 3H-diazepam binding. It was found that about 3 X 10(-5) M GABA was present in the assay medium containing crude synaptosomal fraction. These results suggest endogenous GABA is present in, and influences the results of 3H-diazepam binding assays. Furthermore, it appears that GABA and bicuculline affect 3H-diazepam binding through their binding to the specific GABA binding site.

Animals↗

PubMed1982

Changes in biogenic amine and benzodiazepine receptors correlated with conditioned emotional response and its reversal by diazepam.

Groups of littermate rats were trained to respond for food reinforcement on a variable interval one-min (VI 1) schedule, after which they were classically conditioned to associate a conditioned stimulus (CS) with footshock (conditioned emotional response; conditioned suppression; CER). Two control groups received yoked footshock (no CS) or the visual-auditory stimulus only (no footshock). On test day, a group of the CER conditioned animals received injections of either vehicle or diazepam prior to exposure to the VI 1 food-reinforced schedule. After 30 min of the VI 1 schedule, the CS was presented continuously for 15 min, after which the animals were decapitated, the brains removed, membranes prepared and in vitro receptor binding evaluated. During the CS, the CER animals suppressed responding and exhibited conditioned fear (emotional) behavior, while the control groups, and animals given acute diazepam, maintained normal responding. [3H]Diazepam binding was reduced in the CER animals, yet acute benzodiazepine administration did not effect this binding. [3H]QNB binding was reduced by CER and increased by diazepam administration. Adrenergic, serotonergic and dopaminergic systems were also evaluated. Traditional biogenic amine systems may respond to CER and diazepam administration in some compensatory manner.

Animals↗

PubMed1983

Antagonism of the discriminative effects of diazepam by pyrazoloquinolines in rats.

The diazepam-like agonist and diazepam antagonist properties of the pyrazoloquinoline benzodiazepine receptor ligands CGS8216, CGS9895 and CGS9896 were evaluated in rats trained to discriminate between saline and 1.0 mg/kg of diazepam in a two-choice, discrete-trial procedure. None of the three pyrazoloquinolines produced diazepam-like discriminative effects over the dose range of 1.0-30 mg/kg. The effects of 1.0 mg/kg of diazepam were antagonized by CGS8216 and CGS9895, but not by CGS9896. The present results provide behavioral evidence for benzodiazepine receptor heterogeneity.

Animals↗

PubMed1987

Effects of chronic diazepam exposure on GABA sensitivity and on benzodiazepine potentiation of GABA-mediated responses of substantia nigra pars reticulata neurons of rats.

This study examined the effects of chronic diazepam treatment on GABA sensitivity of substantia nigra pars reticulata neurons and on the ability of benzodiazepines to enhance GABAergic responses of these neurons in rats. Chronic diazepam exposure failed to significantly alter the sensitivity of reticulata neurons to microiontophoretically applied GABA. However, following chronic diazepam treatment for 1 day, or 1, 3 or 7-11 weeks, reticulata neurons showed tolerance to additional systemically or iontophoretically applied benzodiazepines and displayed an increased firing rate following injection of Ro 15-1788. These changes were not apparent 24 h after cessation of chronic treatment. Thus, tolerance to the effects of benzodiazepines on reticulata neurons appeared to develop after a single day of diazepam exposure and to dissipate by 24 h after cessation of treatment. When compared to our previous studies on dorsal raphe neurons, these results demonstrate regional differences in neuronal responses to chronic diazepam exposure, which may help elucidate neural systems which are involved in tolerance to the various functional aspects of benzodiazepines.

Animals↗

PubMed1987

Intravenous self-administration of diazepam in rats.

Diazepam 0.5-2.0 mg/kg per injection was self-administered intravenously by rats on a continuous reinforcement schedule in a dose-dependent manner over a 30 day period. The rates of diazepam self-administration were relatively stable after responding was established, in comparison with rats self-administering morphine 0.5 mg/kg per injection whose rates continued to increase. At a fixed ratio 4 or 8 schedule, higher maximum rates of responding were seen with diazepam than with morphine. During withdrawal, reductions in body weight tended to occur in a manner dependent on the preceding rates of diazepam self-administration and were possibly caused by physical dependence. These findings suggest that diazepam acts as an intravenous reinforcer in rats and that the procedure we describe is of use to predict the dependence liability of drugs considered to have only a weak potential for abuse.

Animals↗

PubMed1988

Theophylline antagonizes the effect of diazepam on ventricular automaticity.

The effect of diazepam on ventricular automaticity induced by a local injury was investigated in the isolated right ventricle of the rat in the presence of the diazepam central antagonist, RO 15-1788, and of the adenosine antagonist, theophylline. Theophylline but not RO 15-1788 antagonized the inhibitory effect induced by diazepam on ventricular automaticity. The inhibitory effect of adenosine but not that of 2-chloroadenosine was potentiated in the presence of diazepam. The results suggest that the inhibitory effect of diazepam on ventricular automaticity results from the inhibition of adenosine uptake.

Adenosine↗

PubMed1991

Ethopharmacology of maternal aggression in mice: effects of diazepam and SM-3997.

The present study investigated whether there is any difference between the effects of benzodiazepine and non-benzodiazepine anxiolytics on maternal aggression in lactating mice, using an ethological technique. We used SM-3997, a 5-HT1A receptor ligand, as a non-benzodiazepine anxiolytic. Behavior towards an intruder male mouse was assessed on postpartum days 5 and 7 in female mice that had been housed alone since the end of the 4-day mating period. Acute oral administration of diazepam had a biphasic effect on the frequency of bites: 1 mg/kg diazepam significantly increased bite frequency, while 2.5 mg/kg diazepam significantly decreased it. However, 2.5 mg/kg diazepam also caused a significant decrease in locomotor activity. In contrast, SM-3997 (1, 2.5 and 5 mg/kg p.o.) significantly decreased the frequency of bites in a dose-dependent manner without causing motor dysfunction. Chronic treatment with 5 mg/kg SM-3997 significantly decreased the frequency of bites when compared with vehicle, whereas diazepam was ineffective at the doses used (0.5 and 1 mg/kg p.o.). The findings suggest that the proaggressive effect is specific to benzodiazepines, and that 5-HT1A receptors may be involved in the suppression of maternal aggression in mice.

Aggression↗

PubMed1995

Effects of desipramine and alprazolam on forced swimming behaviour of adult rats exposed to prenatal diazepam.

Pregnant rats were treated with a single daily s.c. injection of diazepam (2 mg/kg) over gestation days 14-20. This treatment led to a reduction in GABA receptor complex function since adult male offspring showed a strong decrease in electrographic hippocampal responses to alprazolam and a strongly increased response to picrotoxin after intra-locus coeruleus injection of the two compounds. No difference in immobility time in the forced swimming test and in spontaneous motor activity was observed between prenatally vehicle- and diazepam-exposed offspring. Conversely, prenatal exposure to diazepam potentiated the anti-immobility effect of subchronic desipramine (10 mg/kg i.p.) and made active a dose of desipramine (5 mg/kg i.p.) that was ineffective in prenatally vehicle-exposed rats. This effect was observed only in pretested rats. Prenatal exposure to diazepam blocked the anti-immobility effect of subchronic alprazolam (15 mg/kg i.p.) in both non-pretested and pretested rats. Spontaneous motor activity was strongly reduced in all groups. These findings suggest that a persistent reduction in GABA receptor complex function, induced by prenatal exposure to diazepam, does not alter the mobility of adult progeny in the forced swimming test, but it may have consequences when drugs acting on the GABA receptor complex are used.

Alprazolam↗

PubMed1995

Blockade of morphine-induced place preference by diazepam in mice.

The effects of diazepam on morphine-induced place preference were examined in mice. Pretreatment with diazepam (2 mg/kg i.p.) 30 min prior to morphine injection significantly abolished the morphine (5 mg/kg s.c.)-induced place preference, and this effect of diazepam was antagonized by pretreatment with flumazenil. In addition, pretreatment with diazepam prevented the morphine (5 mg/kg s.c.)-induced increase in dopamine turnover in the limbic forebrain. These results suggest that pretreatment with diazepam may suppress the rewarding effects of morphine.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1996

Diazepam-insensitive GABAA receptors in rat cerebellum and thalamus.

Three major populations of GABAA receptor binding sites are present in cerebellar membranes: diazepam-sensitive [3H]Ro15-4513 binding sites, diazepam-insensitive [3H]Ro15-4513 binding sites and high-affinity [3H]muscimol binding sites. All three populations contain a beta subunit as shown by immunoprecipitation with antibodies that recognize all beta subunits. The beta 3 subtype of beta subunit is contained in all three populations, but only a similar low fraction (< 20%) in each. Thus, the majority contain beta subunits other than beta 3 (beta 2 and beta 1) and beta 3 subunits are not selectively associated with nor lacking in any of the three binding populations. Antibodies to the gamma 2 subunit precipitated similar fractions of [3H]Ro15-4513, [3H]flunitrazepam and [3H]muscimol binding sites, showing that gamma 2 subunits are present in high-affinity muscimol binding isoforms, as well as a significant fraction of the diazepam-insensitive [3H]Ro15-4513 binding sites. Under conditions that identify the 56 kDa alpha 6 subunit on SDS-PAGE as the diazepam insensitive site of [3H]Ro15-4513 binding in cerebellum, no polypeptide showing diazepam-insensitive binding of [3H]Ro15-4513 could be photoaffinity-labeled in rat thalamus. These results suggest that alpha 4 subunits in the thalamus participate primarily in subunit combinations which bind muscimol but not any benzodiazepine site ligands.

Affinity Labels↗

PubMed1989

Modification of evoked hippocampal dentate inhibition by diazepam and three antagonists in urethane-anesthetized rats.

Urethane-anesthetized rats with perforant pathway stimulating electrodes and recording electrodes placed in the hippocampal dentate gyrus were exposed to increasing doses of either the benzodiazepine agonist diazepam or an antagonist (PK-11195, CGS-8216, and RO15-1788). Analysis of the monosynaptic evoked field potentials indicated that none of the four compounds altered the threshold for eliciting the excitatory postsynaptic potential (EPSP). Reductions in field population spike (PS) amplitudes were seen after exposure to RO15-1788, CGS-8216, and diazepam, but not PK-11195. Using a paired-pulse paradigm, diazepam significantly increased early gamma-aminobutyric acid (GA-BAA)-mediated recurrent inhibition. The antagonist RO15-1788, but not CGS-8216 or PK-11195, also significantly increased early GABAA-mediated inhibition. The increase in GABAA-mediated inhibition after diazepam was reversed by the subsequent administration of the central antagonists RO15-1788 or CGS-8216, but not the peripheral antagonist PK-11195. Pretreatment with CGS-8216 or RO15-1788 prevented diazepam-induced inhibition. These data support the important modulatory role of the central benzodiazepine receptor in early GABAA-mediated inhibition at this synapse. They also suggest that basal granule cell excitability is not importantly modulated by this benzodiazepine receptor.

Anesthesia↗

PubMedDate not supplied

Diazepam: how much better than placebo?

In a six week, double-blind, predictive, clinical study 224 neurotic and anxious outpatients were randomly assigned to treatment with diazepam (Valium) of placebo and weekly brief psychotherapy administered by experienced psychiatrists. Although diazepam was significantly more effective than placebo for the first week of treatment, it accounted for only 1-4% of the outcome variance, while nonspecific variables contributed 11-22%. After the first revisit and at endpoint, only nonspecific variables accounted for outcome variance ranging from 20 to 26% over the four outcome measures. According to physicians' global and scaled ratings of improvement, diazepam had a treatment advantage (p less than 0.01-0.05) over placebo at the end of the first week of treatment for both the total and completed samples, but not thereafter. According to patients' global ratings of improvement, diazepam was moderately superior (p less than 0.05) to placebo for the total sample only at the end of the first week of treatment and modestly better (p less than 0.10) than placebo for the completed sample on a highly reliable measure of reported anxiety at the same time point. However, patient ratings did not indicate an advantage for diazepam at any of the six points of observation on global ratings of improvement for the completed sample and on reported anxiety for the total sample.

Adult↗

PubMed1983

Behavioral interferences modify the acceleration in memory decay caused by diazepam.

A staircase maze has been used to test the modification induced by a chronic administration of different doses of diazepam in the decay of the rat performance caused by an interruption of 20 days in the daily training. The possibility that behavioral interferences modify the diazepam effect has been examined by testing the rat in an open field or in a Y maze during the interruption of the training in the staircase maze. The diazepam effect on the rat behavior in the staircase maze increased linearly with the doses; an intercalated training in the open field increased the diazepam effect, while an intercalated training in a Y maze completely abolished the increase of forgetting caused by diazepam.

Animals↗

PubMed1983

Selective effects of diltiazem, a benzothiazepine calcium channel blocker, and diazepam, and other benzodiazepines on the Na+/Ca2+ exchange carrier system of heart and brain mitochondria.

Diltiazem, diazepam, and clonazepam effectively inhibit Na+-induced Ca2+ release from mitochondria isolated from rabbit heart and rat brain. At 10 mM NaCl, the 50% inhibition of the rate of Ca2+ release occurred at 5, 7, 40 and 350 microM of clonazepam d-cis-diltiazem, diazepam and 1-cis-diltiazem, respectively. Ro 15-1788 (imidazobenzodiazepine), a pharmacological antagonist presumably at the high affinity site of diazepam, had no effect either alone or in combination with diltiazem or diazepam. We suggest that the Na+/Ca2+ exchange carrier in mitochondria may be a common receptor for diltiazem and diazepam.

Animals↗

PubMed1983

Reversal of the muscle relaxant effect of diazepam by the specific benzodiazepine antagonist Ro 15-1788: an electromyographic study in morphine model of muscular rigidity in rats.

The effects of the benzodiazepines diazepam and midazolam on the rigidity produced by systemic administration of morphine (15 mg/kg i.p.) were studied in rats. The rigidity was recorded as a tonic activity from the gastrocnemius-soleus muscle of non-anesthetized rats in the electromyogram. Both diazepam (1-5 mg/kg i.p.) and midazolam (2.5 and 5 mg/kg i.p.), when administered 45 min after morphine, temporarily antagonized the muscular rigidity. When the competitive antagonist Ro 15-1788 (ethyl-8-fluoro-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5a]-[1,4]benzodiazepine-3 -carboxylate) (5 mg/kg i.p.) was administered together with diazepam (5 mg/kg i.p.), it prevented the effect of diazepam, although by itself it did not affect the morphine-induced muscular rigidity. Our results suggest that diazepam, by acting on benzodiazepine receptors, can antagonize the morphine-induced muscular rigidity. The latter phenomenon might serve as a model for some types of muscular rigidity observed in humans.

Animals↗

PubMed1993

Effects of Ca2+ channel blockers on physical dependence on diazepam in mice.

The effects of Ca2+ channel blockers on the development of physical dependence on diazepam were examined in mice. Co-administration of flunarizine (T-type Ca2+ channel sensitive blocker), but not of either nifedipine or diltiazem (L-type Ca2+ channel sensitive blockers), with diazepam significantly suppressed the hypersensitivity to FG 7142 following chronic treatment with diazepam. The hypersensitivity to FG 7142 may reflect benzodiazepine withdrawal convulsions. These results suggest that flunarizine, but not nifedipine or diltiazem, may suppress the development of physical dependence on diazepam, and that T-type Ca2+ channels in the brain, rather than L-type Ca2+ channels, may be involved in the development of physical dependence on diazepam.

Animals↗

PubMed1995

Interaction of abecarnil, bretazenil, and RO 19-8022 with diazepam-sensitive and -insensitive benzodiazepine sites in the rat cerebellum and cerebral cortex.

Abecarnil, bretazenil, and Ro 19-8022 inhibited the binding of [3H]Ro 15-4513 to diazepamsensitive and -insensitive sites in the rat cerebellum and cerebral cortex, but all three had a much higher affinity for the diazepam-sensitive sites in both tissues. The GABA-shift for bretazenil and Ro 19-8022 was low ( < 2) for all sites studied, consistent with their partial agonistic profile. The GABA-shift for abecarnil was appreciably higher for diazepam-sensitive binding in the cerebellum than in the cerebral cortex (1.97 vs 1.18). Furthermore, the GABA-shift for abecarnil was markedly different for the diazepam-sensitive and -insensitive sites in the cerebellum (1.97 vs 0.71). All three compounds inhibited [3H]Ro 15-4513 binding to the diazepam-sensitive sites with a slope factor > 1, suggestive of positive cooperativity in their binding to GABAA receptors. Abecarnil only partially inhibited diazepam-insensitive binding of [3H]Ro 15-4513 in the cerebellum, indicating that this site can be differentiated into abecarnil-sensitive and -insensitive components.

Animals↗

PubMed1996

Diazepam pretreatment suppresses morphine withdrawal signs in the mouse.

The effect of diazepam on the development of physical dependence on morphine and on the naloxone-precipitated increase in cortical NA turnover were investigated in mice. Co-administration of diazepam (1-4 mg/kg, i.p.) during chronic morphine treatment suppressed the expression of naloxone (3 mg/kg, s.c.)-precipitated withdrawal signs (jumping, exploratory rearing and weight loss). However, a single injection of diazepam (4 mg/kg, i.p.) in morphine-dependent mice did not affect the expression of naloxone-precipitated withdrawal signs. The 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) level and noradrenaline (NA) turnover (MHPG/NA) in the cerebral cortex were increased by naloxone (3 mg/kg) challenge. These increases in the cortical MHPG level and NA turnover were significantly prevented by co-administration of diazepam (4 mg/kg, i.p.) during chronic morphine treatment. These findings suggest that the co-administration of diazepam during chronic morphine treatment may prevent some neurochemical changes in the central noradrenergic system during chronic morphine treatment, and may suppress the development of physical dependence on morphine. Therefore, the inhibitory action of GABA via benzodiazepine binding sites may play an important role in the development of physical dependence on morphine.

Adrenergic alpha-Agonists↗