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PubMed1991

Gestational exposure to diazepam increases sensitivity to convulsants that act at the GABA/benzodiazepine receptor complex.

Experiments examining seizure sensitivity were conducted on adult male offspring exposed to diazepam at 1.0 or 2.5 mg/kg per day in utero over gestational days 14-20. Threshold dosages to facial clonus, myoclonic jerk, clonic seizure, and extensor tonus were determined via i.v. infusion of bicuculline, methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), picrotoxin, pentylenetetrazol, caffeine and strychnine. Relative to uninjected and vehicle-exposed adult male offspring, prenatal diazepam administration reduced the threshold for bicuculline- and DMCM-induced facial clonus and myoclonic jerk by 40-50%. The threshold dosages to facial clonus, myoclonic jerk and clonic seizure from picrotoxin infusion were similarly reduced in animals exposed to diazepam in utero. In contrast, seizure thresholds to pentylenetetrazol, caffeine and strychnine were not affected by early developmental exposure to diazepam. In parallel biochemical studies, an increased sensitivity to the antagonistic effects of bicuculline methiodide on gamma-aminobutyrate (GABA)-stimulated chloride influx was observed in cortical synaptoneurosomes from adult male progeny of diazepam-treated dams. The results are interpreted to reflect a long-lasting alteration in the function of the GABA/benzodiazepine receptor complex by prenatal diazepam exposure that is manifest at the behavioral and neurochemical level in a pharmacologic specific manner.

Animals↗
PubMed1992

Substrate specificity of diazepam-insensitive cerebellar [3H]Ro 15-4513 binding sites.

[3H]Ro 15-4513, a negative modulator at the benzodiazepine receptor, binds with high affinity to all known benzodiazepine binding sites associated with the GABAA receptors. The present experiments surveyed a number of benzodiazepine receptor ligands with different chemical structures and different intrinsic pharmacological profiles for their ability to displace [3H]Ro 15-4513 binding in rat cerebellar membranes. The latter have been shown to possess two types of binding sites, one sensitive to positive modulators such as diazepam and the other insensitive to them (diazepam-insensitive). Whereas the full positive modulators from the benzodiazepine, beta-carboline, and quinoline classes did not displace binding at the diazepam-insensitive sites, the partial positive modulators' affinities for these sites varied much more, some being very potent and others having no affinity at all. All the neutral antagonists tested displaced binding at both types of binding sites, while some of the negative modulators were apparently not potent at the diazepam-insensitive sites. In an alcohol-sensitive rat line (ANT, alcohol non-tolerant), with an enhanced affinity for positive modulators at the diazepam-insensitive sites, these sites also exhibited enhanced affinity for some of the partial positive and negative modulators. The results suggest that the cerebellar diazepam-insensitive [3H]Ro 15-4513 binding sites have unique substrate specificity. It remains to be established which behaviours are affected by activation or inhibition of these receptors that are characterized by their insensitivity to benzodiazepine-positive modulators.

Animals↗
PubMed1982

Modification of the anticonvulsant efficacy of diazepam by Ro-15-1788 in the kindled amygdaloid seizure model.

The effects of various doses of diazepam and the new central benzodiazepine antagonist Ro-15-1788 were investigated in fully amygdaloid kindled rats. Diazepam had a pronounced dose-dependent anticonvulsant effect in this model. Ro-15-1788 dose-dependently reduced the behavioral ranks of the elicited kindled seizures to a maximum of 60% of control without consistently modifying the afterdischarge duration. No prestimulation convulsant effects were seen with Ro-15-1788. When 2 mg/kg i.p. of Ro-15-1788 was given after various doses of diazepam, the prestimulation sedation and ataxia anticonvulsant effects of diazepam (0.5-2.0 mg/kg) were attenuated by treatment with 2 mg/kg dose of Ro-15-1788. At the low dose of diazepam (0.25 mg/kg), increased reduction of behavioral rank and after discharge duration was seen after the 2 mg/kg dose of Ro-15-1788. Thus, Ro-15-1788 appears not to have proconvulsant properties in the kindled amygdaloid seizure model. Further, Ro-15-1788 appears to have some anticonvulsant properties of its own. Mixed agonist and antagonist effects were seen with Ro-15-1788 when given after various doses of diazepam in this model.

Amygdala↗
PubMed1984

CGS8216 noncompetitively antagonizes the discriminative effects of diazepam in rats.

The benzodiazepine antagonist properties of CGS8216 were evaluated in rats trained to discriminate between saline and 1.0 mg/kg of diazepam in a two-choice, stimulus-shock termination procedure. CGS8216 (0.3 to 100 mg/kg) administered alone, either s.c., p.o. or i.p., occasioned only saline-appropriate responding. When administered concomitantly with a constant 1.0 mg/kg dose of diazepam, CGS8216 produced dose-related decreases in drug-appropriate responding. CGS8216 was most potent by the i.p. route, and approximately tenfold less potent by the oral route. CGS8216 was dermatotoxic after s.c. administration. CGS8216 i.p. had a long duration of action. A dose of 30 mg/kg completely antagonized the discriminative effects of the 1.0 mg/kg training dose of diazepam when the antagonist was administered 8 hr before the start of the test session. In order to determine the type of antagonism by CGS8216, the dose-effect curve for diazepam was redetermined in the presence of varying doses of CGS8216 (0.3 to 3.0 mg/kg, i.p.). CGS8216 produced a dose-related rightward shift in the diazepam dose-effect curve, but also decreased the slope and appeared to decrease the maximal effect. These results are consistent with the interpretation that CGS8216 antagonizes diazepam in a noncompetitive manner. It may do so because either it interacts with a subpopulation of benzodiazepine receptors, it functions as a pseudo-irreversible antagonist due to its high affinity, or because it is an antagonist with agonist properties.

Animals↗
PubMed1987

Diazepam withdrawal as demonstrated by changes in plasma corticosterone: a role for the hippocampus.

Elevations in plasma corticosterone were shown to be a reliable indication of antagonist-precipitated withdrawal from diazepam in the rat. Dependence to the benzodiazepine was produced by a single daily injection for eight days at which time CGS-8216 was injected i.v. via a chronic indwelling catheter. This injection and subsequent serial blood samples were withdrawn from conscious, unrestrained animals that were placed previously in sound-attenuated one-way vision boxes. The magnitude of the hormone change was correlated with either the chronic dose of diazepam or the dose of the antagonist used to precipitate withdrawal. When CGS-8216 was administered chronically with the diazepam, antagonist-precipitated abstinence did not occur. Additional results showed that dependence could be produced by bilateral intracerebral placement of micropellets of diazepam into the dorsal and ventral hippocampus. These data show that dependence to diazepam can be demonstrated in a relatively short time using modest doses of drug, and, further, that exposure of the hippocampus, an area with a high concentration of benzodiazepine receptors, to diazepam will initiate dependence.

Animals↗
PubMed1989

Diazepam: endocrine effects and hypothalamic binding sites in the developing male and female rat.

The ontogeny of diazepam's endocrine effects in male and female rats, and of 3H-diazepam binding in the hypothalami of both sexes was studied. Diazepam inhibited basal prolactin levels in 38 day-old male rats and, if prolactin levels were stimulated by Haloperidol the inhibition occurred in 28 day-old males, indicating that the hypoprolactinemic effect of the drug could be evidenced earlier if prolactin titers were high. The prolactin inhibition in females did not reach statistical significance at any studied age. Diazepam significantly released LH only in male rats at 12 days, showing thus, a period of special sensitivity of LH release to the drug. Benzodiazepine-hypothalamic binding sites increased in number from birth to puberty, reaching a plateau at 20 days of age. No sexual differences or changes in affinity were found throughout the studied period. These results suggest that the maturation of diazepam's hypoprolactinemic effect could be partially related to the increase in hypothalamic binding sites, whereas the sexual differences observed in diazepam's endocrine actions could be due to sexual differentiation of endocrine control mechanisms.

Animals↗
PubMed1991

Diazepam administered prior to coronary artery occlusion increases latency to ventricular fibrillation.

Few studies have addressed the antiarrhythmic potential of pretreatment with diazepam in acute myocardial infarction. Thus, the effect of diazepam pretreatment prior to coronary artery occlusion was examined in conscious pigs. Animals were instrumented with aortic catheters to measure arterial pressure, a pulmonary artery catheter for drug administration, and a snare around the left anterior descending coronary artery for permanent occlusion one week later. Diazepam (1 mg/kg iv bolus) or vehicle was administered 10 minutes prior to occlusion. Eight of 14 animals receiving diazepam (57%) and 13 of 22 receiving vehicle animals (59%) developed ventricular fibrillation following coronary occlusion. However, the latency to ventricular fibrillation was significantly shorter (7 +/- 1 min) in animals receiving vehicle compared to animals receiving diazepam (11 +/- 1 min). Significant increases in heart rate were seen up to 5 hours after coronary occlusion only in animals receiving vehicle. The results indicate that diazepam pretreatment can increase ventricular fibrillation latency and prevent heart rate increases following acute myocardial infarction.

Animals↗
PubMed1994

Potentiation of physical dependence on diazepam by ondansetron in rats.

The effects of ondansetron, a 5-HT3 antagonist, on the development of physical dependence on diazepam were examined in rats using a drug-admixed food method. Rats were treated with diazepam or diazepam in combination with ondansetron for 26 days. After an abrupt withdrawal from diazepam, the incidence of withdrawal signs, such as jerks, tremors and convulsions, and withdrawal scores, were potentiated by co-administration of ondansetron. On the other hand, rats which had been treated with ondansetron alone for 33 days did not show any withdrawal signs after abrupt withdrawal from ondansetron. These findings suggest that ondansetron does not possess physical dependence liability, but does potentiate the development of physical dependence on diazepam. Regulation of serotonergic neurons through 5-HT3 receptors may affect the development of physical dependence on diazepam.

Animals↗
PubMed1996

Regionally specific effects of diazepam on brain serotonin metabolism in rats: sustained effects following repeated administration.

The effects of single (1mg/kg) and repeated (1mg/kg 2* daily for 4 days) diazepam administration are investigated on brain regional 5-hydroxytryptamine (5-HT; serotonin) and 5-hydroxy indoleacetic acid (5-HIAA) concentration in rats. Daily treatment decreased food intakes but body weights did not decrease. Administration of diazepam (1mg/kg) to 4 day saline injected rats on the 5th day decreased 5-HT levels in the hippocampus and increased it in the hypothalamus. 5-HIAA levels were increased in the striatum and decreased in the hypothalamus 4 day diazepam injected rats injected with saline on the 5th day also exhibited similar changes of 5-HT and 5-HIAA. Cortical levels of 5-HIAA were also smaller in these rats. Administration of diazepam to 4 day diazepam injected rats again decreased 5-HT in the hippocampus and 5-HIAA in the hypothalamus. 5-HT and 5-HIAA were both decreased in the striatum. Regionally specific effects of diazepam on brain serotonin metabolism are discussed in relation to their possible functions.

Animals↗
PubMed1987

Enhancement of a diazepam withdrawal symptom by bicuculline and yohimbine.

The role of the GABA system in producing a pentylenetetrazol-like interoceptive discriminative stimulus during withdrawal from diazepam was investigated in rats by determining the sensitivity of this system to GABAergic drugs before and after chronic treatment with diazepam. Food-restricted rats were trained to obtain a reward of food by responding on one lever following an injection of pentylenetetrazol (PTZ; 20 mg/kg) and the other lever following an injection of saline (1 ml/kg). After rats had acquired this discrimination, the effectiveness of Ro 15-1788, bicuculline and yohimbine to substitute for pentylenetetrazol was determined. Prior to chronic treatment with diazepam, rats selected the appropriate lever for saline after Ro 15-1788 and the appropriate lever for pentylenetetrazol after bicuculline (0.04-2.5 mg/kg) or yohimbine (0.16-5.0 mg/kg). Although the selection of the appropriate lever for pentylenetetrazol was dose-dependent, full substitution for pentylenetetrazol was not obtained with either drug as larger doses of bicuculline produced convulsions while the rats began to select the appropriate lever for saline after larger doses of yohimbine (bell-shaped curve). Diazepam blocked the pentylenetetrazol-like interoceptive discriminative stimulus for bicuculline. The rats were then injected with diazepam (80 mg/kg/8 hr) for 24 days. Upon termination of the administration of diazepam, the animals were tested for lever-selection following the administration of saline, Ro 15-1788 (10 mg/kg), bicuculline (0.32, 0.64 and 1.25 mg/kg) or yohimbine (0.16, 0.64 and 2.5 mg/kg). After saline, 33% of the rats selected the appropriate lever for pentylenetetrazol whereas selection of this lever was enhanced after Ro 15-1788, bicuculline or yohimbine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Desensitization of adenosine A2 receptors in the striatum of the rat following chronic treatment with diazepam.

Following prolonged treatment (7 days) with diazepam (10 mg/kg/day, using ALZET mini-osmotic pumps) in rats, the function of adenosine receptors was assessed in specific structures of the brain, using both agonist ligand binding and adenylate cyclase assays. Binding to A1 receptors was quantified using [3H]N6-[(R)-1-methyl-2-phenylethyl] adenosine, a selective ligand at A1 receptors. Differences in the binding of this ligand and that of [3H]5'-N-ethylcarboxamide adenosine, which binds to both A1 and A2 subtypes of receptors with similar affinities, were used to quantify A2 receptors. Treatment with diazepam failed to alter the binding of [3H]N6-[(R)-1-methyl-2-phenylethyl] adenosine in all areas of the brain studied. However, the binding of A2 receptors and A2 receptor-mediated stimulation of adenylate-cyclase were significantly attenuated in striatal membranes from diazepam-treated rats. Thus, the present study indicated that functional adenosine A2 receptors were desensitized after prolonged treatment with diazepam, since decreased agonist binding to A2 receptors paralleled an attenuation in the stimulation by adenosine of the activity of adenylate cyclase, an effect mediated by the A2 receptor. These results further indicate that the changes in adenosine A2 receptors correlated with significant short-lasting alterations in the sleep-wake cycle during the withdrawal of diazepam. The alterations in sleep-wakefulness did not correlate with the effect of diazepam on benzodiazepine receptors since no changes were observed in the binding of benzodiazepine receptors.

Adenylyl Cyclases↗
PubMed1989

Benzodiazepine receptor autoradiography in corpus striatum of rat after large frontal cortex lesions and chronic treatment with diazepam.

It has previously been shown that diazepam impairs behavioural recovery from partial unilateral ablation of the cerebral cortex in rats. The present study confirmed this in rats with large unilateral lesions of the frontal cortex and showed that diazepam (5 mg/kg i.p. daily for 14 days immediately after surgery) prevented recovery from sensory asymmetry even after 120 days. In saline-treated rats greater than 80% recovery had occurred by this time. A study of binding to benzodiazepine receptors, using an in vitro autoradiographic technique, was performed to determine whether the lack of recovery after administration of diazepam was associated with any long-term receptor changes on the damaged side of the brain. Binding of [3H]Ro15-1788 was increased by up to 40% in the caudate putamen on the decorticated side at 14-120 days. This was not significantly altered by treatment with diazepam. Binding of [3H]Ro15-1788 in the nucleus accumbens was not altered by lesion of the frontal cortex alone or after treatment with diazepam. It is concluded that the lack of recovery from sensory asymmetry, produced by diazepam after lesion of the frontal cortex cannot be correlated with any change in binding to benzodiazepine receptors within the corpus striatum.

Animals↗
PubMed1991

Release of dopamine is reduced by diazepam more in the nucleus accumbens than in the caudate nucleus of conscious rats.

The effects of 1-20 mg/kg diazepam were studied on the extracellular concentrations of dopamine (DA), dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the nucleus accumbens and striatum of conscious rats, using intracerebral microdialysis. Five, but not 1 mg/kg diazepam significantly reduced extracellular DA, DOPAC and HVA in the nucleus accumbens. Twenty mg/kg diazepam significantly reduced extracellular DA, DOPAC and HVA in the striatum. A significant effect on striatal DOPAC, but not on DA and HVA, was seen with 10 mg/kg diazepam, while no changes were found with 5 mg/kg diazepam. The results suggest that diazepam reduces the release and metabolism of DA in the nucleus accumbens more than in the striatum.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1991

Evaluation of the sedative combination of nitrous oxide and orally administered diazepam.

The effects of nitrous oxide/oxygen and oral diazepam, administered individually and in combination, on memory and psychomotor coordination were evaluated. Forty healthy adult volunteers (53% male) were randomly assigned to one of four conditions: (1) 100% oxygen and placebo, (2) 50% nitrous oxide/50% oxygen and placebo, (3) 100% oxygen and 20 mg diazepam, or (4) 50% nitrous oxide/50% oxygen and 20 mg diazepam. There was no significant difference between groups with respect to age or weight. Participants' performance was tested in two areas: (1) a visual recall and recognition task and (2) psychomotor coordination as indicated by performance on Trieger's modification of the Bender Gestalt Test. There was no significant difference between the effects of nitrous oxide or diazepam on memory given individually or in combination. Significant differences in psychomotor coordination were seen when comparing groups 2, 3, and 4 with group 1. However, no significant differences existed between groups 2, 3, and 4, indicating that nitrous oxide and diazepam both affect coordination but that their effects are not additive when combined in this manner. The trends in both the memory and psychomotor data suggest diazepam to have a greater effect than nitrous oxide, and the combination to have a greater effect than either agent individually. Further investigation in this area is needed.

Adult↗
PubMed1982

Onset and offset of the diazepam stimulus complex.

Rats were trained to discriminate 3.0 mg/kg diazepam from saline in a two lever operant procedure. The time from injection to test session was 30 minutes. The diazepam discrimination consisted of initial responses on the lever paired with saline, but after training shifted to the lever paired with diazepam (onset). When tested with saline immediately after injection, animals responded consistently on the saline lever throughout the test. A shift from the drug lever to the saline lever at a later time point was also observed (offset). In addition, it was not possible to establish a peripheral diazepam drug stimulus complex. The results show that diazepam exerts discriminative control from 10 to 210 minutes after intraperitoneal injections, confirming a central action of the diazepam drug stimulus complex. The method might be useful in experimentation on drug control of lever selection.

Animals↗
PubMed1983

Attenuation of the behavioral effects of meperidine and normeperidine by daily administration of diazepam.

The effects of meperidine, normeperidine, morphine, pentobarbital and d-methadone were determined on the key-pecking behavior of pigeons responding under a multiple fixed-ratio (FR), fixed-interval (FI) schedule of grain presentation. Dose-effect curves were obtained for each drug alone and during daily administration of 10 mg/kg of diazepam. The daily administration of diazepam had little effect on the behavior itself. Meperidine and normeperidine caused dose-related decreases in both FI and FR responding. The dose-effect curves for these drugs during daily administration of diazepam were shifted to the right compared to the dose-effect curves determined in the absence of daily diazepam. In contrast, the effects of morphine, d-methadone and pentobarbital either were not affected by daily administration of diazepam or were shifted to the left by daily administration of diazepam. These data further support the hypothesis that the behavioral effects of meperidine and normeperidine are due to a proconvulsive action produced by these drugs. In contrast, the effects of morphine, d-methadone and pentobarbital are not due to such a proconvulsive action.

Animals↗
PubMed1989

The effects of ondansetron (GR38032F) in rats and mice treated subchronically with diazepam.

Using rat and mouse models of aversive behaviour, we have further investigated the properties of the 5-HT3 receptor antagonist ondansetron (GR38032F) that are relevant to its proposed use as an anxiolytic agent. Tolerance to the disinhibitory properties of diazepam was readily demonstrated in the social interaction test in the rat, but did not occur after subchronic treatment with ondansetron. In both the light/dark exploration test in mice and the social interaction test in rats, withdrawal from subchronic treatment with diazepam increased behavioural suppression, whereas this was not observed with ondansetron. The behavioural suppression and weight loss induced by either the withdrawal of diazepam or the administration of the benzodiazepine receptor antagonist, flumazenil, in animals treated subchronically with diazepam, was prevented or antagonised by diazepam or ondansetron. Buspirone was ineffective. It is concluded that, in rats and mice, tolerance to the disinhibitory effects of ondansetron does not occur, that withdrawal from subchronic treatment with ondansetron is not associated with any behavioural disturbances and that ondansetron is highly effective in preventing the behavioural suppression and weight loss following withdrawal from subchronic diazepam treatment. These data suggest that ondansetron may have major therapeutic advantages over currently available anxiolytic agents, particularly in patients who have previously received prolonged benzodiazepine therapy.

Animals↗
PubMed1989

Reinforcing and subjective effects of diazepam in nondrug-abusing volunteers.

Preference for diazepam was assessed in 18 light and 12 moderate social drinkers using a cumulative dosing procedure. The 7-session procedure consisted of: 1) four sampling sessions, during which participants ingested color-coded capsules containing either diazepam (five 4-mg capsules administered at 30-min intervals; total dose 20 mg) or placebo, and 2) three choice sessions, during which they could ingest up to 7 capsules of their preferred color of capsule, each separated by 30 min. Subjective (mood) and behavioral (performance) measures were obtained throughout the 4-hour sessions. The light social drinkers chose diazepam over placebo on 66% of the choice sessions, and ingested a mean dose per session of about 16 mg. The moderate drinkers chose diazepam on 100% of the choice sessions, and ingested an average dose of 25 mg per session. Diazepam produced sedation in both groups, but in the moderate drinkers it also increased measures of subjective effects suggestive of "euphoria." The results indicate that diazepam can serve as a positive reinforcer under laboratory conditions in nondrug-abusing individuals who are moderate users of alcohol and other drugs. Greater reinforcing efficacy may be indicative of higher risk of abuse. The results illustrate the usefulness of the cumulative dosing procedure to measure both drug preference and dose preference.

Adult↗