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PubMed1985

Evidence that 2-phenylpyrazolo[4,3-c]-quinolin-3(5H)-one antagonises pharmacological, electrophysiological and biochemical effects of diazepam in rats.

The effects of the acute administration of 2-phenylpyrazolo[4,3-c]quinolin-3(5H)-one on diazepam-induced behaviour and electrophysiological activity were studied in rat. The compound, in doses of 5-10 mg/kg (i.p.), which per se did not induce alterations in spontaneous locomotor activity, antagonised the sedative effect induced by 5-10 mg/kg (i.p.) of diazepam. The injection of diazepam in rats, induced a profound reduction in the first negative wave of the recording of the visual evoked potential used as a sensitive electrophysiological test, in vivo. 2-Phenylpyrazolo[4,3-c]quinolin-3(5H)-one (10 mg/kg, i.p.) caused a recovery of the amplitude of the first negative wave within a few minutes. This result was confirmed by the finding that 2-phenylpyrazolo[4,3-c]quinolin-3(5H)-one, injected acutely in rats, pretreated with diazepam exhibited the capacity to antagonise the binding of [3H]diazepam determined in vitro on synaptic membrane preparations from cortex. The comparison of the pattern of the visual-evoked potential, recorded after the injection of 2-phenylpyrazolo[4,3-c]quinolin-3(5H)-one (50 mg/kg) with the patterns recorded after the injection of ethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazolo(1,5a) (1,4)benzodiazepine-3-carboxylate (50 mg/kg) and ethyl-beta-carboline-3-carboxylate and 1-methyl-beta-carboline demonstrated that 2-phenylpyrazolo[4,3-c]quinolin-3(5H)-one is devoid of intrinsic activity.

Animals↗

PubMed1988

Influence of oestrogen on spontaneous and diazepam-induced exploration of rats in an elevated plus maze.

An elevated plus-maze, used to identify anxiolytic effects of drugs (Pellow et al., 1985), reflected as increased open-arm exploration, was employed in cycling and ovariectomised rats, to determine the effect of diazepam on the cycle and, after ovariectomy, to investigate possible influences of treatment with oestradiol (10 or 100 micrograms/kg, s.c.) (acute: 1 day or subchronic: 3 days) to ovariectomised rats on the effect of diazepam (1 mg/kg, i.p.), studied 3, 24 and 72 hr after cessation of treatment. Cycling females, exhibiting 3 consecutive 4-day oestrous cycles and ovariectomised rats, 15 days after surgery, were used. There was a tendency for increased open-arm exploration by rats in proestrous and diestrous, as compared to the other phases of the cycle and to ovariectomised rats. Rats treated 24 hr after subchronic treatment with oestradiol also exhibited increased open-arm exploration. The anti-anxiety effect of diazepam was clearly shown in oestrous and metestrous but not in proestrous, diestrous or in ovariectomised rats. The effect of diazepam was abolished in rats tested 3 hr after acute small doses of estradiol and attenuated in rats tested 24 hr after subchronic administration of the hormone. The results suggest that oestradiol, administered in physiological doses, may have an inhibitory effect on the diazepam-induced anxiolysis.

Animals↗

PubMed1979

Disruption of taste aversion learning by pretreatment with diazepam and morphine.

Laboratory rats were pretreated with either morphine (9 mg/kg IP), diazepam (4 mg/kg 1P) or Ringer's solution 2, 3 1/2, and 2 hr, respectively, prior to ingestion of a novel tasting saccharin solution followed immediately by a single injection of one of these agents. Animals pretreated with Ringer's solution followed by an injection of either morphine or diazepam showed a conditioned taste aversion (CTA) as determined by a significant reduction in the mean saccharin intake on a subsequent test trial. Although the drug pretreatments alone produced no conditioned avoidance behavior, the diazepam pretreatment completely blocked the development of both diazepam and morphine-evoked CTAs while the morphine pretreatment prevented a CTA induced by itself but not by diazepam. The results were discussed in terms of the attenuating effects of the pretreatments on the relative saliency of the subsequent conditioning drug injection.

Animals↗

PubMed1981

Effect of diazepam on stress induced changes in brain histamine.

Acute treatment with diazepam (2.5, 5 and 10 mg/kg) did not affect the basal histamine concentration in the hypothalamus, midbrain or in the cortex of the rat. The increase in the hypothalamic histamine level caused by 15 min of "platform stress" was significantly attenuated by diazepam (5 or 10 mg/kg) pretreatment, but the elevation induced by 15 min of air blasts remained unchanged. Diazepam significantly reduced the rise in plasma corticosterone concentration in response to air blast stress but did not affect the increase caused by "platform stress." Thus, in addition to the already known effects of diazepam on stress induced changes in other central neurotransmitters or neuromodulators, diazepam may also affect the hypothalamic histamine elevation induced by certain type of stress.

Animals↗

PubMed1983

Suppression of saccharin-induced drinking in the nondeprived rat by low dose diazepam treatment.

Access to a highly palatable 0.005 M sodium saccharin solution resulted in considerable overdrinking in nondeprived rats over a 6 hr observation period. Contrary to previous reports documenting benzodiazepine-induced hyperdipsia in animals challenged with thirst stimuli or in animals exhibiting schedule-induced drinking, diazepam (0.1-3.0 mg/kg) had no effect to enhance the intake of the saccharin solution. Instead, diazepam produced a significant suppression of fluid consumption, in a manner not monotonically related to dose. Thus, diazepam (0.3 mg/kg) produced maximal suppression which did not dissipate over a 6 hr period, while diazepam (3.0 mg/kg) had no effect. Possible behavioral mechanisms by which low dose diazepam treatment might reduce the drinking are briefly considered.

Animals↗

PubMed1986

Differential antagonism of diazepam-induced loss of the righting response.

Ethyl-beta-carboline-3-carboxylate (beta-CCE), inosine and Ro 15-1788 are antagonists of several actions of the benzodiazepines. These compounds can be differentiated, however, according to their ability to reverse the loss of the righting response induced by diazepam. Ro 15-1788 completely reversed effects of diazepam on the righting response of pigeons and squirrel monkeys but was ineffective against comparable effects produced by pentobarbital. Pretreatment with Ro 15-1788 protected against diazepam-induced righting loss. Neither inosine nor beta-CCE reversed diazepam-induced righting loss or acted prophylactically against this effect. Since beta-CCE has been characterized as an inverse agonist at the benzodiazepine receptor, the absence of antagonism we report would suggest that beta-CCE lacks specific pharmacological activity which opposes suppression of the righting response by diazepam. Research with these preferentially-acting antagonists may lead to the development of anxiolytics devoid of the sedative-hypnotic properties inherent in the drugs currently in a clinical use.

Animals↗

PubMed1986

Brain histamine regulation following chronic diazepam treatment and stress.

Chronic diazepam treatment (5 mg/kg intragastrically, twice daily for 14 days) did not influence either hypothalamic, midbrain or cortical histamine (HA) levels or histidine decarboxylase (HD) activity in male Sprague-Dawley (200-220 g) rats. However, a small but significant decrease in hypothalamic HA concentration and significantly increased HD activity was seen following diazepam withdrawal. Air blast stress induced a significant elevation in hypothalamic HA levels and HD activity in vehicle-treated controls, diazepam-treated and diazepam-withdrawn rats, but the change in HD activity was significantly greater in the last group. The latter group also displayed the greatest elevation in plasma corticosterone levels in response to stress. Hence, diazepam withdrawal in rats results in some changes in the basal hypothalamic HA regulation and may influence the hypothalamic HA and corticosterone response to stress.

Animals↗

PubMed1987

Diazepam and memory: evidence for spared memory function.

The effects of diazepam on several tests of memory were investigated in a double-blind study of 24 healthy young adults. Following a single oral administration of 0.3 mg/kg diazepam or placebo, subjects in the diazepam group showed marked impairment in immediate free recall of words as compared to placebo control subjects. However, diazepam-treated subjects demonstrated performance benefits from prior exposure to the same words on tests of memory priming using word completion and category-generation tasks. The two types of memory tests differ in their demand for conscious recollection. Tests of free recall have explicit (declarative) memory demands whereas the priming test places only implicit (procedural) demands upon memory. The results demonstrate that diazepam spares some forms of memory as does amnesia induced by neurological impairment.

Adolescent↗

PubMed1989

The beta-carboline derivatives ZK 93426 and FG 7142 fail to precipitate abstinence signs in diazepam-dependent cats.

The aim of the present study was to investigate the ability of different benzodiazepine recognition site antagonists (Ro 15-1788 and ZK 93426) and inverse agonists (Ro 15-4513, FG 7142 and CGS 8216) to induce abstinence signs in diazepam-dependent cats. Different groups of cats were challenged with each of the benzodiazepine recognition site ligands under investigation 24 hours after the last dose of chronic treatment with diazepam (7 mg/kg, IP at 8.00 a.m. and 8.00 p.m. for 21 consecutive days). The benzodiazepine derivatives Ro 15-4513 and Ro 15-1788 precipitated an abstinence syndrome within minutes after IP administration. The pyrazoloquinoline derivative CGS 8216 also induced withdrawal signs that were less severe and had a longer latency than those elicited by Ro 15-4513 and Ro 15-1788. Abstinence signs included tremors, increased muscle tone, irritability, fear, arched-back posture, pupillary dilation and vocalizations. On the other hand, the beta-carboline derivatives ZK 93426 and FG 7142 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 depends on the chemical structure of the challenge drug (i.e., benzodiazepine or pyrazoloquinoline), since beta-carboline antagonists like ZK 93426 and partial inverse agonists like FG 7142 lack this property.

Animals↗

PubMed1989

Diazepam reverses the effects of pentylenetetrazole in rat pups by acting at type 2 benzodiazepine receptors.

Pentylenetetrazole (75 mg/kg) induced a characteristic coarse body tremor (accompanied by limb extension) and hyperactivity in 4-day-old rat pups. These effects were reversed by diazepam (0.5 and 2 mg/kg) but not by CL 218,872 (10 and 20 mg/kg) which is selective for type 1 benzodiazepine receptors. Diazepam did not affect the brain concentrations of pentylenetrazole, indicating that the reversal was not based on a pharmacokinetic interaction. Neither diazepam nor CL 218,872 had significant effects on the behavior of the rat pups, although diazepam (2 mg/kg) tended to increase locomotor activity. The results suggest that diazepam displays an anticonvulsant effect in the neonatal rat which is mediated by type 2 receptors.

Animals↗

PubMed1989

Interactions of diazepam and pentobarbital with RO 15-4513 on intracranial self-stimulation discrimination behavior in rats.

Rats implanted with electrodes in the lateral hypothalamus were trained in a discrete trial procedure to make a differential response (right or left lever press) in the presence or absence of brain stimulation. When a high level of accuracy (95% correct) was attained in the discrimination, testing with vehicle, RO 15-4513, diazepam (1.0-10 mg/kg), diazepam plus RO 15-4513 (1.0 mg/kg), pentobarbital (1.0-17.5 mg/kg) and pentobarbital plus RO 15-4513 began. Diazepam, at 10 mg/kg, disrupted the discrimination behavior, and it also decreased the total number of lever-presses and increased the time to complete the session. These effects were blocked by the coadministration of 1.0 mg/kg RO 15-4513. Pentobarbital produced effects similar to those of diazepam, but these effects were only reversed to a limited extent by RO 15-4513. By itself, however, RO 15-4513 also decreased the total number of lever presses and increased the time to complete the session. Results were consistent with our previous findings with alcohol and RO 15-4513, and supported the notion that diazepam and alcohol have some similar effects at the GABA-benzodiazepine receptor complex.

Animals↗

PubMed1990

The actions of diazepam and serotonergic anxiolytics vary according to the gender and the estrous cycle phase.

The anxiolytic effect of diazepam (0.5, 1.0 and 2.0 mg/kg), buspirone (2.5 and 5.0 mg/kg), indorenate (2.5 and 5.0 mg/kg) and ipsapirone (5.0 and 10.0 mg/kg) was evaluated in male and female rats during the proestrus and metestrus phases. The burying behavior test was used to measure the anxiety levels. In this test, increases in the behavior latency are interpreted as prolonged reactivity, while reductions in the burying behavior are considered to reflect anxiolytic states. Diazepam increases in burying behavior latency were consistently higher than those observed after serotonergic anxiolytics. Buspirone, at no dose tested, affected the burying behavior latency, while indorenate and ipsapirone had only minor effects. Male individuals were more sensitive than females to the actions of diazepam on burying behavior. The serotonergic anxiolytics produce similar responses in both sexes. Metestrus females were much less sensitive to the action of all anxiolytics on burying behavior latency than proestrus females. Proestrus females were highly sensitive to the actions of diazepam on burying latency as compared both with males and metestrus females. Data show that a larger gender and within females variation occurs after treatment with diazepam as compared with the serotonergic anxiolytics. The results are discussed considering the relationships between ovarian hormones and the GABA-benzodiazepinic and serotonergic systems.

5-Methoxytryptamine↗

PubMed1990

Differential actions of RO 15-1788 and diazepam on poikilothermia, motor impairment and sleep produced by ethanol.

In adult male Sprague-Dawley rats kept at an ambient temperature of 23-25 degrees C, ethanol was injected intraperitoneally in a dose of 4.0 g/kg to produce a clear-cut impairment of autonomic and motorial functions. Following the injection of ethanol, motor coordination, measured on a rotorod, behavioral sleep, righting reflex and colonic temperature were monitored at predetermined intervals for 5.0-7.0 hr. In the first experiment, either 1.0 mg/kg RO 15-1788 (flumazenil), a benzodiazepine (BZ), receptor antagonist, or 1.0-5.0 mg/kg diazepam, a classical benzodiazepine receptor agonist, were injected intraperitoneally either alone or concurrently with ethanol's administration. In the second study, either RO 15-1788 (1.0 or 2.0 mg/kg) or diazepam (1.0 or 5.0 mg/kg) was injected at the nadir of the fall of body temperature induced by ethanol. Although RO 15-1788 alone failed to affect the rats' temperature, it did not prevent the characteristic ethanol-induced hypothermia but rather potentiated it in a dose-dependent manner. Further, this BZ receptor antagonist exacerbated motor incoordination and other behavioral effects when given either simultaneously with ethanol or at the nadir in the animals' core temperature. Although diazepam evoked a dose-dependent hypothermia, it did not enhance ethanol-induced hypothermia when both drugs were administered simultaneously. However, diazepam augmented motor incoordination and other effects and served to delay their recovery. When given to the rats at the nadir of ethanol hypothermia, diazepam did not potentiate ethanol's thermolysis but retarded the recovery from hypothermia; it caused also a dose-dependent delay in the recovery of motor coordination and other responses.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Diazepam and discriminative motor control: acute, chronic and withdrawal effects.

Rats were trained to hold a force transducer operated with a paw so that it remained between upper and lower limits of a force band for a continuous 1.5-sec period to deliver each food pellet. Acute doses of diazepam impaired measures of this performance. Separate groups received chronic diazepam injections (6 mg/kg, IP) either presession (Before Group) or postsession (After Group), or presession vehicle (Vehicle Group). The After and Vehicle Groups demonstrated that neither chronic postsession diazepam, nor time alone, altered motor performance. The performance of the Before Group was affected by the daily diazepam, and although tolerance to the impairment developed, it was incomplete. Late in the chronic-administration phase (after 75 days) a toxic effect of the suspending agent became evident in all groups as a decrease in work rate, although the other performance indices were not affected. The withdrawal of diazepam from the Before Group led to improved performance which returned to the original baseline level.

Animals↗

PubMed1991

Diazepam impairs acquisition but not performance in the Morris water maze.

Diazepam is known to produce anterograde amnesia in both humans and animals. The present investigation sought to determine if this impairment is a direct result of diazepam's interference with mnemonic processes or a result of deficits in performance or retrieval. Diazepam (3 mg/kg) was administered prior to training in the Morris water maze either before or after the rats had acquired the location of a submerged escape platform. Diazepam was found to impair acquisition but not retrieval of spatial information and this impairment was not due to the sedative, hypothermic or state-dependent learning effects of diazepam. These results replicate previous findings in the Morris water maze and provide new evidence that this deficit is primarily mnemonic in nature.

Animals↗

PubMed1992

Behavioral efficacy of diazepam against nerve agent exposure in rhesus monkeys.

The possibility that nerve agents will be used on the battlefield is real. The traditional therapy against nerve agent exposure consists of pyridostigmine pretreatment and atropine-pralidoxime chloride therapy administered after nerve agent exposure. This therapy regimen is extremely effective in preventing mortality in laboratory animals exposed to multilethal concentrations of nerve agent, yet these animals often display convulsions, brain damage, and behavioral incapacitation. We report here that the addition of diazepam to the traditional therapy for nerve agent (soman) exposure not only decreases the incidence of convulsions, but also attenuates the cognitive impairments of rhesus monkeys trained on a Serial Probe Recognition (SPR) task. Monkeys which received diazepam treatment required only 6 days before their performance on the SPR task returned to presoman exposure levels, compared to nondiazepam-treated monkeys which required 15 days. Moreover, only 1 out of the 5 monkeys which received diazepam treatment suffered tonic-clonic convulsions; in contrast all 5 monkeys which did not receive diazepam treatment experienced severe convulsive episodes. These results suggest that diazepam would be an excellent adjunct to traditional nerve agent therapy to facilitate behavioral recovery from nerve agent intoxication that might be encountered by US military personnel on the battlefield or accidental organophosphate poisoning encountered in industrial or agricultural accidents.

Acetylcholinesterase↗

PubMed1992

Fluctuations in responses to diazepam during the oestrous cycle in the mouse.

Administration of diazepam (0.28 mg/kg, IP; 60 min) to male mice or to female mice at oestrus or dioestrus increased the number of transitions made between the light and dark chambers of a test apparatus, a presumed anxiolytic action. However, the same dose of diazepam had no effect on light/dark transitions at late dioestrus, proestrus, or metoestrus II. At metoestrus I, this test dose of diazepam induced a decrease in the number of light/dark transitions and significant changes in other test parameters indicative of an increase in fearfulness or light aversion. Concentrations of diazepam in the brain after intraperitoneal injection were not influenced by the stage of the oestrous cycle, suggesting that the observed changes in responses to diazepam reflect changes in sensitivity to this drug rather than alterations in distribution or metabolism. The results indicate a physiological influence of ovarian steroid hormones on sensitivity to the benzodiazepine tranquilisers.

Animals↗

PubMed1993

Attenuation of anticonvulsant effects of diazepam after chronic treatment with bicuculline.

Changes in the GABAergic system after chronic treatment with bicuculline were examined in two strains of inbred rats, Fischer 344 (F344) and Lewis (LEW). Rats received an IP injection of either bicuculline (2 mg/kg) or vehicle once a day for 12 days. After this chronic treatment, the effects of diazepam (1 mg/kg, IP) and pentobarbital (20 mg/kg, IP) on bicuculline-induced convulsions were measured. Bicuculline was acutely infused into a tail vein at 0.0415 mg/min, and the infusion was terminated when rats showed seizure. Following the chronic bicuculline treatment, the anticonvulsant effect of diazepam, but not of pentobarbital, was significantly reduced as compared to its effect following chronic vehicle treatment in both strains. Both diazepam and pentobarbital showed a significant difference in anticonvulsant effects between strains (F344 > LEW). The hypnotic effects of muscimol, barbital, pentobarbital, and ethanol following chronic bicuculline treatment were examined. There was no significant difference in sleep time induced by these drugs between bicuculline- and vehicle-treated rats. These results suggest that the attenuation of diazepam's anticonvulsant effect after chronic bicuculline treatment may result from functional changes in benzodiazepine receptors and that the anticonvulsant effects of diazepam and pentobarbital may be influenced by genetic factors. Moreover, the hypnotic effects of several drugs tested are apparently not affected by chronic bicuculline treatment.

Animals↗