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PubMed1992

Oral self-administration of triazolam, diazepam and ethanol in the baboon: drug reinforcement and benzodiazepine physical dependence.

Reinforcing and physical dependence-producing effects of oral diazepam and triazolam (0.01-1.28 mg/ml) were studied in four non-water-deprived baboons in daily 2-3-h sessions. Drinking initially was food-induced, but subsequently it was maintained for greater than year without the inducing procedures; drug intake greater than 10 mg/kg per session was attained. Triazolam and diazepam reinforcement (compared to vehicle) was concluded for only one baboon for each drug under a single-spout procedure and for two baboons for each drug under a two-spout procedure. However, all baboons showed ethanol reinforcement under a two-spout procedure. When a lever-pressing requirement was imposed for each drink (one-spout procedure), ethanol maintained requirements of 128 or 256 responses/drink, and volume of ethanol consumed was greater than vehicle. Neither benzodiazepine maintained lever pressing better than vehicle at any response requirement and drinking was suppressed by requirements of 1-32. Physical dependence to triazolam and diazepam developed after approximately 1 month of daily ingestion, evidenced by a precipitated withdrawal syndrome after injection of the benzodiazepine antagonist flumazenil. A mild spontaneous withdrawal syndrome occurred after substitution of vehicle for triazolam or diazepam. These data indicate a clear dissociation between the reinforcing and physical dependence-producing effects of triazolam and diazepam.

Animals↗

PubMed1992

Are there changes in sensitivity to 5-HT3 receptor ligands following chronic diazepam treatment?

Administration of 1-(3-chlorophenyl)-biguanide (mCPB), a 5-HT3 receptor agonist (1 and 10 mg/kg IP), was found to be significantly anxiogenic in vehicle treated rats tested in the plus-maze, while having no significant effect in rats withdrawn for 24 h from 21 days diazepam treatment (2 mg/kg/day), suggesting a decreased agonist action at 5-HT3 receptors following withdrawal from chronic diazepam treatment. In the social interaction test, diazepam withdrawn rats showed a significant decrease in social interaction when compared to the chronic vehicle treated group. This anxiogenic response was reversed by low doses of zacopride (0.0001-0.01 mg/kg IP); in the vehicle treated animals 0.1 mg/kg was significantly anxiogenic. The overall pattern of results with zacopride is explained by suggesting that the anxiogenic effects of high doses of zacopride are detectable at low levels of 5-HT function and are due to an agonist action of the S-isomer in the rat at 5-HT3 receptors. The anxiolytic action of low doses is attributed to the R-isomer acting at the R-zacopride binding site and is enhanced in conditions of high 5-HT function, e.g. in the diazepam withdrawn rats. If this hypothesis is correct, then we would predict the R-isomer alone would be more effective in reversing the anxiogenic effects of diazepam withdrawal than the racemate, used here.

Animals↗

PubMed1992

Behavioral analysis of diazepam-induced memory deficits: evidence for sedation-like effects.

Rats were trained on a nonmatching-to-sample task with delays of 2, 5, and 10 min. Subsequently, performance was assessed in three groups of rats following treatment with saline or diazepam (2.0 mg/kg) administered acutely or tested chronically in six administrations. Relative to treatment with saline, diazepam produced a deficit in discrimination performance, which was greater in the acutely treated rats than in those treated chronically. The deficit was not dependent on the length of the delays. Diazepam-treated animals differed from controls in erring on trials in which they failed to investigate both test objects, failed to investigate the test object for a long enough period of time, and displaced the test object on the preferred side of the apparatus. The hypothesis that these effects represented a sedation-like reduction in behavioral variability was also supported by evidence of a diazepam-induced decrease in gross bodily activity, increase in inactivity, and increase in latencies to respond to objects. No support was found for the involvement of diazepam-induced changes in habituation, extinction, or reward effects.

Animals↗

PubMed1995

Preferences for ethanol and diazepam in anxious individuals: an evaluation of the self-medication hypothesis.

The self-medication hypothesis of addictive disorders postulates that individuals with psychiatric symptoms use drugs to alleviate their symptoms. Although commonly cited to explain the etiology of substance abuse, self-medication has not been experimentally validated. This study evaluated one version of the self-medication hypothesis by formulating it into a testable hypothesis: are highly anxious volunteers more likely to self-administer anxiolytic drugs than non-anxious controls. Anxious (ANX, n = 22) and control (CTL, n = 23) subjects participated in two double-blind placebo-controlled experiments, one testing ethanol (0.8 g/kg) and the other testing diazepam (20 mg). Subjects sampled and then chose between ethanol and placebo in one experiment, and diazepam and placebo in the other. The main dependent measures were choice of drug over placebo and subjective responses to the drugs. Ethanol decreased self-reported anxiety in ANX subjects, but ANX subjects did not choose ethanol more often than CTL subjects. Diazepam did not measurably reduce anxiety, but ANX subjects nevertheless chose diazepam more often than did CTL subjects. Thus, there were some differences in drug responses between the ANX and CTL subjects, and the study provided limited support for the self-medication hypothesis. However, drug choice was not directly related to anxiolytic drug effects with either ethanol or diazepam. The procedure may be used to test other formulations of the self-medication hypothesis (e.g., examining other psychiatric risk factors).

Adult↗

PubMed1991

Effects of DN-2327, a new anxiolytic, diazepam and buspirone on exploratory activity of the rat in an elevated plus-maze.

In the present study, the effects of a new anxiolytic, DN-2327, were compared to those of diazepam and buspirone in rats in the elevated plus-maze test. Two indices of anxiety were obtained in this test: the number of entries into the open arms expressed as a percentage of the total number of arm entries and the percentage of time spent on the open arms. Both a typical anxiolytic, diazepam, at 2.5, 5 and 10 mg/kg, PO and a new anxiolytic, DN-2327, at 2.5 and 5 mg/kg, PO dose-dependently increased the two indices: the percentage of time spent on the open arms and the percentage of open-arm entries. On the other hand, pentylenetetrazol (PTZ) at 10 and 20 mg/kg, IP decreased the two indices dose dependently as did yohimbine at 1.5 and 3 mg/kg, IP. DN-2327 at 2.5 and 5 mg/kg, PO and diazepam at 5 and 10 mg/kg, PO dose dependently and significantly increased the two indices that were suppressed following administration of PTZ at 10 mg/kg, IP. The effects of both DN-2327, 5 mg/kg, PO, and diazepam, 10 mg/kg, PO, on the two indices were significantly antagonized by the benzodiazepine (BZD) receptor antagonist flumazenil, 20 mg/kg, IP. Buspirone (2.5-20 mg/kg, PO) did not affect either of the two responses but dose dependently decreased the number of rearings, although in the Vogel conflict test, the anti-conflict activity of buspirone was equipotent to that of diazepam and DN-2327 at the minimum effective dose (10 mg/kg, PO) of each drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Influence of prior maze experience on behaviour and response to diazepam in the elevated plus-maze and light/dark tests of anxiety in mice.

A single prior undrugged exposure to the elevated plus-maze has been reported to reduce open arm activity on retest and to attenuate/abolish the anxiolytic response to benzodiazepines at retest intervals ranging from 48 h to 14 days. The present study was designed to examine the generality of these findings by comparing the effects of prior maze experience on baseline behaviour and response to diazepam in two murine models of anxiety. Parallel experiments were conducted in which DBA/2 mice were exposed/not exposed to the plus-maze, treated daily with saline or diazepam (2-4 mg/kg daily for 8 days) and then tested on either the elevated plus-maze or in the light/dark test of exploration. Results show that, in both tests, diazepam reduced behavioural indices of anxiety in maze-naive mice only. However, interpretation of this apparent loss of diazepam efficacy is at least partially confounded by the observation that maze experience per se altered baseline behaviour in both procedures, reducing open arm activity in the plus-maze and increasing light compartment activity in the light/dark test. The apparent elimination of an anxiolytic response to diazepam in two animal models of anxiety by prior plus-maze experience is discussed in relation to experience-related baseline shifts in behaviour.

Animals↗

PubMed1995

Primacy and recency effects in rhesus monkeys (Macaca mulatta) using a serial probe recognition task. I. Effects of diazepam.

In this study, we evaluated the effects of diazepam (0.2, 0.8, 1.6 and 3.2 mg/kg; IM) on the primacy and recency memory effects in four rhesus monkeys trained on a six-item serial probe recognition (SPR) task. Only the highest dose of diazepam (3.2 mg/kg) consistently affected the shape of the monkeys' serial position curves. Accuracy on the probe trials was disrupted for list items which occurred in the middle portion and recency memory component of the serial position curve, without affecting the primacy component. Diazepam, however, also produced several nonspecific effects on SPR performance. Both the 1.6 and 3.2 mg/kg diazepam doses disrupted accuracy on the non-matching probe trials, and the 3.2 mg/kg dose caused an increase in response latencies which were unrelated to any one component of the serial position curve. This is the first demonstration in nonhuman primates showing that the primacy and recency memory effects can be differentiated on the basis of diazepam dose.

Animals↗

PubMed1995

Precipitated withdrawal in squirrel monkeys after repeated daily oral administration of alprazolam, diazepam, flunitrazepam or oxazepam.

The lowest dose of alprazolam, diazepam, flunitrazepam and oxazepam consistently to induce loss of righting reflex in squirrel monkeys or vehicle was orally administered to monkeys on 18 consecutive days: 2 mg/kg alprazolam (n = 4), 30 mg/kg diazepam (n = 4), 1 mg/kg flunitrazepam (n = 4), 280 mg/kg oxazepam (n = 5), or vehicle (n = 4). Tolerance developed rapidly for loss of righting reflex, more slowly for sleep and only minimally for muscle relaxation observed during the period immediately following daily oral administration. Injection of the specific benzodiazepine receptor antagonist flumazenil (10 mg/kg i.v.) 5 h after the ninth daily oral treatment produced signs of precipitated withdrawal (tremor, vomiting and/or convulsions) in one alprazolam-, four diazepam-, one flunitrazepam- and four oxazepam-treated monkeys, but not in the vehicle-treated monkeys. Physiological saline injected intravenously several days later under these same experimental conditions failed to provoke a precipitated withdrawal reaction. When flumazenil-induced precipitated withdrawal was again evaluated after the 18th daily oral treatment, withdrawal signs were observed in all alprazolam- and all diazepam-treated monkeys, as well as in three flunitrazepam- and three oxazepam-treated monkeys, but not in the vehicle-treated monkeys (convulsions were observed in one alprazolam-, two diazepam-, one flunitrazepam- and two oxazepam-treated monkeys). No signs of spontaneous withdrawal were observed in any of the monkeys during a subsequent 3-week drug-free period. Thus, repeated administration of approximately equieffective doses of these four benzodiazepines resulted in a similar development of tolerance and physical dependence (indicated by the occurrence of a precipitated withdrawal reaction).

Administration, Oral↗

PubMed1996

Changes in "withdrawal symptoms" following discontinuation of low-dose diazepam.

The intensity of putative benzodiazepine withdrawal symptoms was evaluated as part of a double blind placebo-controlled study of benzodiazepines and behaviour therapy in the management of agoraphobia. During the first phase of that study, some subjects were switched from low dose diazepam to placebo, and others remained on diazepam. Symptoms were evaluated in long-term benzodiazepine users (n = 30) and non-users n = 32) when they first entered the study and 4 weeks later, after both groups had been randomized to either diazepam or placebo, using eight analog rating scales measuring commonly reported withdrawal symptoms. At baseline, both users and non-users reported a substantial number of symptoms, with higher levels in the more anxious patients, but no differences between groups. After the transition to either diazepam or placebo, the users switched to placebo reported significantly higher levels of symptoms than users switched to diazepam and non-users combined. Multiple regression analysis suggested that the increase in symptoms was associated with the increase in anxiety, which was higher in the withdrawing group than the other three groups. These results raise questions concerning the extent to which withdrawal symptoms uniquely characterize benzodiazepine withdrawal. They confirm the common assumption that an increase in symptoms often accompanies withdrawal from benzodiazepines, but suggest that such symptoms are not so intense as to make withdrawal excessively difficult, at least in low-dose users.

Adult↗

PubMed1987

Mouse lines selected for genetic differences in diazepam sensitivity.

Selective breeding techniques were used to alter allelic frequencies responsible for diazepam sensitivity and resistance. We used the rotarod test to determine the duration of diazepam-induced neurologic deficit in genetically heterogeneous mice. Males were more sensitive than females in the initial population. We then selectively bred for diazepam resistance and sensitivity. A significant difference between the lines was apparent in both sexes after two generations, and divergence has continued over seven generations. Brain benzodiazepine assays indicated that absorption and distribution of diazepam do not differ in the two lines. Differences in brain benzodiazepine concentrations at recovery from ataxia indicated that the two lines differ in central nervous system sensitivity. We found diazepam-induced rotarod impairment to be blocked in a dose-dependent manner by the specific benzodiazepine antagonist Ro 15-1788, indicating that this effect is mediated through BZ receptors. A dose-response curve obtained from generations 6 and 7 indicates a 9- to 14-fold difference in dose required to obtain similar effects in the two lines. These mice are expected to be useful experimental subjects in studies of benzodiazepine mechanisms.

Animals↗

PubMed2001

Effect of diazepam on the contents of amino acids and free radical during ischemia/reperfusion injury.

The protective effect and mechanism of diazepam on ischemia neurons during cerebral ischemia and reperfusion were studied. Sixty-three Wistar rats were divided randomly into nine groups: control group (n = 7), ischemia (is) groups including subgroups of is3 h, is3-h/rep1-h, is3-h/rep2-h, is3-h/rep3-h(n = 7 in each group), diazepam treated groups (10 mg/kg, i.p.), including subgroups of is3-h, is3-h/rep1-h, is3-h/rep2-h, is3-h/rep3-h (n = 7 in each group) with Zea longa's animal model of middle cerebral artery occlusion. The comparison between the ischemia group and diazepam-treated group showed that diazepam could obviously decrease the production of glutamate, asparate, MDA and increase the synthesis and release of GABA, SOD and GSH-PX. It was concluded that diazepam exerted its protective effects on neurons through complex mechanisms of regulating the synthesis and release of excitotary/inhibitory amino acids and free radicals.

Amino Acids↗

PubMed1981

The effect of intravenous diazepam on rise of intraocular pressure following succinylcholine.

Because succinylcholine raised intraocular pressure, its use to facilitate tracheal intubation for ocular surgery, especially in emergency open-eye cases, has been a controversial topic among anaesthetists for more than two decades. In recent years, intravenous diazepam pretreatment before succinylcholine has been reported to reduce the untoward side effects of myalgia, and elevation of serum potassium and creatine phosphokinase. This study was designed to assess the effect of pretreatment with intravenous diazepam 0.1 mg kg-1 on control (base-line) intraocular pressure and to determine if such pretreatment diminished the rise in intraocular pressure following the standard anaesthesia induction sequence of thiopentone 3 - 5 mg kg-1., followed by tracheal intubation. Such diazepam pretreatment was shown to reduce the intraocular pressure from control levels and to diminish the rise of intraocular pressure following succinylcholine and tracheal intubation. Because succinylcholine produces rapid onset of neuromuscular block for tracheal intubation and since only minor intraocular pressure elevation occurs following thiopentone and succinylcholine in patients pretreated with diazepam, its use in ocular surgery, including emergency open-eye cases, can be rationally advocated. The addition of 0.6 mg kg-1 d-tubocurarine to the diazepam pretreatment did not produce a further reduction of the increase of intraocular pressure following succinylcholine.

Adult↗

PubMed1982

Lorazepam and diazepam as adjuncts to epidural anaesthesia for caesarean section.

Lorazepam 0.05 mg X kg-1 and diazepam 0.1 mg X kg-1 administered intravenously were compared as sedatives for 42 patients undergoing Caesarean Section under epidural anaesthesia. After receiving the drug, 15 per cent of the diazepam patients and 32 per cent of the lorazepam patients were still agitated. Ten per cent of the diazepam patients and 36 per cent of the lorazepam patients had severe symptoms of delirium. These included hallucinations, confusion, agitation, restlessness, inappropriate weeping and repetitive hand movements. Memory impairment was greater with lorazepam. Thirty-five per cent of the diazepam patients had pain at the injection site. None of the lorazepam patients had such pain. Respiratory rate, heart rate and mean blood pressure did not change significantly in either group. Half the patients who had been given lorazepam had side effects that were bothersome enough to cause them to complain the following day. Lorazepam and diazepam were both unsatisfactory as sedatives for patients having Caesarean Section.

Adult↗

PubMedDate not supplied

Inhibition of diazepam metabolism in microsomal- and perfused liver preparations of the rat by desmethyldiazepam, N-methyloxazepam and oxazepam.

Hydroxylated metabolites of diazepam can be conjugated and are therefore generally thought not to affect the metabolism of diazepam. Liver microsomes, obtained from phenobarbital-pretreated rats, showed an inhibition of diazepam (10(-5) M) metabolism by desmethyldiazepam as well as by N-methyloxazepam or oxazepam (5 X 10(-5) M). In a single-pass perfusion of the rat liver an inhibition of diazepam disposition by exogenously administered desmethyldiazepam and by hydroxylated diazepam metabolites was also demonstrated. No oxazepam glucuronides were found after oxazepam infusion. However, infusion with N-methyloxazepam resulted in large amounts of oxazepam-glucuronides. The results indicate that administration of N-demethylated as well as hydroxylated metabolites may result in inhibition of the metabolism of their precursor. If hydroxylated metabolites are formed in situ they become more easily conjugated in comparison with administered hydroxylated metabolites and are therefore less effective as inhibitor.

Animals↗

PubMedDate not supplied

Interaction between grapefruit juice and diazepam in humans.

Grapefruit juice has been reported to markedly improve the bioavailability of triazolam, midazolam, terfenadine, cyclosporine and several dihydropyridine calcium channel blockers including felodipine, nifedipine, nitrendipine and nisoldipine. Because these drugs are metabolized by the hepatic cytochrome P450 isozyme (CYP) 3A4, the inhibitory effect of grapefruit juice is thought to results from inhibition of CYP3A4. In this study, our aim was to investigate the effects of grapefruit juice on plasma concentrations of diazepam. Eight healthy male and female subjects participated in this study. Oral (5 mg) diazepam was administered with either 250 ml water and grapefruit juice. Blood samples were collected for a 24 h period, and whole blood concentrations of diazepam were measured enzyme immunoassay. The mean AUC(0-24) of diazepam was increased 3.2-fold (P < 0.001) and Cmax was increased 1.5-fold (P < 0.05) by the grapefruit juice. Grapefruit juice postponed the tmax of diazepam from 1.50 h to 2.06 h (P < 0.01).

Adult↗

PubMedDate not supplied

The response of growth hormone and prolactin to oral diazepam in diabetics.

We studied 8 insulin dependent stable young diabetics with a mean age of 20 yr. Each patient received 10 mg of diazepam orally after with drawing the baseline blood sample. Subsequent samples were obtained at 30 min intervals for 150 min. The oral administration of diazepam resulted in a significant increase in serum GH concentration from a baseline value of 5.3 +/- 1.2 ng/ml (mean +/- SE) at 0 point to a peak response of 16.5 +/- 5.9 ng/ml at 60 min (p less than 0.001). The plasma glucose concentration remained in the range of 200-267 mg/dl and did not change significantly during the entire testing period indicating that diazepam stimulates GH release in diabetics despite endogenous hyperglycemia. Eight normal subjects were also studied in an identical fashion. Although the mean baseline serum GH concentration in these normal subjects was significantly lower than that observed in the diabetics, (1.3 +/- 0.4 vs 5.3 +/- 1.2 ng/ml, p less than 0.05), the peak response did not differ significantly between the two groups (10.7 +/- 2.6 vs 16.5 +/- 5.9 ng/ml; NS). The baseline concentration of serum prolactin was similar in the diabetic and nondiabetic groups and the administration of diazepam resulted in no significant changes in both groups. Diazepam may be a useful agent in testing for GH reserve in normal subjects as well as in stable insulin dependent young diabetics.

Administration, Oral↗

PubMed2002

Orally delivered alprazolam, diazepam, and triazolam as reinforcers in rhesus monkeys.

RATIONALE: Benzodiazepines are among the most frequently prescribed drugs and are usually taken by mouth. However, there have been few studies of oral self-administration of these drugs, and the results of IV self-administration studies indicate that benzodiazepines are modest reinforcers. OBJECTIVES: To determine if orally delivered alprazolam, diazepam, and triazolam could serve as reinforcers for rhesus monkeys, and to determine some of the conditions under which benzodiazepine reinforced behavior occurs. METHODS: Diazepam or midazolam was initially established as a reinforcer by a fading procedure whereby increasing concentrations were added to a 1 or 2% ethanol solution, and subsequently the ethanol concentration was decreased in steps to zero. Diazepam- and midazolam-reinforced responding persisted in the absence of ethanol. Triazolam and alprazolam served as reinforcers when substituted for diazepam or midazolam. RESULTS: Alprazolam, diazepam, and triazolam served as effective reinforcers across a wide range of concentrations and under fixed-ratio sizes of 16 and 32. Rates of responding were usually far higher than that for the concurrently available vehicle, water. Drug intake (mg drug/kg body weight) generally increased with increases in drug concentration. When large drug amounts were consumed, signs of intoxication were observed. CONCLUSIONS: In contrast to reports of low response rates and weakly maintained behavior, the present results show that the three benzodiazepines can serve as effective reinforcers.

Administration, Oral↗

PubMed2005

Influence of inflammatory nociception on the anxiolytic-like effect of diazepam and buspirone in rats.

RATIONALE: The effect of anxiety on nociception has been evaluated but not that of nociception on anxiety. OBJECTIVE: The study was conducted to analyse the influence of nociception on basal levels of anxiety-like behaviour and on the action of anxiolytic drugs. METHODS: Nociception was induced by an intra-articular injection of uric acid at 3.75 or 7.5%. Experimental anxiety was determined in the rat burying behaviour and the elevated plus maze tests. To separate specific anxiety-related drug actions, a spontaneous ambulatory test was included. The anxiolytics, buspirone (2.5 and 5.0 mg/kg, i.p.) and diazepam (0.5, 1.0 and 2.0 mg/kg, i.p.), were used. RESULTS: In the nociception test, the pain-induced functional impairment rat model, uric acid at 3.75 and 7.5% had an effect of around 35 and 75%, respectively. Uric acid (UA) at the lower dose (3.75%) lacked an effect on burying behaviour but significantly increased the time spent and number of entries to the open arms; the higher UA dose (7.5%) produced a significant increase in the time spent and number of entries to the open arms and a statistically significant reduction in cumulative burying. Diazepam and buspirone produced a clear dose-dependent reduction in cumulative burying. In the plus maze, diazepam also induced an increase in the time spent and number of entries to the open arms. In the burying behaviour test, rats with a mild level of nociception (uric acid at 7.5%) were insensitive to the anxiolytic-like effect of these anxiolytic drugs. In the plus maze test, the anxiolytic-like effect of diazepam (1.0 mg/kg) was blocked under both levels of nociception. CONCLUSIONS: These data demonstrate that nociception modifies the response to anxiolytic drugs. The role of factors with anxiogenic properties produced during inflammation, which may modify diazepam and buspirone effects, is discussed.

Analysis of Variance↗