Amnesic and anxiolytic effects of intravenous diazepam in dental anxiety

The effects of intravenous administration of diazepam (average 20 mg) on learning, performance and mood were assessed in dental patients. These patients required sedation due to excessive anxiety in a dental situation, or because they were to undergo stressful surgery. On a verbal learning task, subjects recalled and recognized significantly fewer words from a list presented after drug administration than from a list presented prior to drug administration, when tested at the end of the treatment period. When tested after treatment, subjects recognised few of a series of picture postcards that had been presented to them during the course of treatment. Subjects showed no significant impairments after diazepam treatment on digit-symbol substitution, symbol copying or number cancellation tasks compared to pre-treatment scores; however, there was a small but significant reduction in the number of finger-taps made. Mood-rating scales showed significant increases in sedation and well-being after diazepam treatment compared to pre-treatment scores, and also a significant reduction in anxiety levels. This study shows that the amnesic effects of diazepam are present in a "real-life" stress situation.     

Antidepressant and anxiolytic effects of alprazolam versus the conventional antidepressant desipramine and the anxiolytic diazepam in the forced swim test in rats.

The antidepressant and anxiolytic effects of alprazolam were compared to those of desipramine, diazepam and buspirone in the forced swim test. Subchronic alprazolam induced a reduction in immobility similar to that of desipramine in 'non-pretested' and 'pretested' rats. In 'non-pretested' rats, the anti-immobility effect of desipramine was potentiated by diazepam and alprazolam, given before subchronic desipramine, while the anti-immobility effect of subchronic alprazolam was counteracted by diazepam. Diazepam, administered before the pretest session, counteracted, 24 h later, the anti-immobility effect of subchronic desipramine and alprazolam; alprazolam counteracted the anti-immobility effect of alprazolam but not of desipramine, buspirone at the highest doses tested potentiated the anti-immobility effect of subchronic desipramine but not of alprazolam. These data provide further support for the hypothesis that the GABA/benzodiazepine/Cl complex is directly implicated in the action of antidepressants and that systems other than the GABA system are involved in the antidepressant and anxiolytic effects of alprazolam.     

Toluene inhalation and anxiolytic activity: possible synergism with diazepam

Toluene exposures or injections of diazepam reinstated lever responses that had been suppressed by punishment in laboratory rats. When concentrations of toluene or diazepam that were ineffective or minimally effective in this paradigm were administered in combination, they produced a qualitatively similar effect which was much greater than the sum total of effects produced by the same amount of either substance alone. These observations suggest an anxiolytic action for toluene and a possible synergism between the two substances.     

Effect of calcium on anxiolytic activity of diazepam and verapamil in rats

Objective:

To analyze the role of calcium in anxiety and its effect on anxiolytic activity of diazepam and verapamil.

Materials and Methods:

Study was conducted using female albino rats in light and dark arena; a nonconflicting animal experimental model for anxiety. Animals were divided into six groups with six animals in each group. Test drugs, calcium gluconate (10 mg/kg), diazepam (1 mg/kg), verapamil (5 mg/kg), calcium + diazepam, and calcium + verapamil were administered intraperitoneally. Percentage of time spent in light arena and number of entries into light arena were the two parameters observed for 5 min after 30 min of drug administration. ANOVA test was used for statistical analysis.

Results:

Compared to the control group, diazepam group, and calcium group, only calcium + diazepam group showed considerable increase in mean percentage of time spent in light arena. However, this increase was statistically insignificant. In the case of total number of entries into light arena, animals in calcium + diazepam group showed statistically significant increase in total number of entries into light arena when compared to calcium group and diazepam group.

Conclusion:

Results of the study suggest that calcium may enhance the anxiolytic activity of diazepam, but has no effect on anxiolytic activity of verapamil.     

Tolerance to the benzodiazepine diazepam in an animal model of anxiolytic activity

The antipunishment properties of diazepam (DZP) were investigated in mice treated acutely, or following nine daily treatments with either DZP (5 mg/kg, PO) or its vehicle. Acutely, or following chronic vehicle treatment, DZP produced a dose-related increase in activity punished by footshock. Following chronic DZP, test doses of DZP given 24 or 48 h following the last chronic treatment were no longer, or less effective in enhancing punished activity. Effects on unpunished activity were unaffected. In a study of the time course of tolerance development, tolerance was not seen after one or three daily treatments but was present after 6 days. Following establishment of tolerance by 9 days' treatment, the antipunishment activity of DZP reappeared after 8 days' withdrawal and was restored to acute levels after 16 days. Tolerance was not associated with changes in benzodiazepine (BZ) receptor affinity or numbers, but the ability of GABA to enhance BZ binding was increased. There was no change in the ability of DZP or the convulsant -carboline DMCM to modulate ³⁵S-TBPS binding. The mechanism of tolerance to the antipunshment properties of DZP therefore remains unknown.     

Differential effects of the anxiolytic drugs, diazepam and buspirone, on memory function.

The effects of the anxiolytic drugs diazepam (5 mg) or buspirone (5 or 10 mg) were studied in comparison with placebo on memory function in 39 subjects diagnosed with generalized anxiety disorder. Neither drug altered the immediate recall of a list of 16 nouns or impaired digit span, a second test of immediate memory. Diazepam selectively impaired the recall of nouns after a 20 min delay when compared with placebo. In contrast, neither dose of buspirone altered the delayed recall of the word list. The implications of such different effects of anxiolytic drugs on memory function for the clinical treatment of anxiety are discussed.     

Strain differences in the anxiolytic effects of losartan in the mouse.

Anxiolytic effects of the angiotensin AT(1) receptor antagonist losartan were studied in the elevated plus maze (EPM) and the light/dark test (LDT) in different mouse strains as were responses to angiotensin II and acetylcholine in isolated ascending colon. There were no significant strain differences in behaviour on the EPM, and diazepam was anxiolytic in C57BL/6, DBA/2 and BKW mice. Losartan was anxiolytic in BKW only. In the LDT, there were significant strain differences, with BKW mice exhibiting greatest anxiety-like behaviour; losartan was ineffective in this test. In vitro responses to angiotensin II and acetylcholine were significantly smaller in BKW than in C57BL/6 and DBA/2. These results indicate that the mouse strain exhibiting least angiotensin receptor function is the most responsive to the anxiolytic effects, suggesting a possible relationship between angiotensin receptor function and anxiolytic response to losartan.     

Different effects of diazepam in Fischer rats and two stocks of Wistar rats in tests of anxiety.

The behaviour of animals in tests of anxiety varies between strains, even in identical tests and surroundings. To evaluate the results obtained, a more detailed knowledge of the behaviour of different rat strains is indispensable. Identically raised Fischer 344 rats and two stocks of Wistar rats were examined in two animal tests of anxiety: the X-maze and a modified open-field test following diazepam treatment (0.5-4.0 mg/kg). Harlan-Wistar rats were the least 'anxious' when the behaviour of vehicle treated controls was compared. The largest effect of the anxiolytic diazepam, however, was observed in Harlan-Fischer rats. To determine possible reasons for strain and stock differences, plasma concentrations of diazepam and metabolites and concentrations of serotonin (5-HT) in the CNS were measured. Plasma concentrations of diazepam and metabolites differed between the strains with the Harlan-Fischer rats showing higher diazepam concentrations. 5-HT levels in discrete brain regions varied with Harlan-Fischer rats having higher 5-HT concentrations. Strain differences influence the anxiety-associated behaviour of untreated animals and the effect of anxiolytics.     

Comparative neurologic effects of diazepam and suriclone, a cyclopyrrolone anxiolytic

Suriclone selectively displaces benzodiazepines from their binding sites but is structurally unrelated to benzodiazepines. Neurologic effects of suriclone were compared to those of diazepam in 54 subjects in a sequential, double-blind, single dose, randomized study (placebo; diazepam 10 mg; suriclone 0.2, 0.4, 0.6, or 0.8 mg). Data were collected on-line by microcomputer. Suriclone 0.2 mg did not differ from placebo. Suriclone 0.4 mg and 0.6 mg did not differ from diazepam 10 mg. Suriclone 0.8 mg caused significantly more decrement than diazepam 10 mg (p less than 0.05) in manual tracking, force platform stability, and Heath rail walking and in total severity of symptoms. Suriclone 0.8 mg caused nausea (p = 0.02), clumsiness (p = 0.02), and loss of balance (p = 0.01) more frequently than diazepam 10 mg. Suriclone 0.8 mg produced symptoms and signs qualitatively and quantitatively different from diazepam 10 mg, such as vomiting, unusual ocular movement effects, and difficulty walking. Possibly the differences in CNS drug binding for anxiolytics are associated with clinical differences in toxicity.     

Antidepressants attenuate both the enhanced ethanol intake and ethanol-induced anxiolytic effects in diazepam withdrawn rats.

We have recently shown that the abrupt discontinuation of chronic diazepam (DZM) administration facilitated ethanol consumption and enhanced the anxiolytic properties of ethanol. Tricyclic antidepressants such as desipramine and the selective serotonin reuptake inhibitor fluoxetine have been shown to reduce alcohol intake in rodent models of alcoholism and in alcoholics who are depressed. In the present study, we tested whether desipramine (1.25; 2.5 and 5 mg/kg, i.p.) and fluoxetine (5 mg/kg, i.p.) treatment affect both ethanol intake in a free-choice test and the anxiolytic effect induced by ethanol in DZM withdrawn rats. Adult male Wistar rats were submitted to a chronic DZM treatment (2 mg/kg per day) or vehicle (VEH) for 21 days. Twenty-four hours after the last DZM injection, rats were subjected to a free-choice paradigm between water and increasing ethanol concentrations with or without concurrent desipramine or fluoxetine administration (ethanol concentration (v/v) was increased every 4 days as follows: 2, 4, 6, 8 and 10% for the final 8 days). Chronic treatment with desipramine (24 days, twice a day, 2.5 and 5 mg/kg, i.p.) and fluoxetine (24 days, once a day; 5 mg/kg, i.p.) significantly reduced the amount of ethanol intake in DZM withdrawn rats. Furthermore, subchronic treatments with desipramine (4 days, twice a day, 2.5 and 5 mg/kg) and fluoxetine (4 days, once a day, 5 mg/kg, i.p.) blocked the anxiolytic-like behavior in the elevated plus maze induced by ethanol (1 g/kg; i.p.) in DZM withdrawn rats at day 5 of withdrawal. The present findings suggest that desipramine and fluoxetine could be effective pharmacological tools to prevent the subsequent development of ethanol dependence in rats previously exposed to DZM withdrawal.     

四氢孕酮和地西泮对暴露于架高十字迷宫小鼠的作用

目的比较孕酮的还原性代谢产物四氢孕酮和地西泮抗焦虑作用。方法C57小鼠腹腔注射四氢孕酮、地西泮或赋形剂 ,20min后观察在架高十字迷宫试验中的表现 ,测定其自发活动。结果腹腔注射四氢孕酮0.1mg·kg-1,明显缩短小鼠进入十字迷宫开臂的潜伏期[从(31.30±8.39)s减少到(8.80±6.00)s ,P<0.001] ,并显著增加进入十字迷宫开臂的次数(从1.20±0.42增到4.80±1.75,P<0.001)及在开臂的滞留时间占总时间的百分比 (从7.13 %增加到32.50 %,P<0.001)。而腹腔注射地西泮0.25mg·kg-1的抗焦虑作用弱于四氢孕酮。自发活动实验显示 ,0.5mg·kg-1地西泮明显减少小鼠自发活动 (P<0.01) ,而0.1mg·kg-1地西泮和0.25mg·kg-1 的四氢孕酮均不影响小鼠自发活动。结论试验结果提示神经甾体和地西泮对小鼠行为有不同的作用。四氢孕酮具选择性抗焦虑作用而不影响自发活动 ,可望成为地西泮抗焦虑的代用品     

Harman-induced changes in the anxiolytic effect of diazepam

It has been demonstrated in experiments on rats under conflict situation that intraperitoneal injection of harman in high doses (20 mg/kg) counteracts and, in low doses (1 mg/kg), potentiates the anxiolytic effect of diazepam. A possible mechanism of the dual effect of harman on the anxiolytic action of diazepam is discussed.     

谷维素和维生素B1增强地西泮的抗焦虑作用

目的研究地西泮、谷维素和维生素B1按1∶32∶8的比例合用后的抗焦虑作用,并同地西泮比较.方法采用大、小鼠高架十字谜宫模型和大鼠五甲烯四氮唑辨别效应对抗模型.结果在大、小鼠高架十字迷宫实验中,地西泮与谷维素和维生素B1合用后,大、小鼠在开放臂停留时间百分率明显增加,表现出明显的抗焦虑作用;而且其在开放臂停留时间百分率的增加,明显高于单独使用与其含量相等的地西泮的作用.在大鼠五甲烯四氮唑辨别效应对抗实验中,合用后对抗大鼠五甲烯四氮唑辨别效应的ED50值为23.4 mg·kg-1,其地西泮含量为0.6 mg·kg-1,远低于地西泮单方的ED50值3.5mg·kg-1.结论谷维素和维生素B1具有增强地西泮的抗焦虑作用.     

The inhibitory effect of diazepam on defensive burying: anxiolytic vs. analgesic effects

The hypothesis that analgesic mechanisms might account for the suppressive effect of diazepam on defensive burying was tested in four experiments. In the first experiment, 1 mg/kg of diazepam had no appreciable effect on rat's latency to escape from a painful heat stimulus, but reliably suppressed defensive burying behavior. There was no significant relationship between the diazepam-treated rats' latency to escape and their duration of burying. Rats in Experiment 2 were injected with diazepam during a delay between shock and testing, so that they could not be experiencing the putative analgesic effect of diazepam during the shock. In spite of this, diazepam produced a significant suppression of burying compared to saline control. In the next experiment, the effect of diazepam on defensive burying was assessed in the complete absence of painful stimulation by exposing the rats to a novel stimulus known to elicit burying behavior. Diazepam suppressed burying behavior to the novel stimulus in a dose-dependent fashion. Finally, the ability of 10 mg/kg of naloxone to reverse the suppressive effect of 1 mg/kg of diazepam was assessed in Experiment 4. Naloxone failed to reverse the suppressive effect of diazepam and had no significant effect on defensive burying by itself, suggesting that the modulating influence of diazepam on rats' defensive burying behavior did not depend upon endogenous opiate mechanisms. Taken together, the results of the four experiments did not support the view that benzodiazepines produce their anxiolytic effects through analgesic mechanisms.     

Antidepressant- and anxiolytic effects of the novel melatonin agonist Neu-P11 in rodent models

Aim:

To investigate the potential antidepressant and anxiolytic effects of Neu-P11, a novel melatonin agonist, in two models of depression in rats and a model of anxiety in mice.

Methods:

In the learned helplessness test (LH), Neu-P11 or melatonin (25–100 mg/kg, ip) was administered to rats 2 h before the beginning of the dark phase once a day for 5 days and the number of escape failures and intertrial crossings during the test phase were recorded. In the forced swimming test (FST), rats received a single or repeated administration of Neu-P11 (25–100 mg/kg, ip). The total period of immobility during the test phase was assessed. In the elevated plus-maze test (EPM), mice were treated with Neu-P11 (25–100 mg/kg, ip) or melatonin in the morning or in the evening and tested 2 h later. The percentage of time spent in the open arms and the open arms entries were assessed.

Results:

In the LH test, Neu-P11 but not melatonin significantly decreased the escape deficit and had no effect on the intertrial crossings. In the FST, a single or repeated administration of Neu-P11, either in the morning or in the evening, significantly decreased the duration of immobility. In the EPM test, Neu-P11 significantly increased the percentage of time spent in the open arms and the open arms entries irrespective to the time of administration. Melatonin was effective only when administered in the afternoon.

Conclusion:

The results demonstrate that Neu-P11 exerts antidepressant and anxiolytic activities in rodent models.     

Neuroleptic-induced changes in the anxiolytic and myorelaxant properties of diazepam in the rat.

Diazepam (2.0 mg/kg) was injected (IP) into rats 30 min before chlorpromazine (2.5, 5.0, or 10.0 mg/kg) on ten occasions. All doses of chlorpromazine enhanced the capacity of diazepam to increase rats' exploration of the exposed arms of an elevated plus-maze, an animal screening test for anxiolytic and anxiogenic substances. When maze testing occurred during each of the ten diazepam----chlorpromazine trials (after diazepam but before chlorpromazine), this enhancement effect appeared on Trial 6 and persisted thereafter. Haloperidol (3.0 mg/kg, IP) changed diazepam-elicited plus-maze activity in the same manner as chlorpromazine; however, thioridazine (10.0 mg/kg) and pimozide (2.0 mg/kg) were ineffective. Additionally, haloperidol, like chlorpromazine, was found to reduce diazepam's muscle relaxation effect (inclined plane test) as a consequence of diazepam----haloperidol pairings; once again, thioridazine and pimozide proved ineffective. These results suggested that not all neuroleptics will alter diazepam activity, and also that dopamine blockade per se is not sufficient to induce such changes. While the reasons for the enhanced plus-maze effects of diazepam induced by haloperidol and chlorpromazine remain elusive, the diminished myorelaxant effect may be linked to a neuroleptic's capacity to induce muscular side effects: thioridazine and pimozide are far less likely to yield such effects than are chlorpromazine and haloperidol. Haloperidol administered chronically by itself was found to have an effect on diazepam-induced myorelaxation. Administration of this butyrophenone either orally (2.0 mg/kg daily for 22 days) or in depot form (haloperidol decanoate, 60.0 mg/kg IM once a month for four months) caused a diminished effect of diazepam in rats subjected to the inclined plane test.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ethanol effects on impulsivity in two mouse strains: similarities to diazepam and ketamine

Rationale  The effects of ethanol on attention and impulsivity have been contradictory. Objectives  The aim of the present investigation is to study the effects of acute ethanol administration in measures of attention and response control in the five-choice serial reaction time task (5-CSRTT) in two strains of mice, C57BL/6JOlaHsd and CD1. Materials and methods  Mice were trained in the 5-CSRTT and then were injected intraperitoneally (i.p.) with 0, 0.5, 1 and 2 g/kg ethanol before testing under standard parameters and in a long inter-trial interval (ITI) session, which promotes the emergence of premature responses, a measure of poor inhibitory control. To examine if the effects of ethanol in the 5-CSRTT were due to its actions at GABA_A receptors or at NMDA receptors, the GABA_A receptor agonist diazepam (1 and 2 mg/kg, i.p.) and the non-competitive NMDA antagonist ketamine (10 and 20 mg/kg, i.p.) were tested in long ITI sessions. Results  Ethanol did not affect attention or impulsivity in the standard procedure, but increased premature responding in long ITI sessions. The effects of ethanol were mimicked by diazepam in both strains of mice, whereas ketamine increased premature responding only in the CD1 strain. Conclusions  Ethanol's ability to increase impulsivity in the 5-CSRTT is mediated by both common and different neurotransmitter systems in the two strains of mice and is dependent on the task's parameters. Furthermore, ethanol did not decrease response accuracy, suggesting that attentional mechanisms are preserved after acute ethanol in mice and that the increases in impulsive behaviour are independent of attentional performance.     

Use of the elevated plus-maze test with opaque or transparent walls in the detection of mouse strain differences and the anxiolytic effects of diazepam

The elevated plus-maze is a widely employed behavioural assay for anxiolytic and anxiogenic agents in rodents. Among laboratories, however, the apparatus often differs between the use of transparent and opaque walls. This inconsistency may represent an unnecessary confound in the literature when comparing results. Here, we directly contrasted the two designs with respect to (1) mouse strain differences (C57BL/6, 129/Sv, and C3H/He) and (2) sensitivity to diazepam (0.5, 1.0, and 1.5 mg/kg, intraperitoneal). Both mazes yielded similar results indicating that 129/Sv mice were more anxious than C57BL/6 or C3H mice, with the transparent elevated plus-maze tending to encourage open-arm exploration in all three strains. Next, we examined the effect of diazepam in the 129/Sv strain across the two mazes. Systemic diazepam at 1.5 mg/kg led to increased percentage time spent in the open arms in both elevated plus-mazes; the drug was ineffective in both elevated plus-mazes at a dose of 0.5 mg/kg. Although our results revealed little practical difference between the two mazes in terms of their ability to detect differences in anxiety-related behaviour, the baseline difference in open-arm exploration between the two elevated plus-mazes suggests that the transparent design may be more congenial for the detection of anxiogenic manipulations, and the opaque maze for anxiolytic manipulations.     

Tolerance to the anti-pentylenetetrazole effects of diazepam in the mouse

The protective effects of acute and chronic diazepam administration (4 mg/kg) against seizures induced by pentylenetetrazole (PTZ) and picrotoxin were investigated. Considering the incidence of tonic-clonic convulsions, tolerance to the protective effects of diazepam was evident by day 5 if the mice were challenged with PTZ (120 mg/kg), by day 10 if the challenge was picrotoxin (8 mg/kg) and by day 20 if the challenge was PTZ (105 mg/kg). Diazepam retained its protective effects against tonic-clonic convulsions induced by PTZ (90 and 60 mg/kg) for 45 days, but the incidence of myoclonic jerks revealed tolerance after 5 days.