Buspirone is differentiated from diazepam in humans using a three-response drug discrimination procedure

The discriminative stimulus effects of buspirone and diazepam were examined in 12 healthy volunteers using a three-response drug discrimination procedure and a within-subject design. During an initial sampling phase, the training drug conditions (placebo, 15 mg/70 kg buspirone, and 10 mg/70 kg diazepam) were identified to subjects by letter codes before oral drug administration. During a subsequent training phase, subjects earned money for correct drug identifications made two hours after drug administration. Ten out of 12 subjects acquired the three-response discrimination. When lower doses of buspirone (3.75 and 7.5 mg/70 kg) and diazepam (2.5 and 5.0 mg/70 kg) were tested in a subsequent generalization testing phase, both buspirone and diazepam produced dose-related increases in appropriate drug identifications, without significant cross-generalization. Analyses of standardized and unstructured self report questionnaires revealed that buspirone and diazepam produced different profiles of effects, and that buspirone was associated with a number of “negative” subject-rated effects including tension, nausea, and dizziness. These results demonstrate a distinct profile of discriminative stimulus and subjective effects for buspirone relative to diazepam which is consistent with its distinct pharmacological profile, and provide evidence for the sensitivity of the three-response drug discrimination procedure. Received: 7 July 1997/Final version: 18 December 1997     

Buspirone, chlordiazepoxide and diazepam effects in a zebrafish model of anxiety

Zebrafish are becoming more widely used to study neurobehavioral pharmacology. We have developed a method to assess novel environment diving behavior of zebrafish as a model of stress response and anxiolytic drug effects. In a novel tank, zebrafish dwell in the bottom of the tank initially and then increase their swimming exploration to higher levels over time. We previously found that nicotine, which has anxiolytic effects in rodents and humans, significantly lessens the novel tank diving response in zebrafish. The specificity of the diving effect was validated with a novel vs. non-novel test tank. The novel tank diving response of zebrafish was tested when given three anxiolytic drugs from two different chemical and pharmacological classes: buspirone, chlordiazepoxide and diazepam. When the test tank was novel the diving response was clearly seen whereas it was significantly reduced when the test tank was not novel. Buspirone, a serotonergic (5HT_1A receptor agonist) anxiolytic drug with some D₂ dopaminergic effect, had a pronounced anxiolytic-like effect in the zebrafish diving model at doses that did not have sedative effects. In contrast, chlordiazepoxide, a benzodiazepine anxiolytic drug, which is an effective agonist at GABA-A receptors, did not produce signs of anxiolysis in zebrafish over a broad dose range up to those that caused sedation. Diazepam another benzodiazepine anxiolytic drug did produce an anxiolytic effect at doses that did not cause sedation. The zebrafish novel tank diving task can be useful in discriminating anxiolytic drugs of several classes (serotonergic, benzodiazepines and nicotinic).     

A comparison of the effects of diazepam versus several typical and atypical anti-depressant drugs in an animal model of anxiety

We examined the anxiolytic effects of a variety of anti-depressant drugs, administered either acutely or chronically, in an animal model of anxiety involving novelty-suppressed feeding in food-deprived rats. Following a single injection of desipramine (10 mg/kg), amitriptyline (10 mg/kg), mianserin (10 mg/kg), fluoxetine (10 mg/kg), buspirone (4 mg/kg), gepirone (4 mg/kg) or nomifensine (10 mg/kg), there was no decrease in the latency to begin eating in the novel environment such as occurred with diazepam (2 mg/kg). In fact, an increased latency was observed for desipramine, amitriptyline, fluoxetine, and nomifensine. In contrast, chronic (21 days) treatment with each of the above-mentioned drugs, except nomifensine, significantly reduced the latency to begin eating relative to vehicle controls. These findings suggest that a variety of tricyclic and novel anti-depressant drugs acquire anxiolytic properties following chronic administration.     

Pyrethroid toxicology: Protective effects of diazepam and phenobarbital in the mouse and the cockroach

Diazepam delayed the onset of action of deltamethrin and fenvalerate (pyrethroids producing the Type II syndrome) but not of permethrin and allethrin (pyrethroids producing the Type I syndrome) in both the mouse and cockroach. Phenobarbital was less potent as an anticonvulsant and also less selective since it delayed the onset of signs for both deltamethrin and permethrin in each animal. In vivo extracellular nerve recordings in the cockroach showed differences between deltamethrin and permethrin in the nerves responding, the types of response, and the protective effect of diazepam. A 3 mg/kg ip dose of diazepam protected the mouse against mortality due to a subsequent intracerebroventricular dose of either deltamethrin or permethrin, increasing their LD₅₀ values by six- to ninefold. Possible mechanisms for the Type II pyrethroid syndrome include an action at the GABA receptor complex or a closely linked class of neuroreceptor, or through depolarization of nerve terminals.     

The anticonvulsant effects of diazepam and phenobarbital in prekindled and kindled seizures in rats

The effects of various doses of diazepam (0.5–4 mg/kg) and phenobarbital (7.5–60 mg/kg) were determined on prekindled and kindled amygdaloid seizures in the same rats. Diazepam was ineffective against the prekindled focal seizures, but demonstrated profound and statistically significant control of the kindled seizures. In the kindled state, diazepam reduced the afterdischarge duration and seizure rank score to prekindled levels. Only the largest sedating dose of phenobarbital produced a reduction of both prekindled afterdischarge duration and seizure rank score. Against the kindled seizure, phenobarbital showed a marked and statistically significant increase in effectiveness in all but the smallest dose tested. The afterdischarge duration of kindled seizures was reduced to prekindled levels by 15–60 mg/kg of phenobarbital, while seizure rank score was reduced to prekindled levels by 30 and 60 mg/kg phenobarbital. The effects of two doses of diazepam (0.5 and 2.5 mg/kg) and phenobarbital (7.5 and 30 mg/kg) were tested against prekindled and kindled pentylenetetrazol (PTZ)-induced seizures. Preliminary work with 3 doses of pentylenetetrazol (30, 40 and 60 mg/kg) demonstrated that repeated doses of 30 mg/kg readily kindled seizures without the significant mortality seen with larger doses. Both diazepam and phenobarbital were less effective against seizures kindled with 30 mg/kg pentylenetetrazol compared to prekindled seizures. The comparative lack of effect that was seen with diazepam and phenobarbital against the pentylenetetrazol kindled seizure at doses associated with control of the kindled amygdaloid seizure may reflect an underlying difference in the pathogenesis of kindling between these seizure models. Further, the lack of suppression of the prekindled amygdaloid afterdischarge duration by large doses of diazepam, in contrast to large doses of phenobarbital, may also reflect differences between the mechanisms of action of these two drugs. This paradigm provides a model for testing the effectiveness of anticonvulsants during the progressive development of various epileptogenic seizures.     

The anticonvulsant effects of diazepam and phenobarbital in prek1ndled and kindled cortical seizures

The effects of various doses of diazepam (0.5–4 mg/kg) and phenobarbital (15–60 mg/kg) were determined on prekindled (focal) and kindled (generalized) cortical seizures in the same rats. Only high sedating doses of diazepam or phenobarbital reduced the elicited afterdischarge duration (ADD) and behavioral response in the prekindled focal cortical seizure. Against the kindled seizure, both diazepam and phenobarbital showed a marked and statistically significant increase in effectiveness in all but the smallest doses tested. The ADD of the kindled cortical seizures was reduced to prekindled lengths by diazepam (1–4 mg/kg) or phenobarbital (30–60 mg/kg). The increased anticonvulsant effectiveness found in this study is similar to previous findings with diazepam and phenobarbital against prekindled and kindled amygdaloid seizures, but stands in contrast to findings with prekindled and kindled pentylenetetrazol seizures.     

丁螺环酮与地西泮治疗焦虑症双盲比较

目的：比较丁螺环酮与地西泮治疗焦虑症的疗效及不良反应。方法：采用随机双盲对照研究的方法，分为丁螺环酮组２３例（男性１１例，女性１２例；年龄３８±ｓ１３ａ），予丁螺环酮１５ｍｇ，ｐｏ，ｔｉｄ；４ｗｋ为一个疗程。地西泮组２２例（男性９例，女性１３例；年龄４１±１３ａ），予地西泮７．５ｍｇ，ｐｏ，ｔｉｄ；４ｗｋ为一个疗程。结果：丁螺环酮组有效率为８７％，地西泮组９１％，２组比较Ｒｉｄｉｔ分析Ｐ＞０．０５。药物不良反应发生率地西泮组高于丁螺环酮组，但反应轻微不影响治疗。结论：丁螺环酮与地西泮疗效相同，不良反应少。     

Tranquilizing effects of diazepam in pigs subjected to a punishment procedure

A punishment discrimination was conditioned in pigs by simultaneously rewarding with food and punishing with electric shock all operant responses made in the presence of an odorous stimulus.Suppression of the punished responses did not develop after 5 days of training in pigs chronically treated with diazepam (1 mg/kg). Diazepam (0.25 to 2 mg/kg) consistently increased the number of punished responses on an already learned punished behaviour and decreased the latency of the first response during and after the odorous stimulus signalling the shock contingency. More marked effects were obtained with 1–2 mg/kg.The pig punishment procedure appears to be a useful technique in studying psychopharmacological agents of interest in veterinary therapeutics.     

Multiple oral doses of diazepam, oxazepam and phenobarbital to dogs--behavioural effects and correlation with antipyrine half-life.

The effects of prolonged treatment with phenobarbital, diazepam, and oxazepam on behaviour and on the plasma half-life of antipyrine have been studied in the dog. In this species the biotransformation of diazepam and oxazepam is known to be very similar to man. After equipotent doses of phenobarbital (25 mg/kg) and diazepam (35 mg/kg), antipyrine half-life was found to decrease 80 and 40%, respectively, while after treatment with oxazepam (150 mg/kg) there was an increase of 20%. The behavioural effects declined in the dogs during the course of treatment with diazepam but were rather constant during treatment with oxazepam.     

Distinct effects of diazepam and NK1 receptor antagonists in two conflict procedures in rats

Convergent data suggest that SP, through the activation of neurokinin1 receptors (NK1-R), may be involved in anxiety. In particular, NK1-R antagonists have been reported to exert anxiolytic-like effects in a variety of animal procedures in which anxiety-related behaviour is induced by novelty. The present study investigated the effects of acute blockade of NK1-R in conflict paradigms, another category of anxiety-related procedures, in which positively reinforced responses are suppressed by contingent punishment. For this purpose, three selective antagonists with nanomolar affinity for rat NK1-R, GR205171, RP67580 and [2-cyclopropoxy-5-(5-(trifluoromethyl)tetrazol-1-yl)benzyl]-(2-phenylpiperidin-3-yl)amine (Compound L), were tested in the safety signal withdrawal operant paradigm. In this procedure, suppression of lever pressing for food was induced by the withdrawal of a conditioned signal for safety, with no presentation of a conditioned signal for punishment, and no punishment. Compound L was also tested in the punished drinking test, which consists of the contingent delivery of electric footshocks upon water drinking. As expected, the reference compound, diazepam (2 mg/kg s.c.), induced an anxiolytic-like effect, as indicated by significant increases of the number of responses emitted during conflict period in the operant procedure, and footshocks received in the drinking test. In contrast, GR205171 (10 mg/kg s.c.), RP67580 (0.25-8 mg/kg s.c.) and Compound L (10 and 30 mg/kg s.c.) failed to release lever pressing during the operant conflict period. In addition, punished drinking was not affected by Compound L (3-30 mg/kg s.c.). These data show that NK1-R blockade has no anxiolytic-like effects in conflict paradigms, thereby suggesting that the anxiolytic properties of NK1-R antagonists are less broad than those reported for benzodiazepines.     

安定联合苯巴比妥治疗小儿惊厥的临床效果

目的探索分析安定联合苯巴比妥治疗小儿惊厥的临床效果。方法选取我院收治的惊厥患儿作为研究对象并实施分组治疗,对照组予以安定治疗,研究组联合使用苯巴比妥进行治疗。将临床效果进行对比。结果研究组患儿临床治疗总有效率显著高于对照组;研究组患儿惊厥症状控制时间显著少于对照组;研究组复发率显著低于对照组(P0.05)。结论应用苯巴比妥与安定联合使用药物方式治疗惊厥患儿,可以产生明显效果,有利于促进患儿康复,值得推广应用。     

Convulsions induced by hyperbaric oxygen: Inhibition by phenobarbital,diazepam and baclofen

Summary GABA was injected intraperitoneally to rats in single doses of 2.5 to 1500 mg/kg. Thirty minutes after injection a dose-dependent increase in dopamine (DA) and a decrease in noradrenaline (NA) content were observed in the brain. However, in the lowest dose range these levels showed small but significant changes in the opposite direction. The accumulation of dopa after inhibition of the aromatic L-aminoacid decarboxylase was enhanced by i.p. GABA both in DA- and in NA-predominated brain regions, the dose-response relations being complex. Increased levels of serotonin (5-HT), 5-hydroxyindole-acetic acid (5-HIAA) and tryptophan as well as enhanced accumulation of 5-hydroxytryptophan, induced by decarboxylase inhibition were also observed.The general pattern of effects was similar to that previously observed after intracerebroventricular injection of GABA, although the intraperitoneal doses required were higher. It is suggested that a certain penetration of GABA from the blood into the brain can occur, leading to changes in the physiological activity of monoaminergic neurons.     

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.     

Anxiolytic effects of diazepam and ethanol in two behavioral models: comparison of males and females

The present study compared the anxiolytic effects of the benzodiazepine agonist diazepam and ethanol in adult male and female rats. Varying doses of diazepam (1-3 mg/kg) or ethanol (0.5-2.0 g/kg) were tested using both the elevated plus maze and defensive prod-burying models. Two time points following ethanol administration (10 and 30 min) were tested in the plus maze. Sex differences were seen in some anxiety-related behaviors, with females showing greater open arm time and reduced burying behavior than males. Although this suggests females displayed less anxiety-like behavior than males, the differences in the plus maze were not observed in all testing situations. Both diazepam and ethanol dose-dependently increased open arm times in the plus maze and reduced burying behavior in the defensive prod-burying task. The parallel nature of the dose-response curves suggests that both diazepam and ethanol have similar anxiolytic effects in males and females. No sex differences were seen in the brain levels of diazepam-like activity or blood alcohol levels with these treatments. A greater corticosterone response was observed in females than males with these two behavioral tests, but neither diazepam nor ethanol decreased this response. These results suggest a dissociation between the anxiety-reducing influences of these compounds and the changes in stress-related endocrine responses.     

Buspirone,gepirone, ipsapirone,and zalospirone have distinct effects on the differential-reinforcement-of-low-rate 72-s schedule when compared with 5-HTP and diazepam

The effects of four serotonin (5-HT)-1A compounds (buspirone, gepirone, ipsapirone and zalospirone) were compared with 5-hydroxytryptophan (5-HTP) [a 5-HT precursor with antidepressant (AD) efficacy], and diazepam (a benzodiazepine anxiolytic), on a differential-reinforcement-of-low-rate 72-s (DRL 72-s) schedule. Past research has shown that AD and anxiolytic compounds each have distinct effects on the DRL 72-s interresponse time (IRT) distribution profile. In the present paper, the profile of the IRT distribution was quantitatively characterized by three metrics: burst ratio, peak location and peak area. 5-HTP shifted the IRT distribution peak toward longer IRT durations, increased reinforcement rate and decreased response rate. The profile of the IRT distribution was not disrupted by 5-HTP. Diazepam disrupted the IRT distribution and increased bursting. In general, the arylpiperazine, 5-HT_1A compounds increased reinforcement rate, decreased response rate and disrupted the profile of the IRT distribution. The effects of the four arylpiperazine 5-HT_1A compounds on the IRT distribution profile were different from the AD profile of 5-HTP and the benzodiazepine anxiolytic profile of diazepam. Disruption of the IRT distribution by buspirone, gepirone, ipsapirone and zalospirone may result from decreased 5-HT transmission mediated by the presynaptic, somatodendritic 5-HT_1A receptor.     

Sedative properties of doxepin in comparison with diazepam

Doxepin (Quitaxon^®) at doses of 25, 50, and 75 mg was compared with diazepam 7.5, 15, and 22.5 mg, using as variables the percentage lowering of Critical Flicker Fusion (CFF) and the self-estimated degree of drowsiness. Single doses were given, and repeated effect determinations were made over 6 h. Clear dose-effect relations could be demonstrated. The two drugs differed in speed and duration of action and in steepness of effect increase with dose. Although there were good correlations between CFF effect and subjective drowsiness, it seemed that the two methods interrelated somewhat differently in the different types of drug. CFF was a more stable and reliable method than the subjective estimation of drowsiness. However, when comparing drugs belonging to different classes, both methods preferably should be used together.