Effects of repeated treatment with 5-HT1A agonists on active avoidance responding in the rat

The behavioural effects of the serotonin 1A receptor (5-HT_1A) agonist anxiolytics are generally examined after acute administration. The present study examined the effects of these substances during repeated treatment in the two-way active avoidance (Conditioned Avoidance Response, CAR) procedure. Previously it has been found that the prototypical 5-HT_1A receptor agonist, 8-OH-DPAT, increases avoidance, apparently by increasing general activity, after repeated administration but not on acute administration. In the present study, it was demonstrated that this increase in activity can be blocked by the 5-HT_1A receptor antagonists (–)alprenolol (also beta adrenergic antagonist) and (S)-UH-301, but not by the non-selective 5-HT antagonist metergoline. The relatively full 5-HT_1A agonist, flesinoxan, and the partial 5-HT_1A agonist, ipsapirone, had qualitatively similar effects to 8-OH-DPAT, although the effect of ipsapirone was clearly smaller in magnitude. Buspirone, the 5-HT_1A partial agonist/dopamine D₂ antagonist, markedly decreased activity, and thus avoidance of the shocks, in a manner similar to the antipsychotic drug, haloperidol. However, when the hypothermic effects of these compounds were investigated after acute administration, buspirone induced a strong hypothermic response in rats, like 8-OH-DPAT, whereas haloperidol had no effect. With the exception of buspirone, the effectiveness of these compounds in increasing activity in the CAR test appears to be related to their agonist efficacy at the 5-HT_1A receptor. Similarities between the effects of these compounds and previously reported results with serotonin-depleting agents (Tenen 1967; Breese et al. 1974) suggest that the net effect of 5-HT_1A agonists after repeated administration is to produce a functional reduction in 5-HT activity. The activity suppressing action of buspirone indicates that the dopamine antagonist activity of buspirone predominates in this procedure.     

A rapid punishment procedure for detection of anxiolytic compounds in mice

Rationale Effects of compounds on punished responding have been predictive of anxiolytic efficacy in humans. The use of mice in these tests has been limited, but the utility of this species in drug discovery and for neurobiological inquiry would benefit from a rapid, reliable method.Objectives The present experiments were designed to validate a new procedure in mice.Methods Male, NIH Swiss mice were food deprived and placed in an experimental chamber with two nose-poke holes. Every nose poke (FR1) produced a 20 mg food pellet. On the following day, a drug vehicle was administered and the mice were again exposed to the FR1 schedule. On day 3, a compound was given and the mice were run under a mixed FR1 (food), FR1 (food+shock) schedule in alternating, unsignalled periods of 4 and 10 min for three cycles. In the 10-min periods, nose-pokes produced both food plus brief electrification of the grid floor (0.5 mA for 100 ms). Effects of compounds on food intake were also evaluated in separate groups of mice.Results The introduction of shock substantially decreased responding during the 10-min punishment periods without significantly affecting responding during the non-punishment periods. The clinically effective anxiolytic agents chlordiazepoxide, pentobarbital, and bretazenil, but not buspirone, produced dose-dependent increases in suppressed responding, whereas d-amphetamine, chlorpromazine, and morphine were not effective. Chlordiazepoxide and bretazenil increased food consumption.Conclusions The present method enables rapid and reliable evaluation of potential anxiolytic agents in mice with minimal training. Increases in food intake are not necessary for anxiolytic-like effects under these conditions.     

Impaired action of anxiolytic drugs in mice deficient in cannabinoid CB1 receptors

The role of cannabinoid CB(1) receptors in the action of anxiolytics was examined. Deletion of CB(1) receptors resulted in increased anxiety-like behaviours in light/dark box, elevated plus maze and social interaction tests. Mutant mice presented basal low corticosterone concentrations and low proopiomelanocortin gene expression in the anterior lobe of the pituitary gland compared to wild-type mice. Ten minutes of restraint stress resulted in a twofold increase in corticosterone concentrations in the plasma of mutant mice, compared to wild-type mice. Bromazepam (50 or 100 microg/kg) markedly increased the time spent in light area in wild-type animals, though both doses were without effect in mutant mice. Administration of buspirone (1 or 2 mg/kg) produced anxiolytic effects in wild-type mice. In contrast, only the highest dose of buspirone had anxiolytic results in mutant mice. Our findings reveal that CB(1) receptors are involved in the regulation of emotional responses, and play a pivotal role in the action mechanism of anxiolytics. They suggest that alterations in the functional activity of the CB(1) receptor may be related to the emergence of anxiety disorders, and may affect treatment with anxiolytics.     

The effect of social factors on the anxiolytic efficacy of buspirone in male rats, male mice, and men

Earlier findings suggest that housing conditions in laboratory animals and life events in humans influence the efficacy of anxiolytic drugs. Here we report on the impact of social isolation on buspirone efficacy in male mice and rats as assessed by the elevated plus-maze. In addition, the impact of social support on buspirone efficacy was assessed in male patients. When administered 30 min before testing and irrespective of housing conditions, buspirone significantly suppressed locomotor activity both in mice (6 mg/kg) and rats (10 mg/kg) and, as such, other behavioral changes observed at this time point must be seen as behaviorally nonselective. However, these locomotor disruptive effects of buspirone were not evident in either species at longer injection-test intervals (2 and 4 h). When given 2 h prior to testing, a low (3 mg/kg) but not high (10 mg/kg) dose of buspirone increased the frequency of open arm exploration in rats (but not mice) irrespective of housing conditions. At the longest injection-test interval used (4 h), buspirone increased the duration of open arm exploration in individually housed, but not group-housed, rats. Similar, though somewhat less robust, effects were observed in male mice at this time. In a double-blind placebo-controlled study with male patients, chronic buspirone treatment (3×10 mg daily for 6 weeks) produced a highly significant reduction in scores on the Hamilton Rating Scale for Anxiety (HAM-A). Multiple regression analysis of social support received by patients indicated that the support of nonrelatives (but not of family or other relatives) was a strong positive predictor of buspirone efficacy. Taken together, our data support the hypothesis that social conditions affect the anxiolytic efficacy of buspirone. Results are discussed in relation to differences in the social organization of the three species investigated.     

丁螺环酮与地西泮治疗焦虑症的临床对照研究

目的评价丁螺环酮治疗焦虑症的临床疗效和副反应。方法对56例符合CCMD-3诊断标准的焦虑症患者，应用丁螺环酮（28例）、地西泮（28例）进行对照治疗，疗程4周。采用焦虑自评量表（SAS）、Hamilton焦虑量表（HAMA）和副反应量表（TESS）评定疗效和副反应。结果丁螺环酮与地西泮对焦虑症的疗效无显著性差异（P〉0．05）。治疗第4周末两组SAS、HAMA以及HAMA因子分的减分比较差异有非常显著性（P〈0．01）。副反应两药相似，丁螺环酮的主要副反应为恶心、头晕和失眠。结论丁螺环酮治疗焦虑症有效，副反应轻微。     

Behavioural and pharmacological characterisation of the canopy stretched attend posture test as a model of anxiety in mice and rats

The behavioural element, stretched attend posture (SAP), is an important component of the “risk-assessment” repertoire of defensive behaviour in rodents. The present experimental paradigm was devised as a novel and simple method of eliciting high levels of SAP in mice and rats. The SAP test apparatus comprised an elevated black Perspex circular platform. A smaller clear red Perspex circular “Canopy” was supported directly above the platform by a central pillar, thus dividing the platform into an inner, dimly lit covered zone and an outer, brightly lit exposed zone. In both the rat and mouse version of this model, vehicle-treated animals exhibited a marked preference for exploring the covered zone and also exhibited high baseline levels of SAP, particularly at the covered zone boundary whilst they investigated the exposed zone. In the mouse SAP test, the benzodiazepine receptor agonists, diazepam (0.5 mg/kg SC) and chlordiazepoxide (2 mg/kg SC), and the 5-HT_1A receptor agonists, buspirone (1 and 3 mg/kg SC), ipsapirone (3 mg/kg SC) and 8-OH-DPAT (0.2 mg/kg SC), all significantly decreased the frequency of SAP without impairing motor activity. In the rat SAP test, diazepam (0.5 mg/kg SC) significantly decreased, whilst the anxiogenic 5-HT_2C/1B receptor agonist, mCPP (0.25 and 0.5 mg/kg SC), significantly increased, the frequency of SAP. Ipsapirone (3 mg/kg SC) induced a non-specific behavioural inhibition. These data suggest that the “Canopy” SAP test is a useful paradigm to investigate risk assessment behaviour in both rats and mice, and may provide a sensitive novel rodent model of anxiety. Received: 11 October 1996/Final version: 18 February 1997     

Effects of acute and chronic buspirone on impulsive choice and efflux of 5-HT and dopamine in hippocampus, nucleus accumbens and prefrontal cortex

Rationale Reduced central serotonin (5-HT) activity has been associated with impulsive choice behaviour, but there is no consensus about the precise nature of these effects. Behavioural and neurochemical effects of 5-HT_1A agonists such as buspirone depend critically on the dose and the duration of treatment. We thus undertook a parametric study of the effects of acute and chronic buspirone on the performance on a test of delayed gratification, as well as on the efflux of serotonin and dopamine (DA) in cortical and subcortical regions in rats.Objectives Three experiments examined (i) the effects of acute buspirone on impulsive choice and how such effects were modified by prior chronic exposure to buspirone; (ii) the effects of chronic buspirone on impulsive choice; (iii) the effects on impulsive choice of a selective 5-HT_1A antagonist, WAY-100635 tested alone and in combination with buspirone; (iv) the effects of chronic and acute buspirone on 5-HT and DA efflux in anaesthetised rats.Methods In experiment 1, rats previously trained on the delayed gratification task were tested with acute buspirone (0.5, 1 and 2 mg/kg). The same rats were then treated with chronic buspirone (1 mg/kg/day) over the next 65 days, and the effects of acute buspirone (1 mg/kg) re-determined at 20, 45 and 65 days of chronic treatment. In experiment 2, two groups of rats trained on the delayed gratification task were treated either with saline or buspirone (1 mg/kg/day) continually for 65 days before being tested with acute buspirone (1 mg/kg), WAY-100635 (0.08 mg/kg), or a combination of the two drugs. In experiment 3, rats received the same regimen of buspirone dosing as in experiment 2, before receiving in-vivo microdialysis for 5-HT and DA in the ventral hippocampus, nucleus accumbens and medial prefrontal cortex.Results Acute buspirone dose dependently increased the choice for the small, immediate reinforcer (impulsive choice) but the effects of 1 mg/kg were reversed on chronic administration of buspirone. This increased choice of the large, delayed reinforcer, which was not accompanied by any changes in baseline (non-drugged) performance, was blocked by the 5-HT_1A receptor antagonist WAY-100635. The chronic buspirone regimen did not alter buspirone-evoked reductions in 5-HT efflux in hippocampus but did lead to a differential effect of acute buspirone in medial prefrontal cortex, with the chronic buspirone and saline groups exhibiting decreases and increases in efflux, respectively. There were no systematic changes in DA efflux under any condition.Conclusions These findings show that the effects of acute buspirone on impulsive choice are reversed following chronic treatment and are mediated by 5-HT_1A receptors, and suggest, in addition, that the behavioural effects may involve changes in 5-HT functioning in medial prefrontal cortex.     

丁螺环酮治疗肠易激综合征的临床研究

目的 探讨丁螺环酮治疗肠易激综合征的疗效。方法 对98例肠易激综合征（IBS）患者进行汉密尔顿焦虑量表（HAMA）评分；用丁螺环酮和安慰荆治疗IBS患者，疗程8周，治疗后第4、8周再次评分。结果 和安慰剂组比较，IBS患者接受丁螺环酮治疗8周后，精神和躯体症状有明显改善。结论 丁螺环酮治疗能显著改善IBS患者的精神和躯体两方面的症状.     

万拉法新与丁螺环酮治疗广泛性焦虑症对照研究

目的 验证万拉法新治疗广泛性焦虑症的疗效及副反应。方法 对符合CCMD-2-R广泛性焦虑症诊断标准的患者，随机分为万拉法新组和丁螺环酮组治疗6周。于治疗前及治疗后1，2，4，5周末用汉密尔顿焦虑量表（HAMA），焦虑自评量表（SAS），临床总体评定量表（CGI）及副反应量表（TESS）评定临床疗效及副反应。结果 万拉法新与丁螺环酮疗效相当，起效时间相近，没有严重副反应。结论 万拉法新治疗广泛性焦虑症疗效确切，副反应少而轻，患者服药依从性好。     

西酞普兰合并丁螺环酮对老年抑郁症的对照研究

目的:探讨西酞普兰合用丁螺环酮对老年抑郁症的疗效和安全性.方法:90例老年抑郁症患者,随机分为治疗组(西酞普兰合用丁螺环酮)和对照组(单用西酞普兰),疗程8周,采用汉密尔顿抑郁量表(HAMD-17)、汉密尔顿焦虑量表(HAMA)和治疗中出现的症状量表(TESS)进行评定.结果:治疗两周,治疗组HAMD、HAMA评分较对照组显著下降(P＜0.01),起效快.治疗4、6、8周末,两组间差异有显著性(P＜0.01).治疗组不良反应少,两组间差异有统计学意义(P＜0.01).结论:西酞普兰合并丁螺环酮治疗老年抑郁症起效快,安全性好.