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     

Vigabatrin has an anxiolytic effect in the elevated plus-maze test of anxiety.

tau-Vinyl GABA (vigabatrin, GVG) is a novel antiepileptic drug that irreversibly inhibits GABA transaminase and elevates GABA levels in all parts of the brain. In the present study, we investigated the anxiolytic and behavioral effects of GVG in the elevated plus-maze and the hole board compared to diazepam. Doses of 500 and 1,000 mg/kg GVG were injected IP to different groups of male Wistar rats and animals were tested either 4 or 24 h after injection. Animals administered diazepam (1.5 mg/kg, IP) and saline (1 ml) were tested 20 min after injection. GVG and diazepam were found to decrease significantly the number of squares visited and rearing; both had a suppressant effect on locomotor activity. Neither drug had an effect on exploration (head dipping). GVG at a dose of 1,000 mg/kg was shown to have a similar anxiolytic activity either after 4 or 24 h as diazepam, while GVG at 500 mg/kg did not show any significant anxiolytic effect.     

An evaluation of the elevated plus-maze test using the novel anxiolytic buspirone

Previous work suggests that the elevated plusmaze test of anxiety is insensitive to the anxiolytic effects of the novel anxiolytic buspirone, which shows an anxiogenic-like profile in this test. This paper examines some of the possible reasons for this and the role that buspirone's agonist activity at 5-HT_1A receptors plays in this effect. A variety of 5-HT_1A receptor agonists (p-aminophenylethylm-trifluromethylphenyl piperazine, (+)- and (-)-MDL 72832) showed similar activity to buspirone, as did the related compound ipsapirone. (-)-MDL 72832 was more potent than (+)-MDL 72832, in keeping with its stereoselective action at 5-HT_1A receptors. The ₂-adrenoceptor antagonist properties of 1-pyrimidinyl piperazine, a metabolite of buspirone, did not appear to be relevant to this action of buspirone as neither it nor idazoxan showed an anxiogenic-like profile. Neither chronic treatment with buspirone (1 mg/kg SC twice a day for 16 days) nor depletion of 5-HT withp-chlorophenylalanine changed the anxiogenic-like activity of buspirone in the elevated plus-maze test. These results suggest that an agonist action at postsynaptic 5-HT_1A receptors mediates the anxiogenic-like effects of buspirone in the elevated plus-maze test and that this test may either be insensitive to certain classes of anxiolytics or is measuring something unrelated to human anxiety states.     

Indomethacin does not antagonize the anxiolytic action of ethanol in the elevated plus-maze

The present study was designed to examine whether the prostaglandin (PG) synthesis inhibitor indomethacin (INDO) could antagonize the anxiolytic effects of ethanol (EtOH) in the elevated plus-maze test of anxiety. EtOH (1.6 g/kg) significantly increased the percentage of open arm entries and time spent on the open arms in both inbred C57BL/6J and outbred CD-1 mouse strains. However, this anxiolytic effect of EtOH was not significantly antagonized by pretreatment with INDO (5 and 10 mg/kg) in either strain. EtOH also significantly increased total arm entries in CD-1 mice, but not in the C57BL/6J strain. These data from C57BL/6J mice indicate that the low-dose stimulant properties of EtOH can be dissociated from the anxiolytic action of the drug in the plus-maze task. Finally, although INDO did not antagonize the stimulant effect of EtOH in the plus-maze task (in CD-1 mice), it did attenuate EtOH-induced stimulation of locomotor activity in an open-field arena. Taken together, these results suggest some specificity with regard to the role of PGs in mediating (or modulating) the neurobehavioral actions of EtOH, and further support the notion that the anxiolytic and stimulant effects of EtOH may be mediated by different mechanisms.     

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. In conclusion, the present experiment revealed that the anxiolytic effect of DN-2327 in this test was clear, whereas buspirone showed no apparent effect.     

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.     

Identification of anxiolytic ingredients in ginseng root using the elevated plus-maze test in mice

Ginseng root has been widely used for the management of anxiety and emotional instability, but there is little experimental evidence supporting these clinical applications. We pharmacologically identified the anxiolytic components in ginseng root, using the elevated plus-maze test. Male ICR albino mice and the following drugs were used: diazepam (0.5, 1 and 1.5 mg/kg, p.o.); red ginseng powder (300, 600 and 1200 mg/kg, p.o.); crude saponin and non-saponin ginseng fractions (50, 100 and 200 mg/kg, i.p., for each preparation); and pure ginsenoside Rb1, Rg1, and Ro (2.5, 5 and 10 mg/kg, i.p., for each preparation). Ginseng powder and crude saponin ginseng fraction significantly increased the frequency and duration of open arm entries. Among the three types of pure ginsenoside, only ginsenoside Rb1 significantly increased both the frequency and duration of open arm entries. Our results clearly indicate that ginsenoside Rb1 is one of the active anxiolytic components of ginseng root.     

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.     

Antianxiety effect of cannabidiol in the elevated plus-maze

In order to assess the presence of anxiolytic properties in cannabidiol (CBD) the drug was tested in an elevated plus-maze model of anxiety, in rats. Doses of 2.5, 5.0 and 10.0 mg/kg significantly increased the entry ratio (open/total number of entries), an anxiolytic-like effect. CBD at a dose of 20.0 mg/kg was no longer effective. None of the doses of CBD used changed total number of entries, a measure of total exploratory activity. Diazepam (2.0 mg/kg) also caused an anxiolytic-like effect in this model. These results indicate that CBD causes a selective anxiolytic effect in the elevated plusmaze, within a limited range of doses.     

Microinjection of propranolol into the dorsal periaqueductal gray causes an anxiolytic effect in the elevated plus-maze antagonized by ritanserin

The 5-HT_1A/1B receptor antagonist propranolol was injected into the dorsal periaqueductal gray (DPAG) of rats exposed to the elevated plus-maze in order to investigate the participation in anxiety of 5-HT mechanisms operating in this brain region. Microinjection ofd,l- orl-propranolol into the DPAG increased the percentage of total arm entries without affecting the total number of entries into either open or enclosed arms of the maze, an effect characteristic of anxiolytic drugs injected systemically. The doses of 5 nmoll-propranolol and 10 nmold,l-propranolol caused anxiolytic effects of comparable magnitude, while the doses of 2.5 nmol of the former and 5 nmol of the latter were ineffective. Therefore, thel-isomer is likely to be the main one responsible for the pharmacological activity observed. In addition, the anxiolytic effect of 10 nmold,l-propranolol was antagonized by 10 nmol of the 5-HT_2/1C receptor antagonist ritanserin, previously injected into the DPAG. The present as well as previously reported results suggest that the anxiolytic effect of propranolol injected into the DPAG is due to increased release of 5-HT acting on post-synaptic 5-HT₂ receptors, resultant from blockade of 5-HT_1B autoreceptors that inhibit amine release from serotonergic nerve endings.     

Mianserin-induced 5-HT2 receptor downregulation results in anxiolytic effects in the elevated plus-maze test

Several agents that downregulate 5-HT₂ receptors produce anxiolytic effects in humans, but the role of 5-HT₂ receptor downregulation has been difficult to assess because of their other actions. To test the effects of pharmacological downregulation of 5-HT₂ receptors on exploratory behavior in the mouse, mianserin, a drug known to downregulate 5-HT₂ receptors after a single dose, was administered 30 min, 48 hr, or 18 days prior to testing in the elevated plus-maze. Following testing in the elevated maze, the head-shake response to 4-iodo-R-(—)-2,5-dimethoxyphenylisopropylamine (DOI), a selective 5-HT₂/5-HT_1C agonist was assessed, and in a separate group of animals 5-HT_1A, 5-HT_1B, 5-HT_1C, β₁,β₂, and 5-HT₂ agonist and antagonist binding was quantified autoradiographically. Mianserin pretreatment resulted in a significant dose-related anxiolytic effect in the elevated plus maze evidenced by increases in the percentage of entries to, and time spent on the open arms. Head-shakes induced by DOI were also dose-dependently decreased as a result of mianserin pretreatment. At this time, the binding of the 5-HT₂ receptor antagonist, 7-amino-8[¹²⁵I]ketanserin was decreased by 50%. Binding of DOI to 5-HT₂ receptors was decreased by 46%, and to 5-HT_1C receptors was decreased by 53%, but no other changes were found in any of the other receptor types examined. These findings demonstrate that the 5-HT₂ receptor plays at least a permissive role in anxiety-like behaviors, since an intact 5-HT₂ system is necessary for the full expression of the anxiety-like response, but the role of 5-HT_1C receptor downregulation in the effects of mianserin cannot be ruled out at this time. © 1992 Wiley-Liss, Inc.     

Anxiolytic effect of cannabidiol derivatives in the elevated plus-maze

• 1.1. In order to assess the presence of anxiolytic properties in cannabidiol (CBD) derivatives HU-219, HU-252 and HU-261, these drugs were tested in rats submitted to the elevated plus-maze model of anxiety.
• 2.2. Additional groups received diazepam or CBD. HU-219 (0.03-1 mg/kg) and CBD (5 mg/kg) significantly increased the percentage of open arm entries without changing the total number of entries, an anxiolytic-like effect.
• 3.3. Both HU-252 and HU-261 increased the percentage of time spent in open arms and the total number of entries, but only at the dose of 1 mg/kg.
• 4.4. Diazepam (2.5 mg/kg) increased both the percentage of entries and time spent on open arms and the total number of entries.
• 5.5. The results confirm previous findings with CBD and indicate that its derivative HU-219 may possess a similar anxiolytic-like profile.
• 6.6. Results from HU-252 and HU-261 are less apparent and suggest that the compounds may increase general exploratory activity in a limited range of doses.

     

Effect of valepotriates on the behavior of rats in the elevated plus-maze during diazepam withdrawal

The effect of a mixture of valepotriates on the elevated plus-maze performance of diazepam withdrawn rats was evaluated. The rats were chronically (28 days) treated with diazepam (doses increased up to 5.0 mg/kg) and then treated with control solution for 3 days to induce a withdrawal syndrome. Chronically vehicle-treated rats were used as control.The abstinent animals treated with vehicle showed a significant decrease in the percentage of time spent in the open arms when compared with the control animals. Diazepam and valerian 12.0 mg/kg reversed this anxiogenic effect. Valerian 6.0 mg/kg did not show any difference in relation to the others group.     

Evidence that tolerance develops to the anxiolytic effect of diazepam in rats

The development of tolerance to the anxiolytic effect of diazepam was studied using suppression of defensive burying as an animal model of anxiolytic action. Although tolerance to the suppressive effect of diazepam was not apparent after chronic administration of diazepam when the rats were tested with a low-intensity shock, anxiolytic tolerance was detected under exactly the same drug regimen when the rats were tested with somewhat higher intensity shocks: under the latter conditions, chronically treated rats buried significantly more than acutely treated rats. Furthermore, this tolerance effect did not appear to depend upon the injection environment, the control vehicle, or the strain of rat; under each of these experimental variations rats chronically treated with diazepam buried significantly more than acutely treated rats when they had received a moderately high intensity shock. These results suggested that tolerance to the anxiolytic effects of benzodiazepines may be detectable when the stimuli eliciting anxiety are relatively intense.     

MK-801 produces antianxiety effect in elevated plus-maze in mice

The antianxiety effect of the non-competitive NMDA receptor antagonist, MK-801, was investigated in the present study in the elevated plus-maze paradigm in mice. During a 5-min session of the test, the number of entries the animal made in open/and closed arm, preference of the animal for first entry, and average time each animal spent in open and closed arm were noted as parameters for anxiety-related movements. The effect of MK-801 was further explored by studying its interaction with the specific anxiolytic agent, diazepam; the anxiogenic beta carboline agent, FG 7142; and the central benzodiazepine receptor antagonist, flumazenil (RO 15–1788). MK-801 produced anxiolytic effects at all the doses investigated. It increased the preference of the animal for open arm in a dose-dependent manner and the effect was potentiated by diazepam. Both FG 7142 and flumazenil reversed the effects of MK-801 when these agents were concomitantly administered with MK-801. The study revealed the anxiolytic effect of MK-801, a non-competitive antagonist of NMDA-receptor, and also an interaction of the NMDA-receptor and GABA/BZ-receptor complex in anxiety-related behaviour in mice.     

A lack of tolerance to the anxiolytic effects of diazepam on the plus-maze: comparison of male and female rats

Rationale: The demonstration of tolerance to the anxiolytic effects of benzodiazepines remains inconsistent. Objectives: The present study tested the hypothesis that intact and gonadectomized male and female rats might exhibit differential tolerance to the anxiolytic effects of diazepam (DZ). Methods: Following acute (3 days) or chronic (3 weeks) DZ exposure, all animals were tested on the elevated plus-maze and immediately sacrificed for analysis of corticosterone, adrenocorticotropin hormone, estrogen and progesterone levels in serum. In experiment 2, following acute or chronic DZ exposure, animals were treated with a DZ challenge dose on the test day. Results: In experiment 1, both acute and chronic DZ treatment similarly enhanced percentage open arm time and entries, regardless of the hormonal status of the animal. The results of experiment 2 showed that both acute and chronic DZ-treated animals exhibited a significantly higher percentage open arm time than control animals after the DZ challenge dose, and males and females did not differ in their responses to DZ exposure. Conclusions: The findings from these experiments suggest that tolerance to the anxiolytic effects of DZ did not develop in males or females, and that the hormonal status of the animal does not significantly alter the anxiolytic effects of DZ following either acute or chronic exposure. Following plus-maze exposure, females had significantly higher corticosterone levels than males and acute DZ treatment diminished this stress response. Received: 23 February 1999 / Final version: 28 July 1999     

Anxiogenic effect of sleep deprivation in the elevated plus-maze test in mice

Rationale Several clinical studies demonstrate that the absence of periods of sleep is closely related to occurrence of anxiety symptoms. However, the basis of these interactions is poorly understood. Studies performed with animal models of sleep deprivation and anxiety would be helpful in the understanding of the mechanisms underlying this relationship, but some animal studies have not corroborated clinical data, reporting anxiolytic effects of sleep deprivation.Objectives The aim of the present study was to verify the effects of different protocols of sleep deprivation in mice tested in the elevated plus-maze and to assess the effect of chlordiazepoxide and clonidine.Methods Three-month-old male mice were sleep-deprived for 24 or 72 h using the methods of single or multiple platforms in water tanks. Mice kept in their home cages were used as controls. Plus-maze behavior was observed immediately after the deprivation period.Results Mice that were sleep-deprived for 72 h spent a lower percent time in the open arms of the apparatus than control animals. This sleep deprivation-induced anxiety-like behavior was unaffected by treatment with chlordiazepoxide (5.0 and 7.5 mg/kg IP), but reversed by an administration of 5 or 10 g/kg IP clonidine.Conclusion The results indicate that under specific methodological conditions sleep deprivation causes an increase in anxiety-like behavior in mice exposed to the elevated plus-maze.     

Dissociation between the locomotor and anxiolytic effects of acetaldehyde in the elevated plus-maze: Evidence that acetaldehyde is not involved in the anxiolytic effects of ethanol in mice

Acetaldehyde, the first product of ethanol metabolism, has been suggested to play a major role in many behavioral effects of ethanol. However, very few studies have directly tested the behavioral effects of the acute administration of acetaldehyde. In particular, the role of this metabolite in ethanol-induced anxiolytic effects has never been extensively tested. The aim of the present study was to characterize the anxiolytic effects of acetaldehyde in two strains of mice, C57BL/6J and CD1 mice with the elevated plus-maze procedure. The results show that acute injections of ethanol (1–2 g/kg) induced significant dose-dependent anxiolytic effects in both strains of mice. In contrast, acetaldehyde failed to produce any anxiolytic effect, although it induced a significant hypolocomotor effect at the highest doses. In an independent experiment, cyanamide, an aldehyde dehydrogenase inhibitor, prevented the locomotor stimulant effects of ethanol, although it failed to alter its anxiolytic effects. Together, the results of the present study indicate that acetaldehyde is not involved in ethanol-induced anxiolytic effects, although it may be involved in its sedative/hypolocomotor effects.     

One-trial tolerance to the anxiolytic effects of chlordiazepoxide in the plus-maze

Chlordiazepoxide (CDP 7.5 mg/kg) had a significant anxiolytic effect in rats tested on the plus-maze for the first time. On a second trial the control scores did not change, but those of the CDP group did and they no longer differed from controls. Rats previously tested undrugged or after flumazenil (4 mg/kg) also failed to show an anxiolytic response to CDP. Thus this phenomenon of one-trial tolerance depended on prior experience with the plus-maze. It also depended on CDP acting at the benzodiazepine receptors on trial 2, since the joint administration of CDP and flumazenil on trial 2 reversed the phenomenon.     

Anxiolytic effect of carbamazepine in the elevated plus-maze: possible role of adenosine

In order to extend previously reported observations with other animal models of anxiety, the effect of carbamazepine (CBZ) was presently measured in rats placed on the elevated plus-maze. Intraperitoneal injection of CBZ (5–40 mg/kg) increased the percentage of open arm entries as well as the percentage of time spent on the open arms of the maze, without affecting the total number of arm entries. This effect is characteristic of anxiolytic drugs. The inhibitor of adenosine neuronal uptake papaverine (5–40 mg/kg) caused a similar anxiolytic effect, whereas the adenosine receptor antagonist aminophylline (1–4 mg/kg) selectively decreased the percentage of open arm entries, indicative of an anxiogenic effect. Furthermore, the combination of an anxiogenic dose (4 mg/kg) of aminophylline with an anxiolytic dose (40 mg/kg) of CBZ resulted in cancellation of each other effects. Since reported neurochemical evidence shows that CBZ interacts with adenosine receptors, the present results provide preliminary support for a participation of this neurotransmitter in the anxiolytic action of CBZ.