Agastache mexicana may produce anxiogenic-like actions in the male rat.

Behavioral effects of a water-soluble extract of Agastache mexicana, a plant with purported anxiolytic actions, were studied in male Wistar rats. In the elevated plus-maze test, various doses of the plant extract (3.0 mg/kg body wt.; 9.0 mg/kg body wt.; 12.0 mg/kg body wt.) administered intraperitoneally (i.p.) decreased the exploration of open arms, showing an anxiogenic-like effect. Agastache mexicana (12 mg/kg body wt.; i.p.) did not change immobility in the forced swimming test (i.e., had no anti-depressant effect) but increased the anti-immobility action of 32.0 mg/kg body wt. (i.p.) of desipramine (i.e., increased the antidepressant-like effect of desipramine). A. mexicana had no effect on exploratory activity in an open field test, indicating that it had no sedative effect at the doses used. It is concluded that effects of the water extract of A. mexicana are more consistent with an anxiogenic-like property than an anxiolytic-like one.     

Augmentation of the NO-cGMP cascade induces anxiogenic-like effect in mice.

Several studies have reported the anxiolytic-like effects of various nitric oxide synthase inhibitors in distinct animal models. However, in the context of anxiety, the possible involvement of cyclic GMP, believed to be one of the main targets of NO, remains obscure. Cyclic GMP is degraded by the specific phosphodiesterases in the brain. Therefore, we studied the effect of the selective phosphodiesterase type 5 inhibitor sildenafil in the mouse elevated plus-maze test of anxiety and in the open field test of locomotion. We found that sildenafil (0.05-10 mg/kg i.p.) alone did not affect the behavior of animals in the plus-maze or open field tests, but the anxiogenic beta-carboline DMCM given in a subconvulsive dose (2 mg/kg i.p.) decreased the time spent on open arms in the elevated plus-maze. Treatment with the NO precursor L-arginine (200 mg/kg i.p.) did not modify the behavior of animals in the plus-maze, however, when sildenafil (1 mg/kg i.p.) was administered in combination with L-arginine (200 mg/kg i.p.), both the time spent on the open arms and the percentage of open arm visits were significantly decreased. We conclude that augmentation of the NO-cGMP cascade induces anxiogenic-like effect in mice.     

Gamma-decanolactone effect on behavioral and genotoxic parameters

Gamma-decanolactone is a monoterpene compound, which is shown to be active in some animal models. The psychopharmacological evaluation of this compound in mice has revealed that it has a dose-dependent effect on the central nervous system, including hypnotic, anticonvulsant and hypothermic activities. The aim of the present study was to evaluate the effect of gamma-decanolactone at 0.1 and 0.3 g/kg on behavior parameters related to plus-maze, open field and forced swim tests. In addition, we investigated its genotoxic activity. Gamma-decanolactone at the dose of 0.3 g/kg, but not 0.1 g/kg, decreased the number of crossings and rearings and there were no significant differences among groups regarding the latency to start locomotion in open field. A single i.p. administration of gamma-decanolactone, at the higher, but not at lower dose used, was able to increase the exploratory activity in the test session (24 h after training), as assessed by the number of rearings performed in open field, and induced DNA damage on brain tissue as measured in comet assay, suggesting an impairment of nonassociative, nonaversive learning and a genotoxic effect on CNS. Gamma-decanolactone did not change the behavior of animals in plus-maze and forced swim tests, suggesting this compound shows no anxiolytic or antidepressant activity.     

Rubiscolin-6, a delta opioid peptide derived from spinach Rubisco, has anxiolytic effect via activating sigma1 and dopamine D1 receptors

Rubiscolin-6 (Tyr-Pro-Leu-Asp-Leu-Phe) is a delta opioid peptide derived from the large subunit of spinach d-ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco). We previously reported that rubiscolin-6 had an analgesic effect and stimulated memory consolidation. Here we show that intraperitoneally (i.p.) or orally administered rubiscolin-6 has an anxiolytic effect at a dose of 10 mg/kg or 100 mg/kg, respectively, in the elevated plus-maze test in mice. The anxiolytic effects of rubscolin-6 after i.p. (10 mg/kg) and oral (100 mg/kg) administration were blocked by a delta opioid receptor antagonist, naltrindole (1 mg/kg, s.c.), suggesting that the anxiolytic activity of rubiscolin-6 is mediated by delta opioid receptor. The anxiolytic effect of rubiscolin-6 (10 mg/kg, i.p.) was also blocked by a dopamine D(1) antagonist, SCH23390 (30 microg/kg, i.p.), but not by a dopamine D(2) antagonist, raclopride (15 microg/kg, i.p.). The anxiolytic effect of rubiscolin-6 (10 mg/kg, i.p.) was blocked by sigma(1) receptor antagonist, BMY14802 (0.5 mg/kg, i.p.) or BD1047 (10 mg/kg, i.p.). Taken together, the anxiolytic effect of rubiscolin-6 is mediated by sigma(1) and dopamine D(1) receptors downstream of delta opioid receptor.     

Mimosa pudica may possess antidepressant actions in the rat.

In Mexico, aqueous extracts from dried leaves of Mimosa puolica are employed to alleviate depression. In this study, the behavioral actions of aqueous extracts of M. pudica at various concentrations were tested. Rats having received saline (0.9%; 0.30 ml; I.P.), clomipramine, desipramine or several dosages of aqueous extracts from M. pudica (ml = 2.0 mg/kg; m2 = 4.0 mg/kg; m3 = 6.0 mg/kg; m4 = 8.0 mg/kg) during a 30-day period were submitted to the forced swimming test and to the test for differential reinforcement of low rates of response at 72 sec (DRL-72s). Any possible anxiolytic action resulting from several doses (ml = 2.0 mg/kg; m2 = 4.0 mg/kg; m3 = 6.0 mg/kg; m4 = 8.0 mg/kg) of extracts of M. pudica were compared with those caused by diazepam (1.3 mg/kg, I.P.) in the elevated plus-maze test. Results showed that clomipramine (1.25 mg/kg, I.P.), desipramine (2.14 mg/kg, I.P.) and M. pudica (6.0 mg/kg and 8.0 mg/kg, I.P.) reduced immobility in the forced swimming test and increased the rate of reinforcers received in the DRL-72s test; these data suggest that M. pudica produces antidepressant effects in the rat. Diazepam increased the open-arms exploration time in the elevated plus-maze test, but M. pudica did not show any comparable action at any tested dose. M. pudica therefore produced an antide-pressant-like profile similar to two tricyclic antidepressants.     

Individual differences in the elevated plus-maze and the forced swim test

The elevated plus-maze is an apparatus composed of enclosed and open (elevated) arms and time spent in the open arms by a rat can be increased/decreased by anxiolytic/anxiogenic agents. In the forced swim test, floating behavior is used as an index of behavioral despair and can be decreased by antidepressant agents. As the comorbidity between anxiety and depression is a remarkable issue in human behavioral disorders, a possible relationship between the behaviors seen in the cited tests is of great relevance. In the present study, fifty-four male rats (Rattus norvegicus) were submitted to a plus-maze session and to a 2-day forced swim protocol. According to their time in the open arms, they were divided into three groups: Low Open, Medium Open and High Open. Some plus-maze measures were found to be coherent with time in the open arms and are suggested to also be reliable anxiety indexes. In the forced swim test, the Low Open group showed decreases in floating duration from forced swim Session 1 to Session 2, an alteration opposite to that observed in the other groups (particularly, the Medium Open group). The Low Open group also showed increases in floating latency, again in sharp contrast with the alteration found in the other groups. Accordingly, positive and negative correlation were found between time in the open arms and floating duration and latency, respectively. Results are compared to previous studies and mediation of the effect by reactivity to aversive stimulation or alterations induced by open arm exposure is discussed.     

Effects of chronic buspirone treatment on female mice exposed to the long-lasting psychoemotional influence

The effects of chronic treatment (30 days) with the 5-HT1A receptor partial agonist buspirone (0.05, 1 and 10 mg/kg i.p.) on the behaviour of C57BL/6J female mice exposed to long-lasting psychoemotional influence were studied. The influence involved forced living of each female with an aggressive male separated with a perforated transparent partition in the same cage and daily female's presence during 10-min intermale confrontations behind a partition caused by introducing of another male to the aggressive male. Chronic buspirone injection (in all used doses) did not affect the behaviour of females estimated in the "partitions" and "open field" tests at the end of the drug treatment. The anxiolytic effect of buspirone only at the dose of 1 mg/kg on the female's plus-maze behaviour was revealed. In the Porsolt, test buspirone in the dose of 1 mg/kg caused a slight increase in the duration of immobility indicating a slight pro-depressive effect. Thus, chronic buspirone treatment of females exposed to the long-lasting psychoemotional impact has a different effect on their behaviour depending on the dose and test conditions.     

Anxiolytic Properties of New Chemical Entity, 5TIO1

2-[(2,6-dichlorobenzylidene)amino]-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbonitrile), 5TIO1, is a new 2-aminothiophene derivative with a promising pharmacological activity. The aim of this work was to evaluate the potential anxiolytic effect of 5TIO1 in animal models. In the elevated plus-maze test, 5TIO1 (0.1, 1.0 and 10.0 mg/kg, i.p) increased the time of permanence and the number of entries in the open arms. In the light/dark box test, 5TIO1 at dose of 0.1 mg/kg (i.p) also showed anxiolytic-like effect indicated by an increase in the time spent in the light box, similar to diazepam 2.0 mg/kg (i.p). 5TIO1 groups did not change locomotor and coordination activities in open field and rotarod tests, respectively, when compared to vehicle. Dose dependent process was not observed and the anxiolytic effects demonstrated were not completely reversed by flumazenil 25 mg/kg (i.p). Our results suggest that 5TIO1 can bind with other receptors, besides the benzodiazepine site of the GABA receptor in mouse brain.     

The antianxiety-like effect of astaxanthin extracted from Paracoccus carotinifaciens

Astaxanthin is a red carotenoid pigment and is widely found in living organisms. Astaxanthin has a potent antioxidative ability and has been reported as having various biological effects on the central nerve system, such as a protective effect against ischemia/reperfusion injury and improvement in cognitive function. In this study, to investigate the effects of astaxanthin on anxiety and depression, we performed some behavioral trials including the elevated plus maze test, hole-board test, forced swim test, and tail suspension test. Astaxanthin (100 and 300 mg/kg/day for 10 days, p.o.) significantly increased the time spent in open arms in the elevated plus maze test and increased the head-dipping count and duration in the hole-board test. On the other hand, astaxanthin (10, 100, 300, and 500 mg/kg/day for 10 days, p.o.) did not change the immobility time in the forced swim test or the tail suspension test. In conclusion, in mice, astaxanthin exerted anxiolytic-like effects, but not antidepressant-like effects.     

Effect of honokiol on activity of GAD65 and GAD67 in the cortex and hippocampus of mice

Honokiol, an active agent extracted from magnolia bark, has been reported that induces anxiolytic action in a mouse elevated plus-maze test. However, the mechanism of anxiolytic action induced by honokiol remains unclear. This study was to investigate the change in two forms of glutamic acid decarboxylase (GABA synthesized enzymes) GAD₆₅ and GAD₆₇ in the cortex and hippocampus areas while the anxiolytic actions induced by chronic administration of honokiol in mice. Mice treated with 7 daily injection of honokiol (1 mg/kg, p.o.) caused anxiolytic action which was similar to that was induced by 7 daily injection of diazepam (2 mg/kg, p.o.) in the elevated plus-maze test. In addition, the activity of hippocampal GAD₆₅ of honokiol treated mice was significantly increased than that of the vehicle or diazepam treated groups. These data suggest that honokiol causes diazepam-like anxiolytic action, which may be mediated by altering the synthesis of GABA in the brain of mice.     

Anxiolytic-antidepressant activity of Withania somnifera glycowithanolides: an experimental study.

The roots of Withania somnifera (WS) are used extensively in Ayurveda, the classical Indian system of medicine, and WS is categorized as a rasayana, which are used to promote physical and mental health, to provide defence against disease and adverse environmental factors and to arrest the aging process. WS has been used to stabilize mood in patients with behavioural disturbances. The present study investigated the anxiolytic and antidepressant actions of the bioactive glycowithanolides (WSG), isolated from WS roots, in rats. WSG (20 and 50 mg/kg) was administered orally once daily for 5 days and the results were compared by those elicited by the benzodiazepine lorazepam (0.5 mg/kg, i.p.) for anxiolytic studies, and by the tricyclic anti-depressant, imipramine (10 mg/kg, i.p.), for the antidepressant investigations. Both these standard drugs were administered once, 30 min prior to the tests. WSG induced an anxiolytic effect, comparable to that produced by lorazepam, in the elevated plus-maze, social interaction and feeding latency in an unfamiliar environment, tests. Further, both WSG and lorazepam, reduced rat brain levels of tribulin, an endocoid marker of clinical anxiety, when the levels were increased following administration of the anxiogenic agent, pentylenetetrazole. WSG also exhibited an antidepressant effect, comparable with that induced by imipramine, in the forced swim-induced 'behavioural despair' and 'learned helplessness' tests. The investigations support the use of WS as a mood stabilizer in clinical conditions of anxiety and depression in Ayurveda.     

Anxiolytic activity of Indian Abies pindrow Royle leaves in rodents: an experimental study

Putative anxiolytic activity of ethanolic extract of Indian A. pindrow Royle leaf was investigated in rats using various experimental paradigms of anxiety viz. open field exploratory behaviour, elevated plus maze (EPM) and elevated zero maze (EZM) tests. Pilot studies indicated that single dose administration of extract had little to no acute behavioural effects, hence the extract was administered orally at different dose levels once daily for three consecutive days, while lorazepam (LR) (0.5 mg/kg, i.p.) was administered acutely. Ethanolic extract of A. pindrow (AP) leaves (50 and 100 mg/kg, p.o.) showed significant anxiolytic effects on all the paradigms of anxiety. The results indicate that AP and LR induced a significant increase in open field ambulation and slight increase in rearings and activity in center, whereas grooming and faecal droppings remain unchanged. In EPM, significant augmentation of open arm entries, and time spent on open arms was noted in AP treated rats. In EZM test, significant increase in time spent on open arms and entries in open arms was observed, whereas slight increase in head dips and stretched attend postures was also observed. The AP extract showed consistent and significant anxiolytic activity in all the tests. The effects induced by ethanolic extract of AP were less marked than those of lorazepam were.     

Anxiolytic activity of Indian Hypericum perforatum Linn: an experimental study

The putative anxiolytic activity of 50% ethanolic extract of Indian Hypericum perforatum (IHp) was investigated in rats using various experimental paradigms of anxiety viz. open field exploratory behaviour (OFB), elevated plus maze (EPM), elevated zero maze (EZM), novelty induced suppressed feeding latency (FL) and social interaction (SI) tests. Pilot studies indicated that single dose administration of IHp had little to no acute behavioural effects, hence the extract of IHp was administered orally at different dose levels once daily for three consecutive days, while lorazepam (LR) (0.5 mg/kg, i.p.) was administered acutely. IHp extract (100 and 200 mg/kg, p.o.) showed significant anxiolytic effects on all the paradigms of anxiety. The results indicate that IHp and LR induced a significant increase in open field ambulation and slight increase in rearings and activity in centre, whereas grooming and fecal droppings remain unchanged. In EPM, significant augmentation of open arm entries, open arm/closed arm entries ratio and time spent on open arms was noted in IHp treated rats. In EZM test, significant increase in time spent on open arms and entries in open arms were observed, whereas slight increase in head dips and stretched attend postures were also observed. IHp and LR significantly attenuated the novelty induced increase in feeding latency. IHp treated rats also showed significant increase in social interaction in the novel environment. The IHp extracts showed consistent and significant anxiolytic activity in all the tests. The effects induced by 50% ethanolic extract of IHp were less marked than those of lorazepam were.     

Behavioural characterisation of young adult transgenic mice overexpressing galanin under the PDGF-B promoter

The behavioural phenotype of transgenic mice (3- to 5-months old) overexpressing galanin (GalOE) under the platelet-derived growth factor B (PDGF-B) promoter was evaluated in a battery of tests, including open field, locomotor cages, light-dark exploration test, elevated plus-maze and the Porsolt forced swim test. Learning and memory were assessed in the passive avoidance and the Morris water maze tasks. No difference between genotypes was found in exploratory activity in the open field. GalOE mice showed a slight increase in spontaneous locomotor activity assessed in the locomotor cages, but the amphetamine-induced increase in locomotor activity was somewhat lower in GalOE mice. Anxiety-like behaviour in the three different tests including open field, light-dark exploration and elevated plus-maze did not differ between genotypes. In the Porsolt forced swim test, GalOE mice displayed an increased time of immobility, indicative of increased learned helplessness possibly reflecting increased stress-susceptibility and/or depression-like behaviour. GalOE mice showed normal learning and memory retention in the passive avoidance and the Morris water maze tasks. These data support the hypothesis that galanin may have a role in functions related to mood states including affective disorders.     

Behavioral effects of sinomenine in murine models of anxiety

The present study was designed to investigate the putative anxiolytic-like effect of sinomenine in three experimental models of anxiety in male rats and mice. Use of the elevated plus-maze test revealed that sinomenine (20 and 40 mg/kg, p.o.) increased the percentage of open arm entries and diazepam (2 mg/kg, p.o.) increased the percentage of open arm entries, the percentage of time spent on open arms and total arm entries in mice. In the light/dark transition test, sinomenine (20 and 40 mg/kg, p.o.) increased time spent in the light area and diazepam (2 mg/kg, p.o.) increased time spent in the light area and the overall movements in mice. In the social interaction test, the sinomenine-treated animals significantly increased social interaction time in low light unfamiliar (7 mg/kg, p.o.) and high light unfamiliar conditions (7 and 14 mg/kg, p.o.) as well as diazepam (3 mg/kg, p.o.). Sinomenine (28 mg/kg, p.o.) can also decrease squares entered in rats in social interaction test under low light unfamiliar condition. In the open-field test, sinomenine (160 mg/kg) decreased squares entered in mice. Thus, these findings indicated that sinomenine exhibited anxiolytic-like effect.     

Antidepressant-like effect of 17beta-estradiol: involvement of dopaminergic, serotonergic, and (or) sigma-1 receptor systems

17beta-estradiol has been reported to possess antidepressant-like activity in animal models of depression, although the mechanism for its effect is not well understood. The present study is an effort in this direction to explore the mechanism of the antidepressant-like effect of 17beta-estradiol in a mouse model(s) of behavioral depression (despair behavior). Despair behavior, expressed as helplessness to escape from a situation (immobility period), as in a forced swim test in which the animals are forced to swim for a total of 6 min, was recorded. The antiimmobility effects (antidepressant-like) of 17beta-estradiol were compared with those of standard drugs like venlafaxine (16 mg/kg, i.p.). 17beta-estradiol produced a U-shaped effect in decreasing the immobility period. It had no effect on locomotor activity of the animal. The antidepressant-like effect was comparable to that of venlafaxine (16 mg/kg, i.p.). 17beta-estradiol also exhibited a similar profile of antidepressant action in the tail suspension test. When coadministered with other antidepressant drugs, 17beta-estradiol (5 microg/kg, i.p.) potentiated the antiimmobility effect of subeffective doses of fluoxetine (5 mg/kg, i.p.), venlafaxine (2 mg/kg, i.p.), or bupropion (10 mg/kg, i.p.), but not of desipramine (5 mg/kg, i.p.) or tranylcypromine (2 mg/kg, i.p.), in the forced swim test. The reduction in the immobility period elicited by 17beta-estradiol (20 microg/kg, i.p.) was reversed by haloperidol (0.5 mg/kg, i.p.; a D(2) dopamine receptor antagonist), SCH 23390 (0.5 mg/kg, i.p.; a D(1) dopamine receptor antagonist), and sulpiride (5 mg/kg, i.p.; a specific dopamine D(2) receptor antagonist). In mice pretreated with (+)-pentazocine (2.5 mg/kg, i.p.; a high-affinity sigma-1 receptor agonist), 17beta-estradiol (5 microg/kg, i.p.) produced a synergistic effect. In contrast, pretreatment with progesterone (10 mg/kg, s.c.; a sigma-1 receptor antagonist neurosteroid), rimcazole (5 mg/kg, i.p.; another sigma-1 receptor antagonist), or BD 1047 (1 mg/kg, i.p.; a novel sigma-1 receptor antagonist) reversed the antiimmobility effects of 17beta-estradiol (20 microg/kg, i.p.). Similarly, in mice pretreated with a subthreshold dose of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, a 5-HT1A serotonin receptor agonist), 17beta-estradiol (5 microg/kg, i.p.) produced an antidepressant-like effect. These findings demonstrate that 17beta-estradiol exerted an antidepressant-like effect preferentially through the modulation of dopaminergic and serotonergic receptors. This action may also involve the participation of sigma-1 receptors.     

Rubimetide (Met-Arg-Trp) derived from Rubisco exhibits anxiolytic-like activity via the DP1 receptor in male ddY mice

In this study, we found that Met-Arg-Trp (rubimetide), which had been isolated as a hypotensive peptide from a pepsin-pancreatin digest of spinach ribulose bisphosphate carboxylase/oxygenase (Rubisco), has anxiolytic-like activity in the elevated plus-maze test at a dose of 0.1mg/kg (i.p.) or 1.0mg/kg (p.o.) in mice with p<0.01 and p<0.05, respectively. The anxiolytic-like activity of rubimetide (0.1mg/kg, i.p.) was blocked by BW A868C (60microg/kg, i.p.), an antagonist for the DP1 receptor, suggesting the anxiolytic-like activity of rubimetide is mediated by prostaglandin D2 and the DP1 receptor.     

Anxiolytic-like effect of succinic acid in mice

The putative anxiolytic activity of succinic acid was examined in male mice by using a number of experimental paradigms of anxiety and compared with that of the known anxiolytic compound diazepam. Use of the elevated plus-maze test revealed that diazepam (1.0, 2.0 and 4.0 mg/kg, PO) or succinic acid (3.0 or 6.0 mg/kg, PO) increased the percentage of entries into open arms and of time spent on open arms. In novel food consumption test, succinic acid (3.0, 6.0, and 12.0 mg/kg, IP) caused significant increases in food intake during 5 min when compared with the vehicle. In the stress-induced hyperthermia test, 40 min after drug administration rectal temperature was measured, succinic acid at dose of 1.5 mg/kg, inhibited stress-induced hyperthermia. Thus, these findings indicated that, in contrast with diazepam, succinic acid exhibits anxiolytic-like effect.     

Effect of ACTH on the imipramine- and desipramine-induced decrease in duration of immobility time as measured in a rat forced swimming test.

In a rat forced swimming test (FS), we examined the effect of repeated injections of ACTH (adrenocorticotropic hormone) for 14 days on the decreased duration of immobility time produced by imipramine and desipramine. Both imipramine (15 and 30 mg/kg, p.o.) and desipramine (15 and 30 mg/kg, p.o.) significantly decreased the duration of immobility time in the FS. On the other hand, ACTH (100 microg/kg, i.p.) alone did not affect the duration of immobility time in FS. When ACTH (100 microg/kg, i.p.) was injected for 14 days before the 15-min swim session, it counteracted the decreased duration of immobility time induced by both imipramine and desipramine. Thus, ACTH seems to play a key role in decreasing the duration of immobility time of antidepressants in this test.     

Anxiolytic-like effects of sinapic acid in mice

Sinapic acid is a phenylpropanoid compound and is found in various herbal materials and high-bran cereals. With the exception of its antioxidant activities, the pharmacological properties of sinapic acid have been rarely reported. The purpose of this study was to characterize the putative anxiolytic-like properties of sinapic acid using an elevated plus-maze (EPM) and hole-board test. Control mice were orally treated with an equal volume of vehicle (10% Tween 80 solution), and positive control mice were treated with diazepam (1 mg/kg, i.p.). Sinapic acid (4 mg/kg, p.o.) significantly increased the percentages of time spent in the open arms of the EPM test (P<0.05). In the hole-board test, sinapic acid also significantly increased the number of head-dips at 4 mg/kg (P<0.05). In addition, the anxiolytic-like properties of sinapic acid examined in the EPM test were blocked by flumazenil or bicuculline, which are GABA(A) antagonists. Moreover, sinapic acid markedly potentiated GABA current in single cortical neurons in a dose-dependant manner, and reactive I(GABA) increased to 1.8 times at 1 muM of sinapic acid. These results suggested that sinapic acid is a prominent anxiolytic agent, and that its anxiolytic-like effects are mediated via GABA(A) receptors and potentiating Cl(-) currents.