Anxiolytic-like effect of asiaticoside in mice

The putative anxiolytic activity of asiaticoside was examined in male mice by using a number of experimental paradigms of anxiety, with diazepam being as a positive anxiolytic control. In the elevated plus-maze test, diazepam (1 and 2 mg/kg) or asiaticoside (5 or 10 mg/kg) increased the percentage of entries into open arms and of time spent on open arms. In the light/dark test, as with 1 mg/kg diazepam, asiaticoside (10 and 20 mg/kg) increased the time spent in the light area and the movement in the light area without altering the total locomotor activity of the animals. In the hole-board test, asiaticoside at 10 mg/kg significantly increased head-dipping counts and duration as well as diazepam (0.3 mg/kg). Thus, these findings indicated that asiaticoside exhibited an anxiolytic-like effect. Further studies will be required to assess the generality of present findings to other species and behavioural paradigms.     

Anxiolytic-like effects of Gastrodia elata and its phenolic constituents in mice

The purpose of this study was to characterize the putative anxiolytic-like effects of the aqueous extract of the rhizome of Gastrodia elata along with its phenolic constituents, 4-hydroxybenzyl alcohol (HA) and 4-hyroxybenzaldehyde (HD), using an elevated plus maze (EPM) in mice. The mice were administered either the aqueous G. elata extract orally or received an intraperitoneal injection of the phenolic constituents, 1 h before the behavioral evaluation in the EPM. A single treatment of the aqueous G. elata extract significantly increased the percentage of time spent and arm entries into the open arms of the EPM versus the saline controls. Among the phenolic constituents of G. elata, HA and HD significantly increased the percentage of time spent and arm entries into the open arms of the EPM versus saline controls (p<0.05). Moreover, there were no changes in the locomotor activity and myorelaxant effects in any group compared with the saline controls. In addition, the anxiolytic-like effects of G. elata extract were blocked by both WAY 100635 (0.3 mg/kg, i.p.), a 5-HT(1A) receptor antagonist, and flumazenil (10 mg/kg, i.p.), a GABA(A) receptor antagonist. The anxiolytic-like effects of HA were inhibited by WAY 100635 and the effects of HD were antagonized by flumazenil. These results indicate that G. elata is an effective anxiolytic agent, and suggests that the anxiolytic-like effects of G. elata via the serotonergic nervous system depends on HA and those effects of G. elata via the GABAergic nervous system depends on HD.     

Anxiolytic-like effects of sanjoinine A isolated from Zizyphi Spinosi Semen: Possible involvement of GABAergic transmission

This experiment was performed to investigate the anxiolytic-like effects of sanjoinine A, one of the major alkaloid compounds in Zizyphi Spinosi Semen (ZSS), by using experimental paradigms of anxiety in comparison with a known anxiolytic, diazepam. Sanjoinine A (2.0 mg/kg) increased the percentage of time spent on the open arms and the number of open arms entries in the elevated plus-maze test, increased the number of head dips in the hole-board test, and increased the percentage of time spent in the center zone and the center zone locomotor distance in the open field box experiment. However, sanjoinine A (0.5, 1.0, 2.0 mg/kg) had no effect on locomotor activity, while diazepam (2.0 mg/kg) significantly reduced locomotor activity. Sanjoinine A (0.5, 1.0, 2.0 mg/kg) did not influence the grip force in the grip strength meter test either. Molecular experiments showed that sanjoinine A (2.0, 5.0 μM) increased chloride influx in cultured cerebellar granule cells. In addition, sanjoinine A (5.0 μM) treatment resulted in over-expression of α- and γ-subunits of GABA_A receptors and glutamic acid decarboxylase (GAD65/67) in cultured cerebellar granule cells. It is concluded that sanjoinine A may have anxiolytic-like effects in the elevated plus-maze, hole-board test and open field test, and these effects may be mediated by GABAergic transmission.     

Evaluation of anxiolytic-like effects of some short-acting benzodiazepine hypnotics in mice

Anxiolytic-like effects of some short-acting benzodiazepine hypnotics were examined with experimental paradigms of anxiety using an elevated plus-maze in male ICR mice. Diazepam was used as a positive control. The drug at a dose of 1 mg/kg significantly increased the percentage of time spent in the open arms and percentage of the number of open arm entries in the elevated plus-maze. Triazolam, brotizolam, rilmazafone, and lormetazepam also showed an anxiolytic-like effect as indicated by the significant increase in the percentage of time spent in the open arms and percentage of the number of open arm entries. Effects of short-acting benzodiazepine hypnotics used in the study were more potent than those of diazepam. In addition, the doses affecting the elevated plus-maze by benzodiazepine hypnotics were much smaller than those that showed muscle-relaxant activity measured by the rotarod test, indicating that anxiolytic-like effects of benzodiazepine hypnotics had high specificity and selectivity.     

Involvement of 5-HT1A and GABAA receptors in the anxiolytic-like effects of Cinnamomum cassia in mice

An elevated plus maze (EPM) test was used to determine if the 5-HT1A, GABAA, and benzodiazepine receptors play a role in the anxiolytic-like effects of a 50% EtOH extract of Cinnamomum cassia (C. cassia) in mice. A single treatment with C. cassia (750 mg/kg, p.o.) significantly increased the number of entries into and the time spent in the open arms of the EPM compared with the controls. A repeated treatment with C. cassia (100 mg/kg, 5 days, p.o.) significantly increased the time spent in the open arms of the EPM. Moreover, WAY 100635, (+)-bicuculline, and flumazenil blocked the effect of C. cassia. However, there were no changes in the locomotor activity and horizontal wire test observed in any group compared with the controls. Taken together, these results show that C. cassia has no adverse effects, such as myorelaxant effects, and might be an effective anxiolytic agent by regulating the serotonergic and GABAergic system.     

Anxiolytic-Like Effect of baicalin and its additivity with other anxiolytics

Baicalin, a naturally occurring flavonoid, was previously reported to exert anxiolytic-like effects in the Vogel conflict test. In the present study, the anxiolytic effects of baicalin alone and in combination with other anxiolytics were tested in mice using the elevated plus-maze (EPM). Baicalin treatment (7.5 - 30 mg/kg) significantly increased entries into and time spent in open arms, indicative of an anxiolytic-like effect. Motor-depressive and myorelaxant side effects commonly associated with anxiolytics were not observed with baicalin at effective anxiolytic doses in the hole-board and horizontal wire tests, respectively. Co-administration of baicalin (3.75 mg/kg) with dl-tetrahydropalmatine ( dl-THP; 0.25 mg/kg), an anxiolytic-hypnotic alkaloid, both at sub-effective doses, induced an additive effect resulting in considerable anxiolysis. Similarly, an additive anxiolytic-like effect was observed with baicalin (3.75 mg/kg) and diazepam (DZ; 0.5 mg/kg). Results obtained from this study demonstrate the potential of baicalin as a candidate anxiolytic and its possible application in multidrug therapy. Abbreviations. BZS:benzodiazepine-binding site EPM:elevated plus-maze DZ:diazepam GABA (A):type A gamma-aminobutyric acid dl-THP: dl-tetrahydropalmatine.     

Protective effect of Withania somnifera dunal root extract against protracted social isolation induced behavior in rats

This study investigated the effect of Withania somnifera Dunal (WS) root extract and diazepam in social isolation induced behavior such as anxiety and depression in rats. Rats were isolated for 6 weeks and the assessment of changed behavior were done on elevated plus maze (EPM) and forced swim test (FST). Isolation reared rats spent less time into the open arms on EPM and significantly increased immobility time in FST compared to group housed rats. WS (100, 200 or 500 mg/kg, oral) and diazepam (1 or 2 mg/kg, ip) dose dependently increased the time spent and entries into the open arms on EPM test and showed the anxiolytic activity. Subeffective dose of WS (50 mg/kg, oral) potentiated the anxiolytic action of diazepam (0.5, 1 or 2 mg/kg, ip). WS (100, 200 or 500 mg/kg, oral) also reduced the immobility time in FST, thus showed antidepressant effect in both group housed and social isolates. The investigations support the use of WS as a mood stabilizer in socially isolation behavior in Ayurveda.     

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.     

Anxiolytic-like effect of paeonol in mice

The present study in mice compared the putative anxiolytic-like effect of paeonol, a phenolic component from the root bark of Paeonia moutan, with the benzodiazepine diazepam in the elevated plus maze and the light/dark box-test. The comparison was also with regard to locomotor activity (open-field test) and myorelaxant potential (inclined plane test). As with 2 mg/kg diazepam, paeonol (at 17.5 mg/kg) increased the percentage of time spent on open arms in the elevated plus maze and increased the time spent in the light area of the light/dark box (at 8.75 and 17.5 mg/kg). Since paeonol, in contrast to diazepam, had no effect on either the number of squares entered in the open-field test or in the inclined plane test, its side-effect profile is considered as superior to the benzodiazepine.     

Neurological activities of lapachol and its furano derivatives from Kigelia africana

This study was carried out to investigate some neurological activities of lapachol and other chemical constituents isolated from Kigelia africana in male albino mice using elevated plus-maze (EPM) test, open-field test (OFT), and forced swimming test (FST). The anxiolytic-like and antidepressant effects of these constituents were compared to known active anxiolytic (diazepam, 2 mg/kg) and antidepressant (imipramine, 15 mg/kg) reference drugs. The compounds 1 [50 mg/kg, intraperitoneally (i.p.)] and 3 (100 mg/kg, i.p.) significantly increased the number of lines crossed in the OFT and the duration of immobility in the FST, indicating a possible antidepressant activity, but no significant effect was observed in the EPM test. The compound 4 (100 mg/kg, i.p.) significantly increased the time spent on the open arms, but the increase in number of open arms entries was not significant in the EPM test. Meanwhile, the duration of the immobility time was significant and quite close to that of the standard drug, imipramine used in the FST. The compound 5 (100 mg/kg, i.p.) substantially increased the time spent and entries into open arms of the EPM, and reduced the time spent and entries into closed arms, when compared with saline controls (P < 0.05). This compound also increased the exploratory activity of the mice as well as the swimming duration in the OFT and FST, respectively. These results indicate that among the compounds tested, quinones displayed significant anxiolytic and/or antidepressant effects at all doses tested. Kojic acid, a fungal metabolite whose structure was unambiguously confirmed by single-crystal X-ray studies, is also isolated for the first time from K. africana, suggesting that it is a possible taxonomic marker in the biogenesis of the quinone skeleton.     

Behavioral effects of saredutant, a tachykinin NK2 receptor antagonist, in experimental models of mood disorders under basal and stress-related conditions

The present study was made to investigate the role of tachykinin NK2 receptors in the expression of stress-related behaviors in animals. Under basal conditions, intraperitoneal (i.p.) administration of the selective tachykinin NK2 receptor antagonist, saredutant (1 and 3 mg/kg) or diazepam (1 mg/kg) exerted anxiolytic-like effects in rodents, as they reduced grooming score of Wistar male rats tested in the novelty-induced grooming sampling test (NGT) and increased percentage of time and entries in open arms of Swiss male mice tested in the elevated plus maze (EPM) test. After previous exposure to stress-related conditions, as induced by a 2-min forced swim made 5 min prior to the EPM test, saredutant but not diazepam, exhibited anxiolytic-like effects in mice. To study the antidepressant-like activity of tachykinin NK2 receptor antagonist under basal conditions, different groups of rats were injected i.p. with saredutant (2.5, 5 and 10 mg/kg) or the tricyclic antidepressant, clomipramine (50 mg/kg) and tested in the forced swim test (FST), a widely used antidepressant-responsive test. The influence of stress-related conditions was studied in rats subjected to electric foot-shocks (1 mA, 1 s) 24, 5 and 1 h prior to FST, after drugs injection. In the FST, clomipramine decreased the immobility time only under basal conditions, but not after application of acute foot-shocks. To the contrary, saredutant-treated rats also exhibited more active behavior in FST after previous exposure to stressors. These results give further support to the hypothesis that tachykinin NK2 receptors may be a therapeutic target for pharmacological treatment of stress-related diseases, such as anxiety and depression.     

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.

     

Central injections of nocistatin or its C-terminal hexapeptide exert anxiogenic-like effect on behaviour of mice in the plus-maze test

. Nocistatin (NST) antagonizes several actions of nociceptin/orphanin FQ (N/OFQ), but acts on distinct receptors. As N/OFQ exerts anxiolytic-like actions in various tests, its behavioural actions in the elevated plus-maze (EPM) test were compared with those of bovine NST. 2. Five minutes after i.c.v. treatment, mice were placed on the EPM for 5 min and entries into and time spent on open and closed arms were recorded alongside other parameters. 3. NST (0.1 - 3 pmol) reduced percentages of entries into (control 39.6+/-3.1%, peak effect at 1 pmol NST 8.5+/-2.9%) and time spent on open arms (control 30.8+/-2.3%, NST 2.7+/-1.5%). The C-terminal hexapeptide of NST (NST-C6; 0.01 - 10 pmol) closely mimicked these actions of NST, with peak effects at 0.1 pmol. 4. N/OFQ (1 - 100 pmol) increased percentages of entries into (control 38.5+/-3.4%; peak effect at 10 pmol N/OFQ 67.9+/-4.9%) and time spent on open arms (control 32.0+/-3.8%; N/OFQ 74.9+/-5.8%). Closed arm entries, an index of locomotor activity, were unchanged by all peptides. 5. Effects of NST or NST-C6, but not N/OFQ, were still detectable 15 min after injection. Behaviour of animals co-injected with NST (1 pmol) or NST-C6 (0.1 pmol) plus N/OFQ (10 pmol) was indistinguishable from that of controls. 6. These results reveal potent anxiogenic-like actions of NST and NST-C6, and confirm the anxiolytic-like properties of N/OFQ. As NST and N/OFQ both derive from preproN/OF, anxiety may be modulated in opposing directions depending on how this precursor is processed.     

Influence of inflammatory nociception on the anxiolytic-like effect of diazepam and buspirone in rats

Rationale The effect of anxiety on nociception has been evaluated but not that of nociception on anxiety.Objective The study was conducted to analyse the influence of nociception on basal levels of anxiety-like behaviour and on the action of anxiolytic drugs.Methods Nociception was induced by an intra-articular injection of uric acid at 3.75 or 7.5%. Experimental anxiety was determined in the rat burying behaviour and the elevated plus maze tests. To separate specific anxiety-related drug actions, a spontaneous ambulatory test was included. The anxiolytics, buspirone (2.5 and 5.0 mg/kg, i.p.) and diazepam (0.5, 1.0 and 2.0 mg/kg, i.p.), were used.Results In the nociception test, the pain-induced functional impairment rat model, uric acid at 3.75 and 7.5% had an effect of around 35 and 75%, respectively. Uric acid (UA) at the lower dose (3.75%) lacked an effect on burying behaviour but significantly increased the time spent and number of entries to the open arms; the higher UA dose (7.5%) produced a significant increase in the time spent and number of entries to the open arms and a statistically significant reduction in cumulative burying. Diazepam and buspirone produced a clear dose-dependent reduction in cumulative burying. In the plus maze, diazepam also induced an increase in the time spent and number of entries to the open arms. In the burying behaviour test, rats with a mild level of nociception (uric acid at 7.5%) were insensitive to the anxiolytic-like effect of these anxiolytic drugs. In the plus maze test, the anxiolytic-like effect of diazepam (1.0 mg/kg) was blocked under both levels of nociception.Conclusions These data demonstrate that nociception modifies the response to anxiolytic drugs. The role of factors with anxiogenic properties produced during inflammation, which may modify diazepam and buspirone effects, is discussed.     

Nicotine-induced anxiogenic-like behaviours of rats in the elevated plus-maze: possible role of NMDA receptors of the central amygdala

The objective of the present study was to investigate the possible role of the N-methyl-D-aspartate (NMDA) receptor system of the central amygdala (CeA) in the anxiogenic-like effect of nicotine. Male Wistar rats with cannulas aimed to the CeA were submitted to the elevated plus-maze (EPM). Intraperitoneal (i.p.) injections of nicotine (0.6 and 0.8 mg/kg) decreased percentage open arm time spent (%OAT) and percentage open arm entries (%OAE), but not locomotor activity, indicating an anxiogenic-like response. Bilateral intra-CeA microinjection of NMDA (0.005-0.1 μ g/rat) decreased %OAT, but not %OAE and locomotor activity. Moreover, intra-CeA microinjection of NMDA (0.05 μ g) with an ineffective dose of nicotine (0.4 mg/kg, i.p.) reduced %OAT and %OAE without effect on locomotor activity. On the other hand, intra-CeA microinjection of the NMDA receptor antagonist D-AP5 (0.05-0.5 μ g/rat) increased both %OAT and %OAE, showing an anxiolytic-like effect of the drug. Co-administration of the same doses of D-AP5 with nicotine (0.6 mg/kg, i.p.) increased %OAT and %OAE, but not locomotor activity. Intra-CeA microinjection of D-AP5 reversed the response induced by NMDA (0.1 μ g/rat) in the EPM. The results may support the possible involvement of glutamate transmission, through NMDA receptors of central amygdala in the anxiogenic-like effect of nicotine in the EPM task.     

Effects of taurine on rat behaviors in three anxiety models

In our previous studies using an elevated plus-maze test in mice, taurine was shown to present an anxiolytic-like effect after single and repeated administration. The aim of the present study was to investigate the anxiolytic and behavioral effects of taurine on rats in the open field, hole-board, and social interaction test compared to the positive control diazepam. Taurine (14, 42, and 126 mg/kg, i.p.) was administered 30 min before the tests. In the social interaction and hole-board tests, taurine (42 mg/kg) significantly increased social interaction time and the number and duration of head-dipping. In the open field test, taurine (126 mg/kg, i.p.) presented anxiolytic-like effects by increasing the number of center entries, time spent in the central area and the anti-thigmotactic score while having no effect on the locomotor activity. Results from these experiments suggest that taurine produces an anxiolytic-like effect in these animal models and may act as a modulator or anti-anxiety agent in the central nervous system.     

Neuropeptide S is a stimulatory anxiolytic agent: a behavioural study in mice

BACKGROUND AND PURPOSE: Neuropeptide S (NPS) was recently identified as the endogenous ligand of an orphan receptor, now referred to as the NPS receptor. In vivo, NPS produces a unique behavioural profile by increasing wakefulness and exerting anxiolytic-like effects. In the present study, we further evaluated the effects of in vivo supraspinal NPS in mice. EXPERIMENTAL APPROACH: Effects of NPS, injected intracerebroventricularly (i.c.v.), on locomotor activity (LA), righting reflex (RR) recovery and on anxiety states (measured with the elevated plus maze (EPM) and stress-induced hyperthermia (SIH) tests) were assessed in Swiss mice. KEY RESULTS: NPS (0.01-1 nmol per mouse) caused a significant increase in LA in naive mice, in mice habituated to the test cages and in animals sedated with diazepam (5 mg kg(-1)). In the RR assay, NPS dose dependently reduced the proportion of animals losing the RR in response to diazepam (15 mg kg(-1)) and their sleeping time. In the EPM and SIH test, NPS dose dependently evoked anxiolytic-like effects by increasing the time spent by animals in the open arms and reducing the SIH response, respectively. CONCLUSIONS AND IMPLICATIONS: We provide further evidence that NPS acts as a novel modulator of arousal and anxiety-related behaviours by promoting a unique pattern of effects: stimulation associated with anxiolysis. Therefore, NPS receptor ligands may represent innovative drugs for the treatment of sleep and anxiety disorders.     

Benzodiazepine/GABA(A) receptors are involved in magnesium-induced anxiolytic-like behavior in mice

Behavioral studies have suggested an involvement of the glutamate pathway in the mechanism of action of anxiolytic drugs, including the NMDA receptor complex. It was shown that magnesium, an NMDA receptor inhibitor, exhibited anxiolytic-like activity in the elevated plus-maze test in mice. The purpose of the present study was to examine interaction between magnesium and benzodiazepine/GABA(A) receptors in producing anxiolytic-like activity. We examined behavior of mice treated with magnesium and benzodiazepine/GABA(A) receptor ligands, in the elevated plus maze. The anxiolytic-like effect of magnesium (20 mg/kg) was antagonized by flumazenil (10 mg/kg) (benzodiazepine receptor antagonist) while combined treatment with the non-effective doses of magnesium (10 mg/kg) and benzodiazepines (diazepam (0.5 mg/kg) or chlordiazepoxide (2 mg/kg)) produced synergistic interaction (increased time in open arms and number of open arm entries) in this test. The obtained data indicate that benzodiazepine receptors are nvolved in the anxiolytic-like effects of magnesium.     

A characterization of anxiolytic-like actions induced by the novel NMDA/glycine site antagonist, L-701,324

 The effects of the NMDA/glycine site antagonist, 7-chloro-4-hydroxy-3-(3-phenoxy)phenyl-2(1H)-quinolone (L-701,324), and the benzodiazepine receptor agonist, diazepam, were examined in the elevated plus-maze and in the Vogel’s conflict test. Oral administration of L-701,324 caused a dose-dependent increase (2.5 and 5.0 mg/kg, −30 min) in the percent time spent in the open arms with no change in the total number of arm entries or in the percent entries into the open arms of the plus-maze. The same doses of L-701,324 increased punished responding in the Vogel’s conflict test in a dose-dependent fashion, with no influence on unpunished drinking behavior. The anxiolytic-like effects of L-701,324 were obtained at doses which by themselves had no influence on the locomotor activity of the animals. Diazepam (2 mg/kg, IP, −30 min) was slightly more effective than L-701,324 in the plus-maze situation, whereas the increase in punished drinking in the Vogel’s test was of the same magnitude for both compounds. Our present results suggest that inhibition of NMDA receptor activity via a blockade of the NMDA/glycine-sensitive site at the NMDA receptor is accompanied by a reduction of anxiety-like behavior in both non-conditioned and conditioned conflict behavior situations. Received: 13 April 1997/Final version: 22 July 1997