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1.  Evaluation of anxiolytic activity of compound Valeriana jatamansi Jones in mice 
Background
Compound Valeriana jatamansi Jones is a formula for treating anxiety-related diseases in the clinic, which is composed of Valeriana jatamansi Rhizoma et Radix, Ziziphi Spinosae Semen, Albiziae Cortex and Junci Medulla. The purpose of this study was to explore the anxiolytic properties of this compound in mice.
Methods
Male ICR mice were treated with compound Valerianae Jatamansi Jones (1.2 g/kg, 2.4 g/kg, 4.8 g/kg), saline, diazepam (2 mg/kg) orally for 10 days and then exposed to elevated maze-plus (EPM) and light–dark box (LDB). The effects of the compound on spontaneous activity were evaluated by locomotor activity test. We further investigated the mechanism of action underlying the anxiolytic-like effect of compound by pre-treating animals with antagonists of benzodiazepine (flumazenil, 3mg/kg) prior to evaluation using EPM and LDB.
Results
Compound Valerianae Jatamansi Jones (2.4, 4.8 g/kg, p.o.) significantly increased entries (P<0.05) into and time spent (P<0.05) on the open arms of the EPM, and number of transitions (P<0.05) and time spent (P<0.05) in the light compartment of the LDB. However, the anxiolytic-like effects of compound were significantly reduced by pre-treatment with flumazenil (P>0.05). In addition, compound Valerianae Jatamansi Jones treatment didn’t affect the spontaneous activity in mice (P> 0.05).
Conclusions
The present study supports the hypothesis that compound Valeriana jatamansi Jones exert anxiolytic action but no sedative effects in mice and that this effect might be mediated by benzodiazepine receptors.
doi:10.1186/1472-6882-12-223
PMCID: PMC3526556  PMID: 23171285
Compound Valeriana jatamansi Jones; Anxiolytic; Elevated maze-plus; Light–dark box; Benzodiazepine receptors
2.  A Novel Elevated Plus-Maze Procedure to Avoid the One-Trial Tolerance Problem 
The elevated plus-maze (EPM) test is one of the most commonly used behavioral assays to evaluate anxiety-related behavior in rodents. It is an economic test (5 min duration) without prior conditioning of the animals. The critical measure for anxiety is the time spent in the open arms of the maze. A confounding problem of the EPM is the so called one-trial tolerance (OTT), characterized by a marked decrease of open arm exploration in spite of treatment with anxiolytic acting benzodiazepines upon re-exposure to the EPM. This consistent finding is often raised as an evidence for the inappropriateness to re-test rodents in the EPM. However, a reliable re-test paradigm would broaden the usability and effectiveness of this test. Therefore, we tested how an extension of the inter-trial interval to 28 days (instead of the usual 24 h), and an additional change of the testing room would affect the open arm time and other behaviors on the EPM. In two experiments, drug-naive Wistar rats were exposed to the EPM on trial 1, and treated intraperitoneally with either vehicle or midazolam (0.25 mg/kg) 30 min before trial 2. Then, trial 2 (28 days after trial 1) was carried out in either the same testing room (Experiment 1) or in another unfamiliar room (Experiment 2). Twenty-eight days after trial 1 the open arm time of the rats in the vehicle treated control rats of both experimental groups was comparable to that of the first trial, independent of the testing room. Most importantly, we found that the treatment with the benzodiazepine midazolam had a significantly anxiolytic-like (i.e., increase of open arm time) effect in trial 2 only when conducted in the previously unfamiliar testing room (Experiment 2). We suggest that in order to reliably re-test the EPM and to prevent confounding effects due to the OTT, an inter-trial interval of 28 days and a change in testing rooms reinstates anxiolytic-like actions of benzodiazepines.
doi:10.3389/fnbeh.2011.00043
PMCID: PMC3146044  PMID: 21845176
re-test EPM; one-trial tolerance; midazolam; motivation; memory
3.  Evaluation of Anxiolytic-Like Effect of Aqueous Extract of Asparagus Stem in Mice 
There are few studies on the neuropharmacological properties of asparagus, which was applied in Chinese traditional medicine as a tonic and heat-clearing agent. The present study was designed to investigate the anxiolytic-like activity of the aqueous extract of asparagus stem (AEAS) using elevated plus maze (EPM) and Vogel conflict tests (VCT) in mice. AEAS significantly increased the percentage of time spent in open arms in EPM, when compared with control group. In the Vogel conflict drinking test, the numbers of punished licks increased to 177% and 174% by the treatment of AEAS at the doses of 1.5 and 3.0 g/kg (250 and 500 mg sarsasapogenin per kilogram of body weight), compared with control group. The serum cortisol level decreased significantly, at the same time. In conclusion, these findings indicated that the aqueous extract of asparagus stem exhibited a strong anxiolytic-like effect at dose of 1.5 and 3.0 g/kg (250 and 500 mg sarsasapogenin per kilogram of body weight) in experimental models of anxiety and may be considered an alternative approach for the management of anxiety disorder.
doi:10.1155/2013/587260
PMCID: PMC3853311  PMID: 24348707
4.  Interaction between Antagonist of Cannabinoid Receptor and Antagonist of Adrenergic Receptor on Anxiety in Male Rat 
Basic and Clinical Neuroscience  2014;5(3):218-224.
Introduction
Anxiety is among the most common and treatable mental disorders. Adrenergic and cannabinoid systems have an important role in the neurobiology of anxiety. The elevated plus-maze (EPM) has broadly been used to investigate anxiolytic and anxiogenic compounds. The present study investigated the effects of intraperitoneal (IP) injection of cannabinoid CB1 receptor antagonist (AM251) in the presence of alpha-1 adrenergic antagonist (Prazosin) on rat behavior in the EPM.
Methods
In this study, the data were obtained from male Wistar rat, which weighing 200- 250 g. Animal behavior in EPM were videotaped and saved in computer for 10 min after IP injection of saline, AM251 (0.3 mg/kg), Prazosin (0.3 mg/kg) and AM251 + Prazosin, subsequently scored for conventional indices of anxiety. During the test period, the number of open and closed arms entries, the percentage of entries into the open arms of the EPM, and the spent time in open and closed arms were recorded. Diazepam was considered as a positive control drug with anxiolytic effect (0.3, 0.6, 1.2 mg/kg).
Results
Diazepam increased the number of open arm entries and the percentage of spent time on the open arms. IP injection of AM251 before EPM trial decreased open arms exploration and open arm entry. Whereas, Prazosin increased open arms exploration and open arm entry. This study showed that both substances in simultaneous injection have conflicting effects on the responses of each of these two compounds in a single injection.
Discussion
Injection of CB1 receptor antagonist may have an anxiogenic profile in rat, whereas adrenergic antagonist has an anxiolytic effect. Further investigations are essential for better understanding of anxiolytic and anxiogenic properties and neurobiological mechanisms of action and probable interactions of the two systems.
PMCID: PMC4202541  PMID: 25337383
Cannabinoid Receptor Antagonist; Adrenergic Antagonist; Elevated Plus-maze; Diazepam; Rat; Anxiety
5.  Anxiolytic and Hypnotic Effects of Aqueous and Ethanolic Extracts of Aerial Parts of Echium italicum L. in Mice 
Background
Research in the area of herbal psychopharmacology has clearly improved in recent decades. Self-administration of herbal medicines has been the most popular therapeutic alternative to standard medicine.
Objectives
Since the extract of Echium amoenum exhibits an anxiolytic effect, the aim of this study is to evaluate the anxiolytic and hypnotic effects in mice of the aqueous and ethanolic extracts of aerial parts of E. italicum, a member of the Boraginaceae family.
Materials and Methods
Mice were administered the agents intraperitoneally before the start of the experiments for evaluation of hypnotic activity (induced by sodium pentobarbital, 30 mg/kg, i.p.), anxiolytic activity (elevated plus-maze [EPM] test), locomotor activity (open field test), and motor coordination (rotarod test).
Result
The ethanolic and aqueous extracts of E. italicum, at doses of 1.2 and 2.1 g/kg, increased the percentage of time-spent and the percentage of arm entries in the open arms of the EPM and decreased the percentage of time-spent in the closed arms of the EPM. Moreover, both extracts decreased the pentobarbital-induced latency to sleep and significantly increased the total sleeping time induced by pentobarbital. In addition, locomotor activity was affected by aqueous extracts and ethanolic extract (at higher doses). Both extracts showed no effect in the rotarod test.
Conclusions
These results suggest that both ethanolic and aqueous extracts of E. italicum may have anxiolytic effects and sedative activity but no effect on muscle relaxation.
PMCID: PMC3941860  PMID: 24624158
Hypnotics and Sedatives; Rotarod Performance Test; Anti-Anxiety Agents
6.  Evaluation of Behavioral and Pharmacological Effects of Hydroalcoholic Extract of Valeriana prionophylla Standl. from Guatemala 
There are few studies on the pharmacological properties of Valeriana prionophylla Standl. (VP), known as “Valeriana del monte”, and used in Mesoamerican folk medicine to treat sleep disorders. This study examines the pharmacological effects of the hydroalcoholic extract of the dry rhizome using the open field, rota rod, elevated plus-maze (EPM), forced swimming (FST), strychnine- and pentobarbital-induced sleeping time, PTZ-induced seizures, and the inhibitory avoidance tests. VP did not show any protective effect against PTZ-induced convulsions. In the EPM, exhibited an anxiolytic-like effect through the effective enhancement of the entries (38.5%) and time spent (44.7%) in the open arms, when compared with control group. Time spent and the numbers of entrances into the enclosed arms were decreased, similar to those effects observed with diazepam. In the FST, acute treatment with VP, produced a dose-dependent decrease in immobility time, similarly to imipramine. VP also produced a significant dose-dependent decrease in the latency of sleeping time, while producing an increase in total duration of sleep; influenced memory consolidation of the animals only at lower doses, unlike those that produced anti-depressant and anxiolytic effects. In summary, the results suggest that VP presents several psychopharmacological activities, including anxiolytic, antidepressant, and hypno-sedative effects.
doi:10.1155/2011/312320
PMCID: PMC3132466  PMID: 21754942
7.  Antidepressant- and anxiolytic effects of the novel melatonin agonist Neu-P11 in rodent models 
Acta Pharmacologica Sinica  2010;31(7):775-783.
Aim:
To investigate the potential antidepressant and anxiolytic effects of Neu-P11, a novel melatonin agonist, in two models of depression in rats and a model of anxiety in mice.
Methods:
In the learned helplessness test (LH), Neu-P11 or melatonin (25–100 mg/kg, ip) was administered to rats 2 h before the beginning of the dark phase once a day for 5 days and the number of escape failures and intertrial crossings during the test phase were recorded. In the forced swimming test (FST), rats received a single or repeated administration of Neu-P11 (25–100 mg/kg, ip). The total period of immobility during the test phase was assessed. In the elevated plus-maze test (EPM), mice were treated with Neu-P11 (25–100 mg/kg, ip) or melatonin in the morning or in the evening and tested 2 h later. The percentage of time spent in the open arms and the open arms entries were assessed.
Results:
In the LH test, Neu-P11 but not melatonin significantly decreased the escape deficit and had no effect on the intertrial crossings. In the FST, a single or repeated administration of Neu-P11, either in the morning or in the evening, significantly decreased the duration of immobility. In the EPM test, Neu-P11 significantly increased the percentage of time spent in the open arms and the open arms entries irrespective to the time of administration. Melatonin was effective only when administered in the afternoon.
Conclusion:
The results demonstrate that Neu-P11 exerts antidepressant and anxiolytic activities in rodent models.
doi:10.1038/aps.2010.80
PMCID: PMC4007730  PMID: 20581849
melatonin; Neu-P11; antidepressant; anxiolytic; sleep disorders; stress-related illnesses; learned helplessness; forced swimming test; elevated plus-maze
8.  Reproductive Experience Modifies the Effects of Estrogen Receptor Alpha Activity on Anxiety-Like Behavior and Corticotropin Releasing Hormone mRNA Expression 
Hormones and Behavior  2011;61(1):44-49.
Previous studies have demonstrated that prior reproductive experience can influence anxiety-like behaviors, although neural mechanisms underlying this shift remain unknown. Studies in virgin females suggest that activation of the two estrogen receptor subtypes, ERα and ERβ, have differing effects on anxiety. Specifically, ERβ activation has been shown to reduce anxiety-like behaviors, while ERα activation has no significant effect. The purpose of the present study was to examine the possible roles of ERα and ERβ subtypes in parity-induced alterations in anxiety-like behavior, as tested on the elevated plus maze (EPM). Groups of ovariectomized, age-matched, nulliparous and primiparous females were tested on the EPM following administration of the ERα agonist 4,4′,4″-(4-Propyl-{1H}-pyrazole-1,3,5-tryl)trisphenol (PPT; 1 mg/kg), the ERβ agonist Diarylpropionitrile (DPN; 1 mg/kg) or vehicle (DMSO). All drugs were administered once daily for 4 days prior to testing as this dosing paradigm has previously been used to demonstrate anxiolytic effects of DPN in virgin rats. In addition, as exposure to the EPM is a psychological stressor, physiological markers of the stress response were measured in both plasma (corticosterone) and brain (corticotropin releasing hormone; CRH) post-EPM testing. Unexpectedly, the ER α agonist PPT selectively increased the time spent exploring the open arms of the EPM in non-lactating, primiparous females, with no significant effects of DPN observed in either nulliparous or primiparous subjects. All females administered PPT and tested on the EPM demonstrated significantly reduced corticosterone secretion when compared to vehicle-treated controls. In addition, significant effects of both reproductive experience and PPT administration on CRH mRNA expression were observed in both the paraventricular nucleus and amygdala using qPCR. These findings indicate that reproductive experience modulates the effects of ERα activation on both EPM behavior related to anxiety and CRH gene expression.
doi:10.1016/j.yhbeh.2011.10.001
PMCID: PMC3264805  PMID: 22033279
9.  The Anxiolytic Effects of Valtrate in Rats Involves Changes of Corticosterone Levels 
Valtrate is a principle compound isolated from Valeriana jatamansi Jones, which is a Traditional Chinese Medicine used to treat various mood disorders. The aim of the present study was to investigate the anxiolytic effects of valtrate in rats. The animals were orally administered valtrate (5, 10, and 20 g/kg daily) for 10 days and exposed to open field test (OFT) and elevated plus-maze (EPM). Then the corticosterone levels in the rat serum were measured by enzyme-linked immunosorbent assay (ELISA). The valtrate (10 mg/kg, p.o.) exhibited the anxiolytic effect in rats by increasing the time and entry percentage into the open arms in the EPM and the number of central entries in the OFT. Valtrate (10 mg/kg, p.o.) significantly reduced the corticosterone level in the rat serum. Taken together, these results suggest that the valtrate has anxiolytic activity in behavioral models that might be mediated via the function of hypothalamus-pituitary-adrenal axis.
doi:10.1155/2014/325948
PMCID: PMC3978903  PMID: 24782906
10.  Anti-anxiety Activity of Methanolic Extracts of Different Parts of Angelica archangelica Linn. 
Angelica archangelica Linn.is a herb distributed in tropical and subtropical regions of the world. In Indian and Chinese system of medicine, it is used for nervous disorders and cerebral diseases. Previously the aqueous extract of the A. archangelica was evaluated for anxiolytic activity and was found to have significant potential for the same. The present study is aimed to evaluate the anxiolytic activity of methanol extract of root (MER), stem (MES), leaf (MEL), fruit (MEF) and whole plant (MEW) of Angelica archangelica Linn. All the extracts (MER, MES, MEL, MEF and MEW) were evaluated for anxiolytic effects using elevated plus maze test (EPM) model in rats. Methanol extracts of different parts of A.archangelica had increased number of entries and time spent in open arms while they decreased the number of entries and duration of time spent in closed arm of the EPM. In a similar fashion, the diazepam increased the percentage of time spent and percentage of arm entries in the open arms (*P <0.05, **P <0.01). Whole plant and the root had the maximum, leaf and fruits showed intermediate, while stem had the least anxiolytic activity (*P <0.05, **P <0.01) in EPM (Figure 1-5). The head dip count in DZ, SMR400, SML400, SMF400 and SMW400 in open arm are significantly shown in Table 1. The DZ, SMF400 and SMW did not show the fecal bolus while other groups were reduced the fecal bolus significantly (**P <0.01) as compared to control (Table 1). Whole plant and leaf showed the most, root and fruit the intermediate and stem the least anxiolytic activity (**P <0.01) in EPM.
PMCID: PMC3942901  PMID: 24716138
Angelica archangelica; Anxiolytic; Elevated plus maze test
11.  Alpha-Asarone, a Major Component of Acorus gramineus, Attenuates Corticosterone-Induced Anxiety-Like Behaviours via Modulating TrkB Signaling Process 
We investigated the anxiolytic-like activity of α-asarone (AAS) from Acorus gramineus in an experimental rat model of anxiety induced by repeated administration of the exogenous stress hormone corticosterone (CORT). The putative anxiolytic effect of AAS was studied in behavioral tests of anxiety, such as the elevated plus maze (EPM) test and the hole-board test (HBT) in rats. For 21 consecutive days, male rats received 50, 100, or 200 mg/kg AAS (i.p.) 30 min prior to a daily injection of CORT. Dysregulation of the HPA axis in response to the repeated CORT injections was confirmed by measuring serum levels of CORT and the expression of corticotrophin-releasing factor (CRF) in the hypothalamus. Daily AAS (200 mg/kg) administration increased open-arm exploration significantly in the EPM test, and it increased the duration of head dipping activity in the HBT. It also blocked the increase in tyrosine hydroxylase (TH) expression in the locus coeruleus (LC) and decreased mRNA expression of brain-derived neurotrophic factor (BDNF) and its receptor, TrkB, in the hippocampus. These results indicated that the administration of AAS prior to high-dose exogenous CORT significantly improved anxiety-like behaviors, which are associated with modification of the central noradrenergic system and with BDNF function in rats. The current finding may improve understanding of the neurobiological mechanisms responsible for changes in emotions induced by repeated administration of high doses of CORT or by elevated levels of hormones associated with chronic stress. Thus, AAS did exhibit an anxiolytic-like effects in animal models of anxiety.
doi:10.4196/kjpp.2014.18.3.191
PMCID: PMC4071171  PMID: 24976758
Anxiety; Brain-derived neurotrophic factor; Corticosterone; Tyrosine hydroxylase; α-asarone
12.  GABAA Receptor α Subunits Differentially Contribute to Diazepam Tolerance after Chronic Treatment 
PLoS ONE  2012;7(8):e43054.
Background
Within the GABAA-receptor field, two important questions are what molecular mechanisms underlie benzodiazepine tolerance, and whether tolerance can be ascribed to certain GABAA-receptor subtypes.
Methods
We investigated tolerance to acute anxiolytic, hypothermic and sedative effects of diazepam in mice exposed for 28-days to non-selective/selective GABAA-receptor positive allosteric modulators: diazepam (non-selective), bretazenil (partial non-selective), zolpidem (α1 selective) and TPA023 (α2/3 selective). In-vivo binding studies with [3H]flumazenil confirmed compounds occupied CNS GABAA receptors.
Results
Chronic diazepam treatment resulted in tolerance to diazepam's acute anxiolytic, hypothermic and sedative effects. In mice treated chronically with bretazenil, tolerance to diazepam's anxiolytic and hypothermic, but not sedative, effects was seen. Chronic zolpidem treatment resulted in tolerance to diazepam's hypothermic effect, but partial anxiolytic tolerance and no sedative tolerance. Chronic TPA023 treatment did not result in tolerance to diazepam's hypothermic, anxiolytic or sedative effects.
Conclusions
Our data indicate that: (i) GABAA-α2/α3 subtype selective drugs might not induce tolerance; (ii) in rodents quantitative and temporal variations in tolerance development occur dependent on the endpoint assessed, consistent with clinical experience with benzodiazepines (e.g., differential tolerance to antiepileptic and anxiolytic actions); (iii) tolerance to diazepam's sedative actions needs concomitant activation of GABAA-α1/GABAA-α5 receptors. Regarding mechanism, in-situ hybridization studies indicated no gross changes in expression levels of GABAA α1, α2 or α5 subunit mRNA in hippocampus or cortex. Since selective chronic activation of either GABAA α2, or α3 receptors does not engender tolerance development, subtype-selective GABAA drugs might constitute a promising class of novel drugs.
doi:10.1371/journal.pone.0043054
PMCID: PMC3418228  PMID: 22912786
13.  The Metabolic Responses to Aerial Diffusion of Essential Oils 
PLoS ONE  2012;7(9):e44830.
Anxiety disorders are the most prevalent psychiatric disorders and affect a great number of people worldwide. Essential oils, take effects through inhalation or topical application, are believed to enhance physical, emotional, and spiritual well-being. Although clinical studies suggest that the use of essential oils may have therapeutic potential, evidence for the efficacy of essential oils in treating medical conditions remains poor, with a particular lack of studies employing rigorous analytical methods that capture its identifiable impact on human biology. Here, we report a comprehensive gas chromatography time-of-flight mass spectrometry (GC-TOFMS) based metabonomics study that reveals the aromas-induced metabolic changes and the anxiolytic effect of aromas in elevated plus maze (EPM) induced anxiety model rats. The significant alteration of metabolites in the EPM group was attenuated by aromas treatment, concurrent with the behavioral improvement with significantly increased open arms time and open arms entries. Brain tissue and urinary metabonomic analysis identified a number of altered metabolites in response to aromas intervention. These metabolic changes included the increased carbohydrates and lowered levels of neurotransmitters (tryptophan, serine, glycine, aspartate, tyrosine, cysteine, phenylalanine, hypotaurine, histidine, and asparagine), amino acids, and fatty acids in the brain. Elevated aspartate, carbohydrates (sucrose, maltose, fructose, and glucose), nucleosides and organic acids such as lactate and pyruvate were also observed in the urine. The EPM induced metabolic differences observed in urine or brain tissue was significantly reduced after 10 days of aroma inhalation, as noted with the loss of statistical significance on many of the metabolites in the aroma-EPM group. This study demonstrates, for the first time, that the metabonomics approach can capture the subtle metabolic changes resulting from exposure to essential oils and provide the basis for pinpointing affected pathways in anxiety-related behavior, which will lead to an improved mechanistic understanding of anxiolytic effect of essential oils.
doi:10.1371/journal.pone.0044830
PMCID: PMC3440318  PMID: 22984571
14.  L-Tetrahydropalmatine Ameliorates Development of Anxiety and Depression-Related Symptoms Induced by Single Prolonged Stress in Rats 
Biomolecules & Therapeutics  2014;22(3):213-222.
Abnormal adaptation of the stress-response system following traumatic stress can lead to alterations in the hypothalamic-pituitary-adrenal (HPA) axis that may contribute to the development of post-traumatic stress disorder (PTSD). The present study used several behavioral tests to investigate the anxiolytic-like and antidepressant activity of L-tetrahydropalmatine (L-THP) in an experimental rat model of anxiety and depression induced by single prolonged stress (SPS), an animal model of PTSD. Male rats were treated intraperitoneally (i.p.) with vehicle or varied doses of THP 30 min prior to SPS for 8 consecutive days. Daily THP (50 mg/kg) administration significantly increased the number and duration of open arm visits in the elevated plus maze (EPM) test, reduced the anxiety index, increased the risk assessment, and increased the number of head dips over the borders of the open arms after SPS. THP was also associated with increased time spent at the center of the open field, reduced grooming behaviors in the EPM test, and reduced time spent immobile in the forced swimming test (FST). It also blocked the decrease in neuropeptide Y (NPY) and the increase in corticotrophin-releasing factor (CRF) expression in the hypothalamus. This is the first study to determine that THP exerts pronounced anxiolytic-like and antidepressant effects on the development of the behavioral and biochemical symptoms associated with PTSD, indicating its prophylactic potential. Thus, THP reversed several behavioral impairments triggered by the traumatic stress of SPS and is a potential non-invasive therapeutic intervention for PTSD.
doi:10.4062/biomolther.2014.032
PMCID: PMC4060081  PMID: 25009702
Post-traumatic stress disorder; Single prolonged stress; Anxiety; Neuropeptide Y; L-tetrahydropalmatine
15.  Effect of Cissampelos Pareira Leaves on Anxiety-like Behavior in Experimental Animals 
The present study was undertaken to evaluate anxiolytic effect of 70% hydroethanolic extract of leaves of Cissampelos pareira in murine models. C. pareira (Menispermaceae) is rich in alkaloids, and phytochemical results showed that it contains alkaloids, flavanoids, terpenoids, steroids, etc., Anxiolytic activity was evaluated by using elevated plus maze test (EPM), light dark (LandD) model, and forced swim test (FS) models in rats. The efficacy of extract (100, 200, 400 mg/kg) was compared with control as well as standard diazepam (DZ; 2 mg/kg, p.o.) in EPM, LandD model, and imipramine (IM; 2.5 mg/kg, p.o.) in FS model. The results showed that DZ and extract significantly increased the number of entries, time spent in open arm, head dip counts, and rearing time, while they decreased fecal count in EPM. DZ and extract also significantly increased the number of crossings and time spent in light compartment, while they decreased duration of immobility in LandD model. In case of FS model, IM and extract significantly increased mobility and swimming time. Thus, the results confirm that hydroethanolic extract of C. pareira has the potential to be used in the management of anxiety-like behavior in a dose of 200 and 400 mg/kg. Further study is required to explore the plant and its parts for anxiolytic potential.
doi:10.4103/2225-4110.114902
PMCID: PMC3924988  PMID: 24716177
Anxiolytic; Cissampelos pareira; Elevated plus maze; Forced swim test; Light dark model
16.  Enhancement of endocannabinoid signaling with JZL184, an inhibitor of the 2-arachidonoylglycerol hydrolyzing enzyme monoacylglycerol lipase, produces anxiolytic effects under conditions of high environmental aversiveness in rats 
Dysregulation in signaling of the endocannabinoid 2-arachidonoylglycerol (2-AG) is implicated in hyperresponsiveness to stress. We hypothesized that blockade of monoacylglycerol lipase (MGL), the primary enzyme responsible for 2-AG deactivation in vivo, would produce context-dependent anxiolytic effects in rats. Environmental aversiveness was manipulated by varying illumination of an elevated plus maze. Percentage open arm time and numbers of open and closed arm entries were measured in rats receiving a single intraperitoneal (i.p.) injection of either vehicle, the MGL inhibitor JZL184 (1–8 mg/kg), the benzodiazepine diazepam (1 mg/kg), the cannabinoid CB1 receptor antagonist rimonabant (1 mg/kg), or JZL184 (8 mg/kg) coadministered with rimonabant (1 mg/kg). JZL184 (8 mg/kg) produced anxiolytic-like effects (i.e. increased percentage open arm time and number of open arm entries) under high, but not low, levels of environmental aversiveness. Diazepam produced anxiolytic effects in either context. Rimonabant blocked the anxiolytic-like effects of JZL184, consistent with mediation by CB1. Anxiolytic effects of JZL184 were preserved following chronic (8 mg/kg per day × 6 days) administration. Chronic and acute JZL184 treatment similarly enhanced behavioral sensitivity to an exogenous cannabinoid (WIN55,212-2; 2.5 mg/kg i.p.) 24 or 72 h following the terminal injection, suggesting a pervasive effect of MGL inhibition on the endocannabinoid system. We attribute our results to alterations in emotion rather than locomotor activity as JZL184 did not alter the number of closed arm entries in the plus maze or produce motor ataxia in the bar test. Our results demonstrate that JZL184 has beneficial, context-dependent effects on anxiety in rats, presumably via inhibition of MGL-mediated hydrolysis of 2-AG. These data warrant further testing of MGL inhibitors to elucidate the functional role of 2-AG in controlling anxiety and stress responsiveness. Our data further implicate a role for 2-AG in the regulation of emotion and validate MGL as a therapeutic target.
doi:10.1016/j.phrs.2011.04.010
PMCID: PMC3140828  PMID: 21600985
anxiety; 2-arachidonoylglycerol (2-AG); endocannabinoid; environmental aversiveness; JZL184; monoacylglycerol lipase (MGL)
17.  Uptake of Workplace HIV Counselling and Testing: A Cluster-Randomised Trial in Zimbabwe 
PLoS Medicine  2006;3(7):e238.
Background
HIV counselling and testing is a key component of both HIV care and HIV prevention, but uptake is currently low. We investigated the impact of rapid HIV testing at the workplace on uptake of voluntary counselling and testing (VCT).
Methods and Findings
The study was a cluster-randomised trial of two VCT strategies, with business occupational health clinics as the unit of randomisation. VCT was directly offered to all employees, followed by 2 y of open access to VCT and basic HIV care. Businesses were randomised to either on-site rapid HIV testing at their occupational clinic (11 businesses) or to vouchers for off-site VCT at a chain of free-standing centres also using rapid tests (11 businesses). Baseline anonymised HIV serology was requested from all employees.
HIV prevalence was 19.8% and 18.4%, respectively, at businesses randomised to on-site and off-site VCT. In total, 1,957 of 3,950 employees at clinics randomised to on-site testing had VCT (mean uptake by site 51.1%) compared to 586 of 3,532 employees taking vouchers at clinics randomised to off-site testing (mean uptake by site 19.2%). The risk ratio for on-site VCT compared to voucher uptake was 2.8 (95% confidence interval 1.8 to 3.8) after adjustment for potential confounders. Only 125 employees (mean uptake by site 4.3%) reported using their voucher, so that the true adjusted risk ratio for on-site compared to off-site VCT may have been as high as 12.5 (95% confidence interval 8.2 to 16.8).
Conclusions
High-impact VCT strategies are urgently needed to maximise HIV prevention and access to care in Africa. VCT at the workplace offers the potential for high uptake when offered on-site and linked to basic HIV care. Convenience and accessibility appear to have critical roles in the acceptability of community-based VCT.
Editors' Summary
Background.
Since the first case of AIDS (acquired immunodeficiency syndrome) was reported 25 years ago, AIDS has become a major worldwide epidemic, with 3 million people dying from it in 2005. AIDS is caused by the human immunodeficiency virus (HIV), which is usually spread through unprotected sex with an infected partner. HIV damages the immune system, leaving infected individuals unable to fight off other viruses and bacteria. HIV infections can be treated with drugs know as “antiretrovirals,” and in an effort to deal with the global epidemic, world leaders have committed themselves to providing universal access to these drugs for everyone who needs them by 2010. Unfortunately, although access to antiretrovirals is rapidly increasing, so is the number of people infected with HIV. Last year, there were about 5 million new HIV infections, suggesting that more emphasis on prevention will be needed to halt or reverse the spread of HIV and AIDS. An important part of prevention is testing for HIV infection, but globally only 10% of people who need testing can access it. And even where such services are available, few people use them because of the stigma attached to HIV infection and fear of discrimination.
Why Was This Study Done?
There is limited understanding about the factors that determine whether an individual will decide to have an HIV test. Yet, to reduce HIV spread, as many people at risk of infection must be tested as possible. Previous studies on VCT—a combination of voluntary testing and counseling about the implications of HIV infection and how to avoid transmitting the virus—have indicated that the convenience of getting the test, whether the test is directly offered, and the attitude of staff supplying it are all very important. In this study, the researchers asked whether providing VCT in the workplace could improve the “uptake” of HIV testing in Africa, where the HIV/AIDS epidemic is most widespread.
What Did the Researchers Do and Find?
The researchers identified businesses with occupational health clinics in Zimbabwe, a country where 25% of adults carry HIV, and divided them into two “intervention” groups. Employees at half the businesses were offered “on-site VCT”—pre-test counseling followed by same-day on-site rapid testing, results, and post-test counseling. Employees at the other businesses had the same pre-test counseling but were offered a voucher for an HIV test at an off-site testing center and a later appointment to discuss the results—so-called off-site VCT. Everyone had the same access to limited HIV care should they need it. Although half of the employees at the on-site VCT businesses took up the option of HIV testing, only a fifth of employees at the off-site VCT businesses accepted vouchers for testing, and only one in five of these people actually used their voucher. This means that on-site VCT resulted in about 12 times as many HIV tests as off-site VCT. In both interventions, most of the people who accepted testing did so soon after entering the study and very few people were tested more than once. Finally, people 25 years old or younger, manual workers, and single people were most likely to accept testing in both interventions.
What Do These Findings Mean?
These results suggest that on-site VCT in the workplace might be one way to improve uptake of HIV testing in Africa from its current low level and that providing VCT intermittently might be as effective as continuous provision. Importantly, say the researchers, the results of their study show that a relatively minor change in accessibility to testing can translate into a major difference in test uptake. This may hold true in non-occupational settings. However, these observations need to be repeated in more businesses and other settings, including those where there is no linked HIV care, before they can be generalized. Also, this study reports on the acceptability of this approach to providing VCT, but not on its impact on HIV prevention. As such the results do not indicate whether workplace VCT prevents HIV spread as effectively as other ways of delivering VCT. This will require research investigating how HIV incidence among HIV-negative employees and the partners of HIV-positive employees are affected by different VCT strategies.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030238.
• United States National Institute of Allergy and Infectious Diseases factsheet on HIV infection and AIDS
• United States Department of Health and Human Services information on HIV/AIDS treatment, prevention, and research
• US Centers for Disease Control and Prevention information on HIV/AIDS
• UNAIDS (Joint United Nations Programme on HIV/AIDS) information on political issues related to the HIV/AIDS epidemic and the 2004 UNAIDS/World Health Organization policy statement on HIV testing
•  Aidsmap: information on HIV and AIDS provided by the charity NAM, which includes the latest scientific and political news
• MedlinePlus encyclopedia entry on HIV/AIDS
Voluntary counseling and testing for HIV has the potential for high uptake when it is offered on-site at the workplace and linked to basic HIV care.
doi:10.1371/journal.pmed.0030238
PMCID: PMC1483908  PMID: 16796402
18.  Chemical composition and anxiolytic evaluation of Achillea Wilhelmsii C. Koch essential oil in rat 
Herbal based remedies are used worldwide to treat psychiatric disorders. The aim of this study was to analyse the essential oil composition of Achillea Wilhemsii C. Koch (Asteraceae) and to evaluate its anxiolytic effects in the elevated plus maze (EPM) model of anxiety in rat. Gas chromatography/mass spectrometry (GC/MS) analysis of the essential oil showed that the main compounds of the oil were p-ocimen (23%), 1, 8-cineole (20.8%) and carvone (19.13%). The EPM results showed that 1 mg/kg (i.p.) of the oil significantly (P<0.05) increased the percentage of the time spent and the number of entries in the open arms of the maze while it did not change the total number of entries in the maze arms. These effects were not reversed with 2 mg/kg flumazenil and 5 mg/kg naloxone. We concluded that a minimum dose of 1 mg/kg of the oil has anxiolytic effects which are not probably mediated through GABA and opioid receptors.
PMCID: PMC3757592  PMID: 24082896
Achillea Wilhelmsii C. Koch; Anxiolytic; Essential oil; GC/MS; Elevated plus maze
19.  Anxiolytic-like effect of (4-benzylpiperazin-1-yl)(3-methoxyquinoxalin-2-yl)methanone (6g) in experimental mouse models of anxiety 
Indian Journal of Pharmacology  2013;45(3):248-251.
Aim:
The present study was designed to investigate the anxiolytic activity of 6g, a novel serotonin type-3 receptor (5-HT3) receptor antagonist in experimental mouse models of anxiety.
Materials and Methods:
The anxiolytic activity of “6g” (1 and 2 mg/kg, intraperitoneally [i.p.]) was evaluated in mice by using a battery of behavioral tests of anxiety such as elevated plus maze (EPM), light-dark (L&D) box, hole board (HB), and open field test (OFT) with diazepam (2 mg/kg, i.p.) as standard anxiolytic. None of the tested dose of “6g” affects the base line locomotion.
Results:
The new chemical entity “6g” (2 mg/kg, i.p.) and diazepam (2 mg/kg, i.p.) significantly (P < 0.05) increased the percentage of time spent and number of entries in open arm in the EPM test. In the L&D test compound “6g” (2 mg/kg, i.p.) and diazepam (2 mg/kg, i.p.) significantly (P < 0.05) increased the total time spent in light compartment as well as number of transitions from one compartment to other. Compound “6g” (1 and 2 mg/kg, i.p.) and diazepam (2 mg/kg, i.p.) also significantly (P < 0.05) increased number of head dips, whereas significantly (P < 0.05) decreased the head dipping latency in HB test as compared to vehicle control group. In addition, 6g (2 mg/kg, i.p.) and diazepam (2 mg/kg, i.p.) significantly (P < 0.05) increased the ambulation scores (square crossed) in OFT and there was no significant effect of 6g (1 and 2 mg/kg, i.p.) and diazepam (2 mg/kg, i.p.) on rearing scores.
Conclusion:
In conclusion, these findings indicated that compound “6g” exhibited an anxiolytic-like effect in animal models of anxiety.
doi:10.4103/0253-7613.111923
PMCID: PMC3696295  PMID: 23833367
Anxiety; elevated plus maze; hole-board; 5-HT3 receptor antagonist; open field test
20.  Increased Anxiety-Like Behaviors in Rats Experiencing Chronic Inflammatory Pain 
Behavioural brain research  2012;229(1):10.1016/j.bbr.2012.01.001.
For many patients, chronic pain is often accompanied, and sometimes amplified, by co-morbidities such as anxiety and depression. Although it represents important challenges, the establishment of appropriate preclinical behavioral models contributes to drug development for treating chronic inflammatory pain and associated psychopathologies. In this study, we investigated whether rats experiencing persistent inflammatory pain induced by intraplantar injection of complete Freund’s adjuvant (CFA) developed anxiety-like behaviors, and whether clinically used analgesic and anxiolytic drugs were able to reverse CFA-induced anxiety-related phenotypes. These behaviors were evaluated over 28 days in both CFA- and saline-treated groups with a variety of behavioral tests. CFA-induced mechanical allodynia resulted in increased anxiety-like behaviors as evidenced by: 1) a significant decrease in percentage of time spent and number of entries in open arms of the elevated-plus maze (EPM), 2) a decrease in number of central squares visited in the open field (OF), and 3) a reduction in active social interactions in the social interaction test (SI). The number of entries in closed arms in the EPM and the distance travelled in the OF used as indicators of locomotor performance did not differ between treatments. Our results also reveal that in CFA-treated rats, acute administration of morphine (3 mg/kg, s.c.) abolished tactile allodynia and anxiety-like behaviors, whereas acute administration of diazepam (1 mg/kg, s.c) solely reversed anxiety-like behaviors. Therefore, pharmacological treatment of anxiety-like behaviors induced by chronic inflammatory pain can be objectively evaluated using multiple behavioral tests. Such a model could help identify/validate alternative potential targets that influence pain and cognitive dimensions of anxiety.
doi:10.1016/j.bbr.2012.01.001
PMCID: PMC3848972  PMID: 22245257 CAMSID: cams3733
complete Freund’s adjuvant; chronic pain; comorbidity; elevated-plus maze; social interaction test; open field test; light/dark box exploration test; actimetry
21.  Midazolam Ameliorates the Behavior Deficits of a Rat Posttraumatic Stress Disorder Model through Dual 18 kDa Translocator Protein and Central Benzodiazepine Receptor and Neurosteroidogenesis 
PLoS ONE  2014;9(7):e101450.
Post-traumatic stress disorder (PTSD) is a debilitating anxiety disorder that may develop after an individual has experienced or witnessed a severe traumatic event. It has been shown that the 18 kDa translocator protein (TSPO) may be correlated with PTSD and that the TSPO ligand improved the behavioral deficits in a mouse model of PTSD. Midazolam, a ligand for TSPO and central benzodiazepine receptor (CBR), induces anxiolytic- and anti-depressant-like effects in animal models. The present study aimed to determine whether midazolam ameliorates PTSD behavior in rats as assessed by the single prolonged stress (SPS) model. The SPS rats received daily Sertraline (Ser) (15 mg/kg, p.o.) and midazolam (0.125, 0.25, 0.5, and 1 mg/kg, p.o.) during the exposure to SPS and behavioral assessments, which included the open field (OF) test, the contextual fear paradigm (CFP), and the elevated plus-maze (EPM). The results showed that, like Ser (15 mg/kg, p.o.), midazolam (0.25 and 0.5 mg/kg, p.o.) significantly reversed the behavioral deficiencies of the SPS rats, including PTSD-associated freezing and anxiety-like behavior but not the effects on spontaneous locomotor activity. In addition, the anti-PTSD effects of midazolam (0.5 mg/kg, p.o.) were antagonized by the TSPO antagonist PK11195 (3 mg/kg, i.p.), the CBR antagonist flumazenil (15 mg/kg, p.o.) and the inhibitor of steroidogenic enzymes finasteride (30 mg/kg, p.o.), which by themselves had no effect on PTSD-associated freezing and anxiety-like behavior. In summary, this study demonstrated that midazolam improves the behavioral deficits in the SPS model through dual TSPO and CBR and neurosteroidogenesis.
doi:10.1371/journal.pone.0101450
PMCID: PMC4079590  PMID: 24988461
22.  Anxiolytic effects of 5-HT1A receptors and anxiogenic effects of 5-HT2C receptors in the amygdala of mice 
Neuropharmacology  2011;62(1):474-484.
The aim of the present study is to test a hypothesis that 5-HT1A and 5-HT2C receptors in the amygdala play an important role in the regulation of anxiety behaviors. We examined alterations in anxiety-like behaviors after manipulation of the expression of 5-HT1A and 5-HT2C receptors in the amygdala using recombinant adenovirus approaches. Recombinant adenoviruses containing a 5-HT1A promoter-controlled 5-HT1A antisense sequence or a 5-HT2C promoter-controlled 5-HT2C sense sequence were injected into the amygdala. Elevated plus maze (EPM) and open field tests were conducted to determine anxiety-like behavior and locomotor activity. Reductions in the expression of 5-HT1A receptors in the amygdala significantly attenuated the time spent in the open arms of EPM and time spent in the center of an open field. Reduction in the percent of time spent in the open arms of EPM is negatively correlated with the density of 5-HT1A receptors in the central amygdala. On the other hand, increased expression of 5-HT2C receptors reduced the time spent in the open arms of EPM and time spent in the center of an open field. The reductions in the time spent and distance traveled in the open arms of EPM were correlated to the density of 5-HT2C receptors in the basolateral nucleus of amygdala. These data suggest that amygdaloid 5-HT1A receptors produce anxiolytic and 5-HT2C receptors produce anxiogenic effects. Together, the present results demonstrate the important role of the amygdaloid 5-HT1A and 5-HT2C receptors in the regulation of anxiety-like behaviors.
doi:10.1016/j.neuropharm.2011.09.002
PMCID: PMC3196065  PMID: 21925519
5-HT1A receptors; 5-HT2C receptors; amygdala; anxiety-like behaviors; recombinant adenovirus
23.  Effect of Resveratrol on Behavioral Performance of Streptozotocin-induced Diabetic Mice inAnxiety Tests 
Experimental Animals  2014;63(3):277-287.
The aim of this study was to evaluate with anxiety tests the effect of resveratrol (RSV) on streptozotocin (STZ)-induced diabetic mouse behavioral performance at the second and fourth week of treatment. Confirmed diabetic mice (>250 mg/dl of glucose in blood after STZ injection) were treated with RSV (RDM, n=12) or control treated (DM, n=12) for 4 weeks. DM and RDM were tested in the Open Field Test (OFT) and Elevated Plus Maze (EPM). In the second week of RSV treatment, a higher grooming frequency (P<0.05) and a lower defecation and rearing frequency (P<0.05) were detected in the OFT in the RDM group compared with the DM. There was a higher grooming frequency (P<0.05) and higher percentage of entries in open arms (P<0.05) in the RDM group than in the DM group in the EPM. However, in the fourth week of RSV treatment, the only effect observed was a higher grooming frequency in the RDM group than in the DM group (P<0.05) in the EPM. In conclusion, RSV treatment in diabetic mice provoked anxiolytic-like effects in both tests (OFT and EPM), and these effects were observed in a short time window (2 weeks). It is suggested that RSV may help diabetic animals to adapt to new stressing and anxiety situations and thus to improve their welfare.
doi:10.1538/expanim.63.277
PMCID: PMC4206731  PMID: 25077757
diabetes; flavonoid; mouse; resveratrol; stress
24.  Participation of GABAA Chloride Channels in the Anxiolytic-Like Effects of a Fatty Acid Mixture 
BioMed Research International  2013;2013:121794.
Human amniotic fluid and a mixture of eight fatty acids (FAT-M) identified in this maternal fluid (C12:0, lauric acid, 0.9 μg%; C14:0, myristic acid, 6.9 μg%; C16:0, palmitic acid, 35.3 μg%; C16:1, palmitoleic acid, 16.4 μg%; C18:0, stearic acid, 8.5 μg%; C18:1cis, oleic acid, 18.4 μg%; C18:1trans, elaidic acid, 3.5 μg%; C18:2, linoleic acid, 10.1 μg%) produce anxiolytic-like effects that are comparable to diazepam in Wistar rats, suggesting the involvement of γ-aminobutyric acid-A (GABAA) receptors, a possibility not yet explored. Wistar rats were subjected to the defensive burying test, elevated plus maze, and open field test. In different groups, three GABAA receptor antagonists were administered 30 min before FAT-M administration, including the competitive GABA binding antagonist bicuculline (1 mg/kg), GABAA benzodiazepine antagonist flumazenil (5 mg/kg), and noncompetitive GABAA chloride channel antagonist picrotoxin (1 mg/kg). The FAT-M exerted anxiolytic-like effects in the defensive burying test and elevated plus maze, without affecting locomotor activity in the open field test. The GABAA antagonists alone did not produce significant changes in the behavioral tests. Picrotoxin but not bicuculline or flumazenil blocked the anxiolytic-like effect of the FAT-M. Based on the specific blocking action of picrotoxin on the effects of the FAT-M, we conclude that the FAT-M exerted its anxiolytic-like effects through GABAA receptor chloride channels.
doi:10.1155/2013/121794
PMCID: PMC3791597  PMID: 24163810
25.  Anxiolytic and Antidepressant-Like Effects of the Aqueous Extract of Alafia multiflora Stem Barks in Rodents 
The present study examined the anxiolytic and antidepressant effects of the aqueous extract of Alafia multiflora Stapf (AM) stem barks (150 and 300 mg/kg, 7 days administration) on rats and mice, using experimental paradigms of anxiety and depression. In the open field, the aqueous extract increased significantly the number of center square crossed and the time spent at the center of the field as well as the rearing time, while the grooming time was reduced significantly. In the elevated plus maze, the aqueous extract increased the time spent and the number of entries in the open arms. All these effects were also completely reversed by flumazenil, an antagonist of benzodiazepine receptors and pindolol a β-adrenoceptors blocker/5-HT 1A/1B receptor antagonist. The time spent in the light compartment, the latency time, and the number of the light-dark transitions increased significantly in the light/dark exploration test after the treatment with AM. The extract was able to reduce significantly the immobility time and increase swimming as well as climbing duration. Taken together, the present work evidenced anxiolytic effects of the aqueous extract of AM that might involve an action on benzodiazepine-type receptors and an antidepressant effect where noradrenergic mechanisms will probably play a role.
doi:10.1155/2012/912041
PMCID: PMC3485477  PMID: 23125853

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