Arm Entries Research Articles

Calorie restriction inhibits relapse behaviour and preference for alcohol within a two-bottle free choice paradigm in the alcohol preferring (iP) rat

Among its many beneficial effects, calorie restriction (CR) has also been found to reduce anxiety related behavior in the rodent. With heightened levels of stress and anxiety implicated as a key precipitating factor of relapse and alcohol addiction, it was found that a 25% CR in addition to inducing anxiolytic effects also had the capacity to reduce intake of alcohol and inhibit relapse within a model of operant self-administration. The aim of this study was to investigate if a 25% CR would also display similar effects in a two-bottle free choice paradigm, whereby 24 h ad libitum access to both 10% ethanol and water is provided. All animals were initially tested on the elevated plus maze (EPM) and open field test prior to commencing the two-bottle free choice paradigm. Differences between control and CR25% animals demonstrated the anxiolytic effects of CR, with the CR25% group displaying greater percentage of open arm/total arm duration and open arm/total arm entries in the EPM. During the acquisition phase of the two-bottle free choice paradigm, CR25% animals showed a reduced intake of 10% ethanol in ml/kg, in comparison to the control group. Whilst control animals displayed a strong preference for 10% ethanol, the CR25% group consumed both 10% ethanol and water equally with no differences found in total fluid intake between groups. Similarly this was also the case following forced deprivation. In addition to reduced intake and lack of preference for 10% ethanol, CR 25% animals unlike controls failed to display a typical alcohol deprivation effect following abstinence. Taken collectively the results of this study suggest that CR may act as a protective factor against addiction and relapse in the alcohol preferring (iP) rat. In addition, given CR25% animals did not display a preference for 10% ethanol, results also suggest that CR may be altering the hedonic impact of ethanol within this group.

Sri Lankan orange pekoe grade black tea impairs anxiety

There is an unmet need for the development of new herbal pharmaceuticals as anxiolytics. In this context, the present study, investigated the anxiolytic potential of warm black tea brew/ infusion (BTB) of Sri Lankan low grown orthodox Orange Pekoe (O.P.) grade tea made from Camellia sinensis (L) O. Kruntz (Theaceae). This was tested in rats using three models of anxiety (hole-board, neophobic suppression of eating and drinking tests). Different doses [223 mg/kg (equivalent to 1.5 cups), 446 mg/kg (equivalent to 3 cups) and 1339 mg/kg (equivalent to 9 cups)] or water was orally administered to rats (N = 6-10/group) and anxiolytic effects were determined after 1h. The results showed that BTB possesses dose-dependent anxiolytic action with quick onset (1h). This anxiolytic action of BTB was not accompanied with undesirable side effects: muscle relaxation, motor in co-ordination or sedation. In addition, BTB produced no overt signs of toxicity. BTB induced significant increase in the number of entries, time spent in open arms, % open arm entries and % time on open arms and reduced the time spent in closed arms when tested in elevated plus maze model. This suggest that main mode of anxiolytic action of BTB is GABAergic. It is also suggested that, serotoninergic and dopaminergic mechanisms also play a part in mediating anxiolytic action. It is concluded that, O.P. grade Sri Lankan black tea has oral anxiolytic action as claimed in Sri Lankan traditional medicine and consumption of at least 3 cups of BTB may be useful to impair ‘day to day’ anxiety.

Mood and memory-associated behaviors in neuropeptide Y5 knockout mice

Recent data led to suggest that in addition to Y1 and Y2 subtypes, Y5 receptors may be involved in mood-related behaviors (Morales-Medina et al., 2010). In the present study, using a battery of behavioral tests to assess anxiety and depression-like paradigms, as well as memory function, we evaluated the potential behavioral changes induced in mice devoid of Y5 receptors. Those paradigms were assessed using the open field (OF), elevated plus maze (EPM), forced swim test (FST), social interaction test (SI), object recognition test (ORT) and Morris water maze (MWM) in Y5 knockout (KO) mice and wild type (WT) animals. In the tests associated to anxiety related behaviors (OF, EPM and SI), no difference for locomotion and time spent in the lateral area of open field were observed between Y5 KO and WT mice. Similar results were observed for time and number of entries in open arms in EPM. Additionally, in SI test, Y5 KO mice spent same amount of time and number of entries in the stranger chamber as compared to WT animals. In the FST, as compared to WT mice, Y5 KO mice had similar immobility time on day 1. No memory dysfunction was observed in the MWM and ORT in Y5 KO mice, as compared to WT. Altogether these data suggest that under basal conditions Y5 KO and WT mice display similar mood behaviors and memory functions. However, as compared to WT, Y5 KO mice display increased grooming and rearing in the OF, lower ratio entries in open arms in the EPM and increased immobility time on the second day of the FST.

Anxiolytic-like and sedative effects of Kyllinga brevifolia in mice

Kyllinga brevifolia Rottb., Cyperaceae, rhizomes have been widely used in the Paraguayan folk medicine as digestive, diuretic, sedative, tonic, antispasmodic and sudorific. The purpose of this study is to characterize the putative sedative, anxiolytic effects of the crude hydro-ethanolic extract (CEKb) and fractions of the rhizome of K. brevifolia, in male mice. The behaviour of mice was assessed in the open field, hole board, rota-rod and elevated plus-maze (EPM) test. Oral treatment with single doses of 10, 100 and 1000 mg/kg of CEKb and 10 mg/kg of ethyl acetate fraction (KbF-ethyl-ac) increased the duration of the sleeping time induced by pentobarbital. Oral administration of 1, 10 and 100 mg/kg of CEKb and 0.1, 1 and 10 mg/kg of KbF-ethyl-ac also significantly increased the time-spent and arm entries into open arms of the elevated plus maze (EPM) versus control group. These findings indicate that K. brevifolia exerts a weak sedative and an interesting anxiolytic-like effect in mice and suggest its potential usefulness for the treatment of anxiety in humans.

Modulation of ventral tegmental area dopamine receptors inhibit nicotine-induced anxiogenic-like behavior in the central amygdala

Nicotine, the major addictive substance in tobacco, increases the activity of the central amygdala (CeA). Amygdala is directly implicated in anxiety modulation and sends projections to the vicinity of the midbrain dopamine neurons, including the ventral tegmental area (VTA) which is a key area that controls nicotine dependence processes. In this study, the role of dopamine D(1) and D(2)/(3) receptors of the VTA on anxiogenic-like behavior induced with intra-CeA injection of nicotine has been investigated. Male Wistar rats with cannula aimed to the left CeA and the left VTA were submitted to the elevated plus-maze (EPM). The nicotine injection (1 μg/rat) into the CeA decreased the percentage of open arm time and open arm entries, but not locomotor activity, indicating an anxiogenic-like response. Intra-VTA injection of a dopamine D1 receptor antagonist, SCH23390 (0.25 μg/rat), and a dopamine D2/3 receptor antagonist, sulpiride (0.7 μg/rat), inhibited the anxiogenic-like response caused by intra-CeA injection of nicotine. These results suggest that the relationship between the VTA and the CeA may be involved in nicotine-induced anxiogenic-like behavior via dopamine D(1) and D(2)/(3) receptors. An understanding of these cellular processes will be crucial for the development of new intervention to combat nicotine effect.

Estrous cycle variation in anxiolytic-like effects of topiramate in Wistar rats in two animal models of anxiety-like behavior

The anxiolytic-like effects of topiramate were assessed during several estrous cycle phases in Wistar rats tested in two animal models of anxiety-like behavior. In a conflict operant test, during proestrus, diazepam (1.3, 2.0mg/kg; P<0.05) or topiramate (20.0, 30.0mg/kg; P<0.05) increased the number of immediately punished responses. During metestrus–diestrus only the highest doses of diazepam (2.0mg/kg, P<0.05) or topiramate (30.0mg/kg, P<0.05) increased the number of immediately punished reinforcers. Similar results were obtained in the elevated plus-maze test: during proestrus, diazepam (1.3, 2.0mg/kg; P<0.05) or topiramate (20.0, 30.0mg/kg; P<0.05) produced anxiolytic-like actions. During metestrus–diestrus only the highest doses of diazepam (2.0mg/kg, P<0.05) or topiramate (30.0mg/kg, P<0.05) produced anxiolytic-like actions. Neither diazepam nor topiramate nor estrous cycle phases significantly modified the number of closed arm entries in the elevated plus-maze test. It is concluded that the response to neuromodulatory drugs for anxiety-like behavior varied according to the estrous cycle phases.

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.

Avaliação da Toxicidade Aguda e do Efeito Ansiolítico de um Derivado Sintético da Carvona

Objective: To evaluate the safety of cyano-carvone by means of acute toxicity studies and to investigate its anxiolytic potential. Material and Methods: Swiss male mice were treated with cyano-carvone (v.o) in escalating doses from 25 to 2000 mg/kg and observed for 14 days as regards behavioral changes and mortality rate. After this time period, hematological, biochemical and morphological analyses of the main macroscopic organs were carried out. In addition, other groups of animals were treated with doses of 25, 50 and 75 mg/kg in order to assess locomotor activity, anxiolytic effect and motor coordination. Results: In the Hippocratic test, the compound did not cause any deaths among the mice, thus the LD50 was not determined and clinical signs that emerged were discrete, reversible and observed only in higher doses. Accordingly, hematological and biochemical analyses did not show significant alterations. In the behavioral analysis, it was found a reduction of locomotor activity and a greater number of entries in open arms, as well as a longer time spent with open arms, suggesting an anxiolytic effect. In the Rota-rod test it was observed no change in the permanence time on the spinning rod, as well as no changes were detected for the number of falls. Conclusion: This study demonstrated that cyano-carvone has no acute toxicity, and suggests a possible anxiolytic effect that needs to be further investigated in order to elucidate its mechanism of action. DESCRIPTORS: Anxiety. Monoterpenes. Acute Toxicity. Central Nervous System.

Morphine-induced anxiolytic-like effect in morphine-sensitized mice: Involvement of ventral hippocampal nicotinic acetylcholine receptors

In the present study, the effects of repeated intra-ventral hippocampal (intra-VH) microinjections of nicotinic acetylcholine receptor agonist or antagonist on morphine-induced anxiolytic-like behavior were investigated in morphine-sensitized mice using elevated plus-maze. Intraperitoneal (i.p.) administration of different doses of morphine (5, 7.5 and 10mg/kg) increased the percentage of open arm time (%OAT), open arm entries (%OAE), but not locomotor activity, indicating an anxiolytic-like response to morphine. The maximum response was obtained by 7.5mg/kg of the opioid. The anxiety-like behavior which was induced by a lower dose of morphine (5mg/kg) was significantly increased in mice that had previously received once daily injections of morphine (10 and 20mg/kg, i.p.) for 3days. It should be considered that this treatment also increased locomotor activity in morphine-sensitized mice. Furthermore, the response to an ineffective dose of morphine (5mg/kg, i.p.) in the EPM was significantly increased in the animals that had previously received nicotine for 3days (0.1, 0.3, 0.5 and 0.7μg/mouse; intra-VH), 5min prior to the injections of morphine (5mg/kg/day×3days; i.p.). On the other hand, the increase of morphine-induced anxiolytic-like effect in animals that had previously received the 3-day morphine (20mg/kg) was dose dependently suppressed by once daily injections of mecamylamine (0.5, 1 and 2μg/mouse/day×3days; intra-VH). It is important to note that repeated intra-VH administrations of the same doses of nicotine or mecamylamine alone caused no significant change in morphine (5mg/kg)-induced anxiety-like parameters in the EPM. In conclusion, it seems that morphine sensitization affects the anxiety-like behavior in the EPM and the cholinergic system in the ventral hippocampus, via nicotinic receptors, may play an important role in this effect.

LPA5 receptor plays a role in pain sensitivity, emotional exploration and reversal learning

Lysophosphatidic acid (LPA) is a bioactive lipid acting on the nervous system through at least 6 different G protein-coupled receptors. In this study, we examined mice lacking the LPA5 receptor using an extensive battery of behavioral tests. LPA5-deficient mice showed decreased pain sensitivity in tail withdrawal, faster recovery in one inflammatory pain procedure (complete Freund's adjuvant-induced inflammation) and attenuated responses under specific neuropathic pain conditions. Notably, deletion of LPA5 also induced nocturnal hyperactivity and reduced anxiety in the mutant mice. Several exploratory tasks revealed signs of reduced anxiety in LPA5 knockout mice including increased visits to the arena center and reduced thigmotaxis in the open field, and more open arm entries in the elevated plus maze. Finally, LPA5 knockout mice also displayed marked reduction in social exploration, although several other tests indicated that these mice were able to respond normally to environmental stimuli. While learning and memory performance was not impaired in LPA5-deficient mice, we found differences, e.g., targeted swim strategy and reversal learning, as well as scheduled appetitive conditioning that might indicate differential motivational behavior. These results imply that LPA5 might be involved in both nociception and mechanisms of pain hypersensitivity, as well as in anxiety-related and motivational behaviors. These observations further support the proposed involvement of LPA signaling in psychopathology.

Gut microbiota composition is correlated to grid floor induced stress and behavior in the BALB/c mouse.

Stress has profound influence on the gastro-intestinal tract, the immune system and the behavior of the animal. In this study, the correlation between gut microbiota composition determined by Denaturing Grade Gel Electrophoresis (DGGE) and tag-encoded 16S rRNA gene amplicon pyrosequencing (454/FLX) and behavior in the Tripletest (Elevated Plus Maze, Light/Dark Box, and Open Field combined), the Tail Suspension Test, and Burrowing in 28 female BALB/c mice exposed to two weeks of grid floor induced stress was investigated. Cytokine and glucose levels were measured at baseline, during and after exposure to grid floor. Stressing the mice clearly changed the cecal microbiota as determined by both DGGE and pyrosequencing. Odoribacter, Alistipes and an unclassified genus from the Coriobacteriaceae family increased significantly in the grid floor housed mice. Compared to baseline, the mice exposed to grid floor housing changed the amount of time spent in the Elevated Plus Maze, in the Light/Dark Box, and burrowing behavior. The grid floor housed mice had significantly longer immobility duration in the Tail Suspension Test and increased their number of immobility episodes from baseline. Significant correlations were found between GM composition and IL-1α, IFN-γ, closed arm entries of Elevated Plus Maze, total time in Elevated Plus Maze, time spent in Light/Dark Box, and time spent in the inner zone of the Open Field as well as total time in the Open Field. Significant correlations were found to the levels of Firmicutes, e.g. various species of Ruminococccaceae and Lachnospiraceae. No significant difference was found for the evaluated cytokines, except an overall decrease in levels from baseline to end. A significant lower level of blood glucose was found in the grid floor housed mice, whereas the HbA1c level was significantly higher. It is concluded that grid floor housing changes the GM composition, which seems to influence certain anxiety-related parameters.

Anxiolytic-like effect of linezolid in experimental mouse models of anxiety

Linezolid, an oxazolidinone class antibiotic is a reversible and nonselective inhibitor of monoamine oxidase (MAO) enzyme, mainly for MAO-A subtype. Its antidepressant-like effect has been previously demonstrated in the rodent models of depression. MAO-A enzyme has been shown to play a role in the pathophysiology of anxiety disorders and inhibition of MAO-A in the brain could be used to treat anxiety disorders. Thus, the objective of this study was to investigate the putative anxiolytic effects of linezolid in rodent models of anxiety. Mice were acutely injected with linezolid (5-40 mg/kg, i.p.), diazepam (2 mg/kg, i.p.) and moclobemide (10 mg/kg., i.p.). Linezolid (20 and 40 mg/kg), diazepam and moclobemide significantly (p<0.05) increased the percentage of time spent and entries into open arms in the elevated plus maze (EPM) test without altering the closed arm entries. Linezolid (10-40 mg/kg) significantly (p<0.05) increased the latency time to leave the light compartment, linezolid (20 and 40 mg/kg) significantly (p<0.05) increased total time spent in light compartment and linezolid (40 mg/kg) significantly (p<0.05) increased the number of transition between compartments in the light/dark (L/D) aversion test. Moreover, diazepam and moclobemide also showed significant (p<0.05) effects on all parameters in the (L/D) test. In addition, linezolid (20 and 40 mg/kg), diazepam and moclobemide significantly (p<0.05) increased the number of and time spent in head dipping, whereas significantly (p<0.05) decreased the head dipping latency in hole board (HB) test. In the present study linezolid at higher doses (20 and 40 mg/kg), diazepam and moclobemide showed more pronounced anxiolytic effects as compared to lower doses of linezolid (5 and 10 mg/kg). Whereas, the effects of linezolid at higher doses, diazepam and moclobemide on mice behavior in anxiety models was found quite similar. In conclusion, these results verified, for the first time, the anxiolytic properties of linezolid and suggest that linezolid may be considered an alternative approach for the management of anxiety disorders.

Analysis of emotionality and locomotion in radio-frequency electromagnetic radiation exposed rats

In the current study the modulatory role of mobile phone radio-frequency electromagnetic radiation (RF-EMR) on emotionality and locomotion was evaluated in adolescent rats. Male albino Wistar rats (6-8 weeks old) were randomly assigned into the following groups having 12 animals in each group. Group I (Control): they remained in the home cage throughout the experimental period. Group II (Sham exposed): they were exposed to mobile phone in switch-off mode for 28 days, and Group III (RF-EMR exposed): they were exposed to RF-EMR (900 MHz) from an active GSM (Global system for mobile communications) mobile phone with a peak power density of 146.60 μW/cm(2) for 28 days. On 29th day, the animals were tested for emotionality and locomotion. Elevated plus maze (EPM) test revealed that, percentage of entries into the open arm, percentage of time spent on the open arm and distance travelled on the open arm were significantly reduced in the RF-EMR exposed rats. Rearing frequency and grooming frequency were also decreased in the RF-EMR exposed rats. Defecation boli count during the EPM test was more with the RF-EMR group. No statistically significant difference was found in total distance travelled, total arm entries, percentage of closed arm entries and parallelism index in the RF-EMR exposed rats compared to controls. Results indicate that mobile phone radiation could affect the emotionality of rats without affecting the general locomotion.

The Metabolic Responses to Aerial Diffusion of Essential Oils

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.

The effects of nicotine on nitric oxide induced anxiogenic-like behaviors in the dorsal hippocampus

Nicotine, an active tobacco derived alkaloid, regulates the activity of the neuronal nitric oxide synthase (nNOS) as well as the release of nitric oxide (NO) in the nervous system. Nicotinic acetylcholine receptors and nNOS are abundantly co-expressed in the hippocampal neurons and are found to alter anxiety-like behaviors in rodents. Dorsal hippocampus may be a site for modulation of anxiety. Therefore, in this study, we investigated the possible interactions between nicotine and NO systems of the dorsal hippocampus and the resultant effect on anxiety-like behaviors. The elevated plus-maze (EPM) test has been used to test the anxiety. Intraperitoneal administration of nicotine (0.5mg/kg) decreased the open arm time percentage (%OAT) and open arm entries percentage (%OAE) but not the locomotor activity, indicating an anxiogenic-like response. Intra-CA1 injection of l-arginine (a NO precursor) or l-NAME (a NOS inhibitor) also caused anxiogenic-like effects. On the other hand, injection of the low dose nicotine before different doses of l-arginine or l-NAME blocked the anxiogenic-like response induced by the drugs. Our results suggested that, both NO and nicotinic cholinergic systems not only play a part in the modulation of the anxiety in mice dorsal hippocampus, but also demonstrate a complex interaction in this respect.

Chronic Simvastatin Treatments Attenuate Ethanol Withdrawal Syndrome in Rats

Rodent models of ethanol withdrawal-induced anxiety have been used to explore the neurobiology underlying withdrawal and to evaluate the utility of therapeutic agents aimed at reducing withdrawal severity. Of the many tests of anxiety-like behavior, the elevated plus maze and open field are the most commonly used. In general, ethanol withdrawal decreases most or all of the individual behaviors recorded in these tasks, indicating the occurrence of an anxiogenic-like effect of withdrawal in rodents. Effects of sub-chronic simvastatin treatments on ethanol withdrawal syndrome were inves- tigated in rats. Ethanol (7.2% v/v) was given to adult male Wistar rats by a liquid diet for 30 days. Sub-chronic (once daily) simvastatin (1 or 10 mg/kg) or saline were administered to rats by oral gavage. After 24 hours of ethanol withdrawal on the simvastatin treatment rats were observed in behavior tests. The increases the time open arms entries in the elevated plus-maze and grooming in the open-field through the exposure to sub-chronic treatment with simvastatin in rats submitted to ethanol intake, indicating beneficial effects on ethanol withdrawal syndrome. Our results suggest that sub-chronic simvastatin treatment attenuates ethanol withdrawal syndrome in ethanol-dependent rats and this drug may be useful for treatment of ethanol-type dependence.

Angiotensin-(1–7) central administration induces anxiolytic-like effects in elevated plus maze and decreased oxidative stress in the amygdala

There is increasing evidence that besides the well-known angiotensin (Ang) II, other renin–angiotensin system (RAS) peptides, including Ang-(1–7), could have important effects at the central level.However, very few things are known about the central actions of Ang-(1–7), while the effects of its administration alone on anxiety have not been tested to date, to the best of our knowledge. In this way, we were interested in studying the effects of Ang-(1–7) intracerebroventricular administration on anxiety levels, as studied through some main behavioral parameters in the elevated plus maze, as well as the importance of Ang-(1–7) in the oxidative stress status from the amygdala, which is one of the key brain regions involved in mediating anxiety.We report here a possible anxiolytic-like effect of Ang-(1–7) administration, as demonstrated by the increased percentage of time spent and frequency of entries in the open arms of the elevated plus maze, as well as increased head-dipping behavior in the open arms and decreased stretching in closed arms. Also some antioxidant effects of Ang-(1–7) are suggested since a significant increase of GPX specific activity and a decrease of the main peroxidation marker MDA were observed in the amygdala. Moreover, we found a significant correlation between most of the behavioral parameters in the elevated plus maze and the levels of the oxidative stress markers.However, further studies are necessary in order to elucidate the effects of Ang-(1–7) administration on anxiety and oxidative stress status and also on the possible correlation that might exists between these aspects.

Dopaminergic system in CA1 modulates MK-801 induced anxiolytic-like responses

RationaleToday, there is relatively no debate on the notion that NMDA receptor antagonist agents in the hippocampus induce anxiolytic-like effects through distinct mechanisms. There is also a bulk of studies showing the involvement of the dopaminergic system in NMDA induced behaviors. Thus, on the basis of the involvement of dopaminergic system in anxiety-related behaviors, the present study aimed to investigate the involvement of the dorsal hippocampal (CA1) dopaminergic system in anxiolytic-like responses induced by MK801 (NMDA receptor antagonist) in male Wistar rats. MethodsWe used the elevated plus maze to test anxiety. This apparatus has widely been employed to test parameters of anxiety-related behaviors including the open arm time percentage (%OAT), open arm entries percentage (%OAE), locomotor activity, grooming (the rat rubs its face), rearing (the rat maintains an erect posture) and defecation (the number of boli defection). ResultsThe data showed that, intra-CA1 injection of MK801 (2μg/rat) increases %OAT and %OAE but not other exploratory behaviors, indicating an anxiolytic-like effect. Moreover, sole intra-CA1 injection of SCH23390, dopamine D1 receptor antagonist, (0.25, 0.5 and 1μg/rat) and sulpiride, dopamine D2 receptor antagonist, (0.25, 0.5 and 0.75μg/rat) did not alter anxiety-like behaviors. Co-administration of subthreshold doses of SCH23390 (0.5μg/rat) and MK801 (0.5g/rat), induced anxiolytic-like behaviors. Furthermore, intra-CA1 administration of different doses of sulpiride (0.12, 0.5 and 0.75μg/rat), 5min before the injection of an effective dose of MK801 (2μg/rat), decreased %OAT and %OAE, however did not alter other exploratory behaviors induced by MK801. ConclusionOur results suggested a modulatory effect of the CA1 dopaminergic system on the anxiolytic-like effects induced by MK801.

The differential role of NOS inhibitors on stress-induced anxiety and neuroendocrine alterations in the rat

The inhibitors of nitric oxide synthase (NOS) have been shown to possess antidepressant- and anxiolytic-properties in animal model. In order to examine the involvement of nitric oxide (NO) on stress-induced neurobehavioral changes and the concomitant alterations of neuroendocrinological factors, we studied the effects of the nonselective NOS inhibitor, Nω-Nitro l-arginine methyl ester hydrochloride (l-NAME) and the specific neuronal NOS inhibitor, 7-nitroindazole (7-NI) on restraint stress-induced anxiety in the elevated plus maze (EPM) test and biochemical analysis. Restraint stress significantly reduced the latency time in open arm and the percentage of open arm entries of the plus maze. Pretreatment with l-NAME (10mg/kg) or 7-NI (10mg/kg) significantly attenuated stress-induced anxiety response. In addition, administration of l-NAME (10mg/kg) reversed stress-induced increase in corticosterone and NO metabolites (NOx) in plasma. The administration of 7-NI, but notl-NAME, reversed stress-induced NOx in paraventricular nucleus of the hypothalamus (PVN) and locus coeruleus (LC), accompanying with decrease of NADPH-d reactivity in the PVN and lateral dorsal tegmental nucleus (LTDg). These results showed that l-NAME influences HPA axis activity such as corticosterone levels and NOx in plasma, whereas 7-NI produced anxiolytic-like effects through the direct reduction in NOx in the brain. The results of this study demonstrated that NOS inhibitors have differential effect on stress responses and inhibition of NO could be responsible for the beneficial effect on regulation of stress.

Anxiolytic effects of standardized extract of Centella asiatica (ECa 233) after chronic immobilization stress in mice

Ethnopharmacological relevanceCentella asiatica has long been used for various neurological disturbances in Southeast Asian countries. The present study aims to demonstrate the anxiolytic effect of ECa 233, a standardized extract of C. asiatica containing triterpenoids not less than 80%, in comparison to diazepam. Materials and methodsThe test compound was given orally to non-stressed mice and mice subjected to chronic immobilization stress. Anxiolytic effect was assessed by an elevated plus maze (EPM), a dark-light box and an open-field tests. ResultsAnxiolytic effect of ECa 233 was clearly demonstrated in non-stressed mice subjected to acute stress in all behavioral tests employed. In the EPM test, chronically stressed mice showed significant decrease in the number of open arm entries, shortening the time spent in open arms and an increase of the latency to leave the central area, suggesting their release from the stress. In addition, ameliorating effect of ECa 233 was observed on the body weight and serum corticosterone which were adversely affected by immobilization stress. Madecassoside and asiaticoside, equal to their respective contents of the effective doses of ECa 233, exclusively presented anxiolytic effects in EPM, while no distinct effect was observed on the body weight and serum corticosterone. ConclusionsThe present study demonstrated anxiolytic effect of ECa 233 in both acutely and chronically stressed animals. These effects could be mainly accounted by madecassoside and asiaticoside, suggesting a possible use of ECa 233 for the treatment of both acute and chronic anxiety in the pathological state.