Effects In Elevated Plus-maze Research Articles

Behavioural effects of APH199, a selective dopamine D4 receptor agonist, in animal models

RationaleThe dopamine D4 receptors (DRD4) play a key role in numerous brain functions and are involved in the pathogenesis of various psychiatric disorders. DRD4 ligands have been shown to moderate anxiety, reward and depression-like behaviours, and cognitive impairments. Despite a series of promising but ambiguous findings, the therapeutic advantages of DRD4 stimulation remain elusive.ObjectivesThe investigation focused on the behavioural effects of the recently developed DRD4 agonist, APH199, to evaluate its impact on anxiety, anhedonia, behavioural despair, establishment and retrieval of alcohol reinforcement, and amphetamine (AMPH)-induced symptoms.MethodsMale C57BL/6 J mice and Sprague–Dawley rats were examined in five independent experiments. We assessed APH199 (0.1–5 mg/kg, i.p.) effects on a broad range of behavioural parameters in the open field (OF) test, conditioned place preference test (CPP), elevated plus maze (EPM), light–dark box (LDB), novelty suppressed feeding (NSF), forced swim test (FST), sucrose preference test (SPT), AMPH-induced hyperlocomotion test (AIH), and prepulse inhibition (PPI) of the acoustic startle response in AMPH-sensitized rats.ResultsAPH199 caused mild and sporadic anxiolytic and antidepressant effects in EPM and FST, but no remarkable impact on behaviour in other tests in mice. However, we found a significant increase in AMPH-induced hyperactivity, suggesting an exaggeration of the psychotic-like responses in the AMPH-sensitized rats.ConclusionsOur data challenged the hypothesis of the therapeutic benefits of DRD4 agonists, pointing out a possible aggravation of psychosis. We suggest a need for further preclinical studies to ensure the safety of antipsychotics with DRD4 stimulating properties.

Peptide LCGA-17 Attenuates Behavioral and Neurochemical Deficits in Rodent Models of PTSD and Depression.

We have previously described the LCGA-17 peptide as a novel anxiolytic and antidepressant candidate that acts through the α2δ VGCC (voltage-gated calcium channel) subunit with putative synergism with GABA-A receptors. The current study tested the potential efficacy of acute and chronic intranasal (i.n.) LCGA-17 (0.05 mg/kg and 0.5 mg/kg) in rats on predator odor-induced conditioned place aversion (POCPA), a model of post-traumatic stress disorder (PTSD), and chronic unpredictable stress (CUS) that produce a range of behavioral and physiological changes that parallel symptoms of depression in humans. CUS and LCGA-17 treatment effects were tested in the sucrose preference (SPT) social interaction (SI), female urine sniffing (FUST), novelty-suppressed feeding (NSFT), and forced swim (FST) tests. Analysis of the catecholamines content in brain structures after CUS was carried out using HPLC. The efficacy of i.n. LCGA-17 was also assessed using the Elevated plus-maze (EPM) and FST. Acute LCGA-17 administration showed anxiolytic and antidepressant effects in EPM and FST, similar to diazepam and ketamine, respectively. In the POCPA study, LCGA-17 significantly reduced place aversion, with efficacy greater than doxazosin. After CUS, chronic LCGA-17 administration reversed stress-induced alterations in numerous behavioral tests (SI, FUST, SPT, and FST), producing significant anxiolytic and antidepressant effects. Finally, LCGA-17 restored the norepinephrine levels in the hippocampus following stress. Together, these results support the further development of the LCGA-17 peptide as a rapid-acting anxiolytic and antidepressant.

Effect of Ocimum sanctum leaf extract in animal models of anxiety

Background: Anxiety is one of the most prominent psychiatry disorders related to common stress. Approximately two-thirds of anxious patients respond to currently available treatments but the magnitude of problem is still disappointing. Ocimum sanctum (OS), a perennial shrub grown in India, has anti-stress activity. Yet, there is a paucity of data regarding this. Aims and Objectives: This study aims to evaluate the anti-anxiolytic effect of OS leaf extract (OSLE) in Swiss albino mice. Materials and Methods: Elevated plus maze (EPM) and open field test are standardized tests done for screening anxiolytic effects of drugs. The animals were grouped and the tests were conducted and the results were compared with the standard drug diazepam. Results: There was significant increase in the time spent in open arm and number of open arm entries in the diazepam group and group receiving OSLE at dose of 100 mg/kg and 200 mg/kg in EPM test. Furthermore, in the open field test, there was significant increase in the number of square crossed and rearing in the diazepam group and OSLE at dose of 100 mg/kg and 200 mg/kg. Conclusion: OSLE shows significant anxiolytic effect in EPM and open field test models in Swiss albino mice. This can be further studied to open up new possibilities for new drug development for anxiety.

Selective inhibition of monoacylglycerol lipase is associated with passive coping behavior and attenuation of stress-induced dopamine release in the medial prefrontal cortex

The endocannabinoid system is involved in the regulation of the stress response, but the relative contribution of N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) and their mechanisms have to be elucidated. In this study, we compared the effects of the pharmacological inhibition of the two major endocannabinoid-degrading enzymes [fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) for AEA and 2-AG, respectively] on stress-coping [forced swim test (FST) and tail suspension test (TST)] and anxiety-like [elevated-plus maze (EPM) and light-dark test (LDT)] behaviors in wild-type and FAAH knockout mice. In vivo microdialysis estimated the effects of FAAH and MAGL inhibition on dopamine (DA) and serotonin (5-HT) levels in the medial prefrontal cortex (mPFC) during an FST. Mice were treated with PF-3845 (FAAH inhibitor), JZL184 (MAGL inhibitor), JZL195 (dual FAAH/MAGL inhibitor) or vehicle. Our data showed that PF-3845 increased latency to immobility and decreased total immobility time in FST, but no effects were observed in TST compared with vehicle-treated wild-type mice. By contrast, JZL184 decreased latency and increased immobility in TST and FST. JZL195 in wild-type mice and JZL184 in FAAH knockout mice reproduced the same passive coping behaviors as JZL184 in wild-type mice in TST and FST. In the microdialysis experiment, FST was associated with increased DA and 5-HT levels in the mPFC. However, JZL184-treated wild-type mice displayed a significant attenuation of forced swim stress-induced DA release compared with vehicle-treated wild-type mice and PF-3845-treated wild-type mice. Finally, FAAH and/or MAGL inhibitors induced robust and consistent anxiolytic-like effects in EPM and LDT. These results suggested differences between FAAH and MAGL inhibition in stress-coping behaviors. Notably, MAGL inhibition induced a consistent avoidant coping behavior and attenuated the stress-induced mPFC DA response in FST. However, more investigation is needed to elucidate the functional association between DA and 2-AG signaling pathways, and the molecular mechanism in the regulation of passive coping strategies during inescapable stress.

Pharmacological validation of the anxiolytic, muscle relaxant and sedative like activities of Capsicum annuum in animal model

<p class="Abstract">The current study deals with anxiolytic, muscle relaxant and sedative like activities of Capsicum annuum in animal models. The crude extract was found safe in acute behavior and toxicity studies. However, the n-hexane fraction caused severe acute toxicity. Pretreatment of crude extract and n-hexane fraction elicited marked dose-dependent antianxiety-like effects in elevated plus-maze and dark and light models. The results showed significant (p< 0.05) antianxiety-like effects of crude extract while highly significant (p< 0.001) for n-hexane fraction. Similarly, an effect on muscle coordination was tested in traction model, where both crude extract and n-hexane fraction evoked marked dose-dependent activity. The effect of thiopental-induced sleep test of crude extract and n-hexane fraction was highly significant (p< 0.001). All together, the results revealed potent anxiolytic, muscle relaxant and sedative like activities of C. annuum in animal models and the pharmaco-logically active constituents are mostly non-polar in nature.</p><p><strong>Video Clip of Methodology</strong>:</p><p>4 min 31 sec: <a href="https://youtube.com/v/85ituFAi6sw">Full Screen</a> <a href="https://youtube.com/watch?v=85ituFAi6sw">Alternate</a></p>

Antidepressant- and anxiolytic-like effect of novel 5-hydroxytryptamine3 receptor antagonist 2-[4-(3-chlorophenyl) piperazin-1-yl]-1,8-naphthyridine -3-carboxylic acid (7e)-: An approach using rodent behavioral antidepressant and anxiolytic test battery

Aim: Depression and anxiety are among the most common and prevalent forms of mental disorder. The 5-hydroxytryptamine3 (5-HT 3 ) receptor antagonists modulate serotonergic pathways and show antidepressant- and anxiolytic-like effect in various animal models of depression. The present study was designed to investigate the antidepressant and anxiolytic potential of 2-[4-(3-chlorophenyl) piperazin-1-yl]- 1,8-naphthyridine-3-carboxylic acid (7e), a novel 5-HT 3 receptor antagonist in rodent behavioral models of depression and anxiety. Materials and Methods: The compound 7e was tested using different behavioral models for depression and anxiety such as forced swim test (FST), tail suspension test (TST), mechanistic models such as 5-hydroxytryptophan (5-HTP)-induced head twitch, elevated plus maze (EPM), hole-board (HB) test, open field test (OFT), and light and dark (L and D) aversion test. Results: The compound 7e (1 and 2 mg/kg, intraperitoneally [i.p.]) exhibits antidepressant-like effect in FST. In addition, compound 7e (0.5, 1 and 2 mg/kg, i.p.) exhibits antidepressant-like effect in TST after acute treatment without any significant effect on base line spontaneous locomotor activity. Moreover, compound 7e (2 mg/kg, i.p.) potentiated the 5-HTP-induced head twitch responses in mice. In interaction studies, compound 7e (0.5 mg/kg, i.p.) potentiated the antidepressant effect of bupropion. Furthermore, compound 7e also exhibited anxiolytic-like effect in EPM, HB test, OFT, and L and D aversion test. Conclusion: These preliminary studies reveal that compound 7e exhibits antidepressant- and anxiolytic-like effect in behavioral rodent models of depression and anxiety.

Behavioral effects of Citrus paradisi in rats.

Anxiety and depression adversely affect behavior though these conditions may be handled through environmental and dietary changes. Diet rich in flavonoids and vitamins may support reducing anxiety and depression. Depression is most common but serious illness making life miserable; however the usage of dietary and herbal complements to treat anxiety and depression had been grown by the time. The purpose of this investigation was to characterize the behavioral properties of Citrus paradisi in rats at diverse doses i.e. 0.1, 0.3 and 0.5 ml/kg. Anxiolytic and antidepressant actions were particularly measured twice in 15 days through elevated plus maze, open field and forced swimming tests. C. paradisi, revealed increase in the locomotor activity and the exploratory skills of the animals, as assessed in the open-field. Indeed C. paradisi had a strong anxiolytic effect in elevated plus-maze, as assessed by an augmented number of entries and the proportion of time spent in the open arms. Moreover there was decline in duration of immobility and rise in duration of climbing during forced swimming test. At the tested doses these results suggest that C. paradisi have the potential to exert a range of CNS-mediated biological activities and thus encourage more investigations in this field.

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.

A Chinese herbal medicine production of anxiolytic and cognitive enhancing effects in a rat model of posttraumatic stress disorder

Free and Easy Wanderer Plus (FEWP) is a traditional Chinese medicine that has been used to treat stress- and depression-related diseases in China. To study the effects of FEWP on post-traumatic stress disorder (PTSD), the present study investigated how chronic treatment with FEWP affected rodent behaviors in a modified single-prolonged stress and shock (SPS and S) model, which induces certain behavioral manifestations similar to those seen in PTSD patients. Locomotor activities (LMA), elevated Plus Maze (EPM), and Morris Water Maze (MWM) tests were used to determine its effects on general locomotion, anxiety and cognitive functions following traumatic exposure. The results showed that SPS and S impaired performance in MWM and produced anxiogenic-like effects in EPM, both of which were significantly ameliorated by chronic treatment of FEWP at doses of 5 and 10 mg/kg/d. The effects of FEWP were not due to changes in locomotion. The current findings provide strong evidence that FEWP may be a useful drug for treating PTSD. Key words: Single prolonged stress and shock, post-traumatic stress disorder, Morris water maze, open field, elevated plus maze.

Similar anxiolytic-like effects following intra-amygdala infusions of benzodiazepine receptor agonist and antagonist: Evidence for the release of an endogenous benzodiazepine inverse agonist in mice exposed to elevated plus-maze test

Previous studies have demonstrated that microinjections of midazolam, a benzodiazepine receptor agonist, into the amygdala produce anxiolytic-like effects in elevated plus-maze (EPM)-naïve rodents. However, systemic or intracerebral administration of benzodiazepines (BDZ) fails to alter anxiety in maze-experienced animals, a phenomenon defined as “one trial tolerance” (OTT). This study focused on the effects of intra-amygdala infusion of midazolam in maze-experienced mice. In addition, the effects of flumazenil in the amygdala of maze-naïve and experienced mice were also investigated. To investigate intrinsic effects of intra-amygdala flumazenil on anxiety, animals were systemically treated with the BDZ receptor inverse agonist, DMCM (4-ethyl-6,7-dimethoxy-9H-pyrido[3,4-b]indole-3-carboxylic acid methyl ester hydrochloride). Conventional measures of anxiety (% open arm entries and % open arm time), locomotor activity (frequency of closed arm entries) and a range of ethological measures related to risk assessment were recorded. Intra-amygdala midazolam (3.0 and 30 nmol) attenuated anxiety in maze-experienced mice. A similar behavioral profile was produced by intra-amygdala flumazenil in maze-naïve (4.0 and 16 nmol) and maze-experienced (16 nmol) mice. Intra-amygdala flumazenil (at 2.0 nmol, a dose devoid of any intrinsic effect on anxiety measures in the EPM) selectively and completely blocked the anxiogenic-like effects of systemic administration of DMCM (1.0 mg/kg, i.p.) in maze-naïve mice. Together, these results demonstrate that the GABA A-benzodiazepine receptor complex located within the amygdala does not play a role in the OTT phenomenon. Present results also suggest that the release of an endogenous BDZ receptor inverse agonist within the amygdala seems to be an important correlate of the emotional state induced by the plus-maze test.

Reversal of Oxidative Stress-Induced Anxiety by Inhibition of Phosphodiesterase-2 in Mice

The pathogenesis of several neuropsychiatric disorders, including anxiety and depression, has been linked to oxidative stress, in part via alterations in cyclic nucleotide signaling. Phosphodiesterase-2 (PDE2), which regulates cGMP and cAMP signaling, may affect anxiety-related behavior through reduction of oxidative stress. The present study evaluated the effects of oxidative stress on behavior and assessed the anxiolytic effects of the PDE2 inhibitor Bay 60-7550 [(2-(3,4-dimethoxybenzyl)-7-{(1R)-1-[(1R)-1-hydroxyethyl]-4-phenylbutyl}-5-methyl imidazo-[5,1-f][1,2,4]triazin-4(3H)-one)]. Treatment of mice with L-buthionine-(S,R)-sulfoximine (300 mg/kg), an inducer of oxidative stress, caused anxiety-like behavioral effects in elevated plusmaze, open-field, and hole-board tests through the NADPH oxidase pathway; these effects were antagonized by Bay 60-7550 (3 mg/kg) and apocynin (3 mg/kg), an inhibitor of NADPH oxidase. The Bay 60-7550-mediated decrease in oxidative stress (i.e., superoxide anion and reactive oxygen species generation in cultured neurons and total antioxidant capacity and lipid peroxides in amygdala and hypothalamus) and expression of NADPH oxidase subunits (i.e., p47 phox and gp91 phox expression in amygdala, hypothalamus, and cultured neurons) was associated with increased cGMP and phosphorylation of vasodilator-stimulated phosphoprotein at Ser239, suggesting an important role of cGMP-protein kinase G signaling in reduction of anxiety. Overall, the present results indicate that oxidative stress induces anxiety-like behavior in mice and that PDE2 inhibition reverses it through an increase in cGMP signaling. Thus, PDE2 may be a novel pharmacological target for treatment of anxiety in neuropsychiatric and neurodegenerative disorders that involve oxidative stress.

Sedative and anxiolytic effects of methanolic extract from the leaves of Passiflora actinia

Leaves from several Passiflora species are largely employed in the Brazilian folk medicine as anxiolytic and sedative. In this work the anxiolytic, sedative-like properties and liquid chromatography analysis of methanolic extract of Passiflora actinia were evaluated. The methanol extract and all of its fractions presented significant sedative-like effect in elevated plus-maze and open field tests. Only the aqueous fraction of the methanol extract showed selective anxiolytic activity (30 mg/kg). Chromatographic analysis of the active fractions showed the presence of isovitexin and absence of the classical Passiflora beta-carboline alkaloids or flavonoids such as vitexin, rutin, swertisin, hesperidin and orientin. The tincture obtained from P. actinia leaves presented 0.27 mg/ml of isovitexin and absence of vitexin.

Behavioral effects of systemically administered MK-212 are prevented by ritanserin microinfusion into the basolateral amygdala of rats exposed to the elevated plus-maze

Although 5-HT2 receptors seem to play an important role in anxiety, results from numerous studies are still highly variable. Moreover, little is known about the behavioral effects of centrally administered 5-HT2 compounds in animal models of anxiety. The current study was performed to: (1) further investigate the effects of 5-HT2 receptor activation in rats exposed to the elevated plus-maze (EPM) and the open-field arena, two widely used animal models for studying anxiety and locomotor activity; and (2) evaluate the involvement of the 5-HT2 receptors within the basolateral nucleus of the amygdala (BLA) in the modulation of such effects. In the first experiment, male Wistar rats were exposed for 5 min to the EPM 27 min following intraperitoneal (i.p.) (1.0 ml/kg) injections of the preferential 5-HT2C receptor agonist 6-chloro-2[1-piperazinyl]pyrazine (MK-212) at doses of 1.0, 2.0, or 4.0 mg/kg. Control animals were injected with saline. The percentage of open-arm entries and the percentage of time spent in these arms were employed as anxiety indexes, whereas the number of closed-arm entries was calculated as indicative of locomotor activity. In the second experiment, rats were exposed for 10 min in an open-field arena to further assess the interference of the same MK-212 doses upon locomotor activity. In Experiment 3, rats were microinjected (0.2 microl) either with the mixed 5-HT 2A/2C receptor antagonist ritanserin (0.5, 1.25, 2.5, and 5.0 microg) or its vehicle into the BLA 12 min following i.p. injections of saline or the intermediate dose of MK-212 (2.0 mg/kg). Fifteen minutes later, each animal was exposed to the EPM as before. Whereas the highest dose of MK-212 (4.0 mg/kg) induced motor-suppressant effects in both EPM and open-field arena, the intermediate dose of the drug (2.0 mg/kg) reduced open-arm exploration without significantly affecting the number of closed-arm entries. This behavioral profile, consistent with selective anxiogenic effect in the EPM, was dose-dependently prevented by ritanserin microinfusion into the BLA. In saline-pretreated animals, however, ritanserin (all doses) was ineffective. MK-212 increases anxiety and decreases locomotor activity. The anxiogenic-like profile of 5-HT2 receptor activation is prevented by the blockade of 5-HT2 receptors within the BLA, which does not have an effect by itself upon basal anxiety levels triggered by the EPM.

The effects of CRA 1000, a non-peptide antagonist of corticotropin-releasing factor receptor type 1, on adaptive behaviour in therat

Intracerebrally administered CRF has been demonstrated to elicit several behavioural deficits in novel and potentially stressful experimental paradigms, and to promote activity in familiar situations. This study examined the effect of CRA 1000, a novel non-peptide antagonist of CRF1receptors, on rat behaviour in tests of anxiolytic and antidepressant activity and novelty-oriented behaviour. CRA 1000 (1.25–10mg/kg) had no major effect in elevated plus-maze and social interaction tests. However, CRA 1000 (5mg/kg) significantly reduced immobility in the forced swimming test, suggesting an antidepressant-like effect. In the exploration box test, CRA 1000 (1.25mg/kg) had an anxiolytic effect on rat exploratory behaviour both in intact rats and after lesioning of the projections of locus coeruleus by DSP-4 (50mg/kg) treatment. A higher dose of CRA 1000 (5mg/kg) tended to have anxiolytic-like effects in DSP-4 pretreated rats, but in intact animals this dose prevented the increase in exploration which develops with repeated exposure to initially anxiety-provoking situations. Taken together, these experiments demonstrate that CRF1receptor blockade by CRA 1000 has antidepressant-like effects, does not have a robust anti-anxiety effect in non-stressed animals, but does have anxiolytic-like effects in more complex tasks, which can be observed also after denervation of the locus coeruleus projections. However, large doses of CRF1receptor antagonists may reduce motivation of exploratory behaviour in familiar environments.

A discrimmative stimulus produced by l-(3-Chlorophenyl)-piperazine (mCPP) as a putative animal model of anxiety

1. 1. This study compares behavioral responses to serotonergic (SHT) agonists and pentylenetetrazol (PTZ) in two behavioral paradigms used as animal models of anxiety. PTZ and mCPP were compared for behavioral effects in elevated plus-maze and interoceptive discriminative stimuli they produce. 2. 2. PTZ is a known anxiogenic drug. The discriminative stimuli of mCPP were selected for comparison because this drug produces “anxiety” in human subjects and “anxiety-like” behaviors in rats, and is a potent agonist at 5HT 1B 2C receptors and a partial agonist at 5HT 2A receptors. 3. 3. In rats trained to discriminate mCPP (1.4 mg/kg, training dose) from saline, PTZ substituted for the mCPP suggesting the “anxiety-like” properties of the mCPP stimulus. The mCPP stimulus was blocked in a dose-related manner by methysergide, a 5HT sol2A 2C antagonist but not by the anxiolytic diazepam. TFMPP (a 5HT agonist) and DOI (a 5HT 2A 2C agonist) substituted for mCPP, but 1-NP (a 5 HT 1 agonist and 5HT 2C 2A antagonist) did not. 4. 4. In animals trained to discriminate PTZ (16 mg/kg) from saline, mCPP and DOI substituted for PTZ, while TFMPP and 1-NP do not. 5. 5. In the elevated plus maze, time spent on the open arms was reduced by mCPP, DOI and PTZ but there was no significant dose effect of TFMPP, or 1-NP. 6. 6. Methysergide blocked the “anxiety-like” behavior in the EPM. 7. 7. These data suggest that the discriminative stimuli produced by mCPP are based upon its selective actions on 5HT receptors and their use in behavioral pharmacology may offer another tool in studying pharmacology of 5HT based anxiogenic and anxiolytic drugs.