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Ketamine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, presents a rapid and sustained antidepressant effect in clinical and preclinical studies. Regarding ketamine effects on anxiety, there is a widespread discordance among pre-clinical studies. To address this issue, the present study reviewed the literature (electronic database MEDLINE) to summarize the profile of ketamine effects in animal tests of anxiety/fear. We found that ketamine anxiety/fear-related effects may depend on the anxiety paradigm, schedule of ketamine administration and tested species. Moreover, there was no report of ketamine effects in animal tests of fear related to panic disorder (PD). Based on that finding, we evaluated if treatment with ketamine and another NMDA antagonist, MK-801, would induce acute and sustained (24 hours later) anxiolytic and/or panicolytic-like effects in animals exposed to the elevated T-maze (ETM). The ETM evaluates, in the same animal, conflict-evoked and fear behaviors, which are related, respectively, to generalized anxiety disorder and PD. Male Wistar rats were systemically treated with racemic ketamine (10, 30 and 80 mg/kg) or MK-801 (0.05 and 0.1 mg/kg) and tested in the ETM in the same day or 24 hours after their administration. Ketamine did not affect the behavioral tasks performed in the ETM acutely or 24 h later. MK-801 impaired inhibitory avoidance in the ETM only at 45 min post-injection, suggesting a rapid but not sustained anxiolytic-like effect. Altogether our results suggest that ketamine might have mixed effects in anxiety tests while it does not affect panic-related behaviors., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

There is an urgent need to understand the pathophysiological mechanisms related to anxiety associated with diabetes, seeking more effective alternative treatments to treat it. For that, the effect of a preventive and prolonged treatment with fish oil (FO), a source of omega-3 polyunsaturated fatty acid, was tested in streptozotocin-diabetic (DBT) rats submitted to the anxiety tests. Additionally, an immunohistochemistry for neuronal NO synthase (nNOS) was performed in brain areas related to anxiety, such as lateral amygdala (AMY), hippocampus (HIP) and dorsolateral periaqueductal gray (dlPAG). Lastly, the effect of NO precursor L-arginine (L-Arg) or nNOS inhibitor 7-nitroindazole (7-NI) was tested in DBT animals treated with vehicle (VEH) or FO. Our data demonstrated that vehicle-treated DBT animals exhibited a more pronounced anxiogenic-like response and also presented high nNOS levels in the AMY, HIP and rostral dlPAG, what were both significantly prevented by FO treatment. This treatment was able to prevent the impairment in locomotor activity besides improving the high glycemic levels in DBT rats. Interestingly, while injection of 7-NI or L-Arg in VEH-treated DBT animals induced an anxiogenic-like and anxiolytic-like effect, respectively; the previous treatment with both L-Arg and 7-NI in FO-DBT animals abolished the anxiolytic-like effect induced by FO treatment. Altogether, our data support the hypothesis that a dysregulation in the NO production in brain areas as AMY, HIP and dlPAG may contribute to the mechanisms that link anxiety and diabetes, and the prevention of nNOS brain expression changes induced by a prolonged treatment with FO may be an important mechanism related to its anxiolytic-like effect., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The clinical efficacy of standardized essential oils (such as Lavender officinalis), in treating anxiety disorders strongly suggests that these natural products are an important candidate source for new anxiolytic drugs. A systematic review of essential oils, their bioactive constituents, and anxiolytic-like activity is conducted. The essential oil with the best profile is Lavendula angustifolia, which has already been tested in controlled clinical trials with positive results. Citrus aurantium using different routes of administration also showed significant effects in several animal models, and was corroborated by different research groups. Other promising essential oils are Citrus sinensis and bergamot oil, which showed certain clinical anxiolytic actions; along with Achillea wilhemsii, Alpinia zerumbet, Citrus aurantium, and Spiranthera odoratissima, which, like Lavendula angustifolia, appear to exert anxiolytic-like effects without GABA/benzodiazepine activity, thus differing in their mechanisms of action from the benzodiazepines. The anxiolytic activity of 25 compounds commonly found in essential oils is also discussed.

Ethnopharmacological Relevance: Achillea millefolium L. (Asteraceae), known as yarrow ("mil folhas"), has been used as folk medicine for gastrointestinal disorders, inflammation, anxiety, and insomnia., Aim: To evaluate the potential anxiolytic-like effect of hydroalcoholic extract of Achillea millefolium L. in animal models., Methods: The present study evaluated the effects of the hydroalcoholic extract from the aerial parts of Achillea millefolium L. in mice subjected to the elevated plus-maze, marble-burying, and open-field tests. Additionally, the GABA(A)/benzodiazepine (BDZ) mediation of the effects of Achillea millefolium was evaluated by pretreatment with the noncompetitive GABA(A) receptor antagonist picrotoxin and the BDZ antagonist flumazenil and by [(3)H]-flunitrazepam binding to the BDZ site on the GABA(A) receptor., Results: Achillea millefolium exerted anxiolytic-like effects in the elevated plus-maze and marble-burying test after acute and chronic (25 days) administration at doses that did not alter locomotor activity. This behavioral profile was similar to diazepam. The effects of Achillea millefolium in the elevated plus-maze were not altered by picrotoxin pretreatment but were partially blocked by flumazenil. Furthermore, Achillea millefolium did not induce any changes in [(3)H]-flunitrazepam binding., Conclusion: The results indicate that the orally administered hydroalcoholic extract of Achillea millefolium L. exerted anxiolytic-like effects that likely were not mediated by GABA(A)/BDZ neurotransmission and did not present tolerance after short-term, repeated administration., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Introduction: In Brazil, Erythrina velutina (Fabaceae) is widely used as a tranquilizer and/or sedative, and its extract exerts an anxiolytic-like effect profile in animal models, although these results may be caused by its sedative or amnesic effects. AIMS, MATERIALS AND METHODS: Thus, this study evaluated the effect of acute and chronic (23-26 days) administrations of the hydroalcoholic extract of the stem bark of Erythrina velutina (orally) in mice submitted to the following tests: elevated plus-maze, forced swim, spontaneous locomotor activity, and habituation to active chamber. Chlordiazepoxide and imipramine were used as standard drugs., Results: In the elevated plus-maze test, chronic, but not acute, Erythrina velutina (100mg/kg) administration increased the percentage of open arm entries, an effect also seen in both acute and chronic treatments with chlordiazepoxide (7.5mg/kg). In the forced swim test, only imipramine (25mg/kg) decreased immobility time. Impairment of habituation was seen only with acute imipramine administration and with the lowest doses of Erythrina velutina extract tested in acute (10mg/kg) and chronic (50mg/kg) administrations., Conclusions: These results suggest that chronic administration of the hydroalcoholic extract of the stem bark of Erythrina velutina exerts an anxiolytic-like effect on mice, and it could serve as a new approach for the treatment anxiety, although it may have an amnesic effect at low doses.

Hypericum perforatum extract exhibits an antidepressant effect and since several antidepressant drugs are also effective on generalised anxiety disorder (GAD) and panic disorders (PD), H. perforatum may possess some anxiolytic/antipanic effect. Thus, the aim of the present study was to evaluate the putative antipanic/anxiolytic effect of standardised H. perforatum extract (LI 160) on rats tested in the elevated T-maze, an animal model of innate (panic) and learned (generalised) anxiety, at doses that exhibit antidepressant-like activity. H. perforatum (150, 300 and 500 mg/kg, administered orally 24, 18 and 1h before the test) decreased the immobility time in the forced swim test. Rats were treated orally with H. perforatum (150 or 300 mg/kg) or paroxetine (5mg/kg) 24, 18, and 1h before being tested in the elevated T-maze (subacute treatment). Immediately after this test, the animals were submitted to the open field to evaluate locomotor activity. Paroxetine was used as a positive control, since it was clinically effective in GAD and PD. Other groups of animals were submitted to the same drug treatment for 7 days (subchronic treatment). Paroxetine (5mg/kg) impaired inhibitory avoidance after subacute treatment, while subchronic administration increased one-way escape latency. Subacute treatment with H. perforatum (300 mg/kg) exerts a partial anxiolytic-like effect in the inhibitory avoidance task. Repeated administration of H. perforatum (300 mg/kg) induced an anxiolytic effect (decreased inhibitory avoidance) and an antipanic effect (increased one-way escape). No effect on locomotor activity was found with any treatment. Thus, the results suggest that H. perforatum extract could exert an anxiolytic and antipanic effect.

This article is a transcription of an electronic symposium sponsored by the Brazilian Society of Neuroscience and Behavior (SBNeC). Invited researchers from the European Union, North America and Brazil discussed two issues on anxiety, namely whether panic is a very intense anxiety or something else, and what aspects of clinical anxiety are reproduced by animal models. Concerning the first issue, most participants agreed that generalized anxiety and panic disorder are different on the basis of clinical manifestations, drug response and animal models. Also, underlying brain structures, neurotransmitter modulation and hormonal changes seem to involve important differences. It is also common knowledge that existing animal models generate different types of fear/anxiety. A challenge for future research is to establish a good correlation between animal models and nosological classification.

The present study evaluated the correlation between the behavior of mice in the forced swimming test (FST) and in the elevated plus-maze (PM). The effect of the order of the experiments, i.e., the influence of the first test (FST or PM) on mouse behavior in the second test (PM or FST, respectively) was compared to handled animals (HAND). The execution of FST one week before the plus-maze (FST-PM, N = 10), in comparison to mice that were only handled (HAND-PM, N = 10) in week 1, decreased % open entries (HAND-PM: 33.6 +/- 2.9; FST-PM: 20.0 +/- 3.9; mean +/- SEM; P<0.02) and % open time (HAND-PM: 18.9 +/- 3.3; FST-PM: 9.0 +/- 1.9; P<0.03), suggesting an anxiogenic effect. No significant effect was seen in the number of closed arm entries (FST-PM: 9.5 (7.0-11.0); HAND-PM: 10.0 (4.0-14.5), median (interquartile range); U = 46.5; P>0.10). A prior test in the plus-maze (PM-FST) did not change % immobility time in the FST when compared to the HAND-FST group (HAND-FST: 57.7 +/- 3.9; PM-FST: 65.7 +/- 3.2; mean +/- SEM; P>0.10). Since these data suggest that there is an order effect, the correlation was evaluated separately with each test sequence: FST-PM (N = 20) and PM-FST (N = 18). There was no significant correlation between % immobility time in the FST and plus-maze indexes (% time and entries in open arms) in any test sequence (r: -0.07 to 0.18). These data suggest that mouse behavior in the elevated plus-maze is not related to behavior in the forced swimming test and that a forced swimming test before the plus-maze has an anxiogenic effect even after a one-week interval.

Rats selected as "anxious", "nonanxious," or normal according to their behavior in an elevated plus maze were submitted to memory tasks and the densities of central benzodiazepine receptors in the amygdala and the hippocampus were studied. Anxious rats exibited better retention scores in the inhibitory avoidance task while nonanxious rats exibited worse retention scores in inhibitory and two-way active avoidance tasks compared to normal rats. No significant differences were detected in the retention scores for habituation to an open field. Nonanxious rats presented a lower benzodiazepine receptor density in the hippocampus but not in the amygdala compared to the other groups. These data suggest that the benzodiazepine receptors are involved in the effect of "anxiety" or emotional states on memory storage processes., (Copyright 1999 Academic Press.)

1. The use of the Stroop Color-Word Test as a model of experimentally induced anxiety was evaluated. 2. First, the authors examined the influence of trait anxiety and the type of instructions on the anxiety state level. Subjects with high trait anxiety (above 50 on State-Trait Anxiety Scale--STAI) showed a significant increase in anxiety state only with limited time (2 minutes) and error signal (with a ringing bell) procedures. This increase was blocked by diazepam (DZP) 5.0 mg p.o. both on pre- and post-test measures, but it was not changed by placebo administration. 3. The public performance simulation (with a video-camera) was effective to raise the anxiety state on normal volunteers with mean trait anxiety (between 30 and 50 on STAI). This raise was prevented with diazepam 5.0 mg p.o. but it was not prevented with placebo administration. 4. As a whole, these data suggest that the Video-recorded Stroop Color-Word Test is an effective anxiety provoking test, able to detect the effect of standard anxiolytic drug and stressed the importance of trait anxiety level and the instructions on tests that induced anxiety experimentally.

The present study was designed to evaluate the role of ACTH and/or CRF release and corticosteroid receptors (glucocorticoid and mineralocorticoid) in the anxiolytic effect of corticosterone (CORT). Costicosteroid receptor mediation was evaluated using a dose-response analysis of the effect of CORT and by the action of dexamethasone (DEX), which binds to glucocorticoid receptors but not to mineralocorticoid receptors. DEX administration also permits indirect evaluation of the effect of ACTH/CRF release on the anxiolytic effect of CORT. Male Wistar rats (3 months old) weighing 250-350 g were treated sc with vehicle (N = 38), CORT 1.25 (N = 18), 2.5 (N = 13) and 5.0 (N = 24) mg/kg, or DEX 5.0 (N = 19) and 10.0 (N = 17) mg/kg and tested in the elevated plus-maze 2 h later. The group that received the highest dose of CORT (5.0 mg/kg) showed a significant increase in percent open arm entries (38 +/- 2.6, mean +/- SEM) as well as in percent time spent in open arms (27 +/- 4.0) when compared with the vehicle-treated rats (24.3 +/- 2.8 and 12.4 +/- 1.9, respectively; both P < 0.05). There were no other significant differences among groups in the two parameters tested or in total arm entries. These data corroborate previous findings of the anxiolytic effect of CORT and suggest that inhibition of ACTH/CRF release and corticosteroid receptors do not play a major role in the anxiolytic effect of CORT.