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Anxiety disorders, a prevalent mental health condition often stemming from chronic stress, are characterized by uncontrollable emotional responses, heightened psychological stress, and cognitive impairment. Ziziphi Spinosae Semen, a traditional Chinese medicine (TCM), is widely used for its calming effects. Among its flavonoid components, spinosin serves as a primary bioactive compound, playing a significant role in treating psychiatric disorders. However, the mechanisms underlying the anxiolytic effects of spinosin are not fully elucidated. This study explores the protective effects of spinosin against anxiety in mice subjected to chronic restraint stress (CRS). Male C57BL/6J mice were subjected to restraint stress modeling for 10 consecutive days, and the treatment groups were gavaged with spinosin at doses of 1.25 mg/kg, 2.5 mg/kg, and 5 mg/kg, respectively. Behavioral experiments including the elevated plus maze test (EPM), open field test (OFT), and novelty suppressed feeding test (NSF) were conducted to confirm the successful establishment of the CRS model and the anxiolytic effect of spinosin. Additionally, spinosin normalized neurotransmitter levels and mitigated inflammation and neuronal damage in the hippocampus (HPC) and prefrontal cortex (PFC). Mechanistically, spinosin treatment significantly modulated the extracellular signal-regulated kinase 1/2 (ERK1/2)/cyclic adenosine monophosphate response element-binding protein (CREB)/brain-derived neurotrophic factor (BDNF) signaling pathway, a key axis in anxiety regulation. The upregulation of ERK1/2, p-CREB, and BDNF proteins significantly alleviated anxiety, suggesting that spinosin plays a pivotal role in treating CRS-induced anxiety disorders. Our findings indicate that spinosin treatment can ameliorate anxiety and that it verifies a previously unrecognized mechanism, providing crucial evidence for future research on anti-anxiety medications., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aim: Depression, a prevalent mental disorder, significantly impairs the quality of life and social functioning. Targeting neuroinflammation is a promising therapeutic approach, highlighting the need for natural neuroprotective agents. Gypenosides (Gyp) from Gynostemma pentaphyllum exhibit anxiolytic and antidepressant effects, yet the underlying mechanisms remain unclear. We investigated whether Gyp, isolated and purified by our laboratory, can exert neuroprotective effects by modulating neuroinflammation in the hippocampus and prefrontal cortex (PFC) of mice with LPS-induced anxiety and depression, thereby ameliorating behavioral phenotypes., Methods: LPS (1 mg/kg, i.p.) was used to induce anxiety and depression-like behaviors. Gyp was administered at 50, 100, or 200 mg/kg in pretreatment, with fluoxetine hydrochloride (Flu) as a positive control, for 10 consecutive days., Results: Gyp, especially at 100 mg/kg, significantly ameliorated LPS-induced anxiety and depression in mice, normalizing cytokine expression in the hippocampus and PFC, with IL-1β showing the most pronounced regulation (Hippocampus: Ratio Gyp-100/LPS  = 30.73 %, PFC: Ratio Gyp-100/LPS  = 55.89 %). Gyp also reversed LPS-induced neuronal loss and necrosis, reduced glial cell activation, and prevented the transition of microglia to the M1 phenotype. Mechanistically, Gyp suppressed the activation of the NLRP3 inflammasome in the PFC, and modulated hippocampal synaptic protein loss, thereby mediating neuroinflammation., Conclusions: Gyp improved anxiety and depression in LPS-induced mice, which may be achieved by balancing systemic inflammatory levels, regulating glial cell activation and phenotypic polarization, regulating hippocampal synaptic plasticity, and suppressing the NLRP3/Caspase-1/ASC signaling pathway in the PFC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The secretions of Telodeinopus canaliculatus, a giant millipede, are used in traditional medicine to treat epileptic seizures. Therefore, this work aimed to assess the antiepileptogenic- and anxiolytic-like effects of an extract of T. canaliculatu in mice. Forty-eight mice were divided into six groups of eight each and treated as follows: normal control group received distilled water (10 ml/kg, p.o.); negative control group received received distilled water (10 ml/kg, p.o.); positive control group received sodium valproate (300 mg/kg, p.o.); and test groups received with the extract (30, 50, and 70 mg/kg, p.o.). One hour later, all groups, except the normal control group (distilled water, 10 ml/kg, i.p.), received a daily dose of pentylenetetrazole (25 mg/kg, i.p) until the onset of tonic-clonic seizures on day 24. On day 26 of the experiment, anxious behaviors were assessed. The mice were subsequently sacrificed and brains were collected for neurochemical analyses. The extract (30, 50, 70 mg/kg, p.o.) reduced (p < 0.001) the seizure severity. It also increased the latencies to the onset of seizures. In the elevated plus maze, the extract (50 mg/kg) increased by 51% (p < 0.001) the time spent in the open arms. The extract (50 mg/kg) increased GABA concentration by 28% (p < 0.01) and 37% (p < 0.001) respectively in the hippocampus and amygdala. Moreover, the extract (30 mg/kg) decreased the concentration of malondialdehyde by 47% (p < 0.001) and 42% (p < 0.01) respectively in the same regions. The hydroethanolic extract of T. canaliculatus is endowed with antiepileptogenic and anxiolytic effects., Competing Interests: Declarations. Ethics approval: All studies were carried out following Cameroon national ethics governing the use of laboratory animals (N° FWAIRB00001954). This certifies that the study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Conflict of Interest: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Macaiba pulp is a source of bioactive compounds. This study aimed to evaluate the effects of macaiba pulp on anxiety behavior, memory and brain oxidative stress in dyslipidemic rats. The animals were divided into four groups (n = 10): Control (CG), Macaíba (MG), Dyslipidemic (DG) and Dyslipidemic Macaiba (DMG). Animals from the DG and DMG were induced to dyslipidemia consuming a high fatty emulsion for 14 days before treatment with macaiba pulp. During treatment the MG and DMG received the macaiba pulp (1 g/kg body weight) for 28 days. The rats were evaluated with the open field (OFT) and elevated plus maze (EPM) tests to measure anxiety-like behavior; memory was evaluated using the object recognition test (ORT). After euthanasia, the fatty acid profile of the animals' brain tissue was measured and the levels of malondialdehyde (MDA) and total glutathione (GSH) were quantified. The data were evaluated using one-way ANOVA followed by the Tukey (p < 0.05) test. Both groups (MG and DMG) that consumed the macaiba pulp showed anxiolytic-like behavior for parameters of grooming, rearing and ambulation in the OFT test and time in the center and time and entries in the open arms in the EMP test; The MG and DMG groups increased exploration rate in the ORT. The DMG showed a reduction in MDA levels (p < 0.05); however, MG and DMG had decreased in GSH (p < 0.05). The results showed that macaiba pulp consumption induces anxiolytic-like behavior and reduces brain oxidative damage in dyslipidemic animals, and improves memory in healthy and dyslipidemic rats., Competing Interests: Declarations. Ethics approval: The experimental protocol followed ethical recommendations and was approved by the Ethics Committee for Animal Use of the Federal University of Campina Grande (number 057-2016). Consent to participate: Not applicable. Consent for publication: Not applicable. Conflicts of interest: The authors declare there are no conflicts of interest., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Ethnopharmacological Relevance: Passiflora coriacea Juss., a medicinal plant in the family Passifloraceae, is widely used to treat anxiety and depression in Mexican folk medicine. However, its chemical profile and biological activity have not been characterized., Aim of the Study: The aim of the study was to determine the antidepressant activity, anxiolytic effect, and chemical profile of Passiflora coriacea., Materials and Methods: An organic fraction (PcEA) from a hydroalcoholic extract of the aerial parts of P. coriacea was obtained, followed by a chemical analysis and separation, yielding six fractions (PcEA, T1, T2, T1.1, T2.1, and T2.2). Male ICR mice were used to determine the antidepressant activity of selected treatments (PcEA, T1, T2, and T1.1) based on a forced swim test (FST). The anxiolytic-like effects of various treatments (PcEA, T1, T2, T2.1, and T2.2) were determined using the elevated plus maze (EPM) test., Results: The organic fraction of P. coriacea decreased anxiety-like behaviors in mice and increased the time of mobility in the FST. After chemical separation, two compounds were isolated from the species with antidepressant activity and anxiolytic-like effects, T1.1 (tricin 7-O-glucoside) and T2.2 (harmane), respectively., Conclusions: Compounds isolated from P. coriacea exerted anxiolytic and antidepressant effects in mice based on the EPM and FST. The flavonoid tricin-7-O-glucoside and the alkaloid harmane contributed to these biological activities., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Many neuropsychiatric disorders can be caused by neurotransmitter dysfunction. Experimental studies have demonstrated that histamine and the harmaline affect physiological processes through interaction with other neurotransmitter systems. The objective of these experiments was to investigate the involvement of the histaminergic system in the effects of harmaline on anxiety- and depressive-related effects in male NMRI mice. Behavioral tests were employed to evaluate anxiety-related symptoms (elevated plus maze; EPM), depressive-like symptoms (forced swim test; FST), and cognitive decline (step-down test). The histamine H3 receptor (H3R) agonist α-methylhistamine dihydrobromide (α-MH; 5 mg/kg, i.p.) had anxiolytic- and depressive-like effects, while the H3R antagonist thioperamide (10 mg/kg, i.p.) showed an antidepressive-like property. The subthreshold dose of α-MH resulted in an increase in the tendency of mice treated with the harmaline (2.5 mg/kg) to remain in the EPM open-arms. A subthreshold dose of thioperamide (5 mg/kg) increased the time spent in the open-arms in mice treated with harmaline (2.5 and 5 mg/kg) while a high dose of harmaline decreased the immobility time. Furthermore, two higher doses of harmaline resulted in a reduction in the number of open-arm entries. Similarly, mice administered with thioperamide and a low dose of harmaline decreased locomotor activity in the EPM. Ultimately, the combined thioperamide and harmaline did not impair memory retrieval of mice. These experiments demonstrate that the histaminergic system is implicated in the anxiety- and depressive-related effects of harmaline. The combination of thioperamide and harmaline is effective in treating anxiety and depression without having an adverse effect on memory formation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Plant-based components have helped generate novel lead molecules and scaffolds for anxiety research in psychopharmacology. The present study examined the anxiolytic properties of sesamol (SES), a phenolic lignan derived from Sesamum indicum, employing both in vivo and computational methods to understand its mechanisms of action. In this experiment, adult Swiss albino mice received various doses of SES (25 and 50 mg/kg, p.o.) orally. Afterward, a series of behavioral assessments, including open field, swing, hole cross, and light-dark testing, were conducted. The impact of the GABAergic agonist diazepam (DZP-1 mg/kg, i.p.) along with the antagonist flumazenil (FLU-0.1 mg/kg, i.p.) has been studied as provided concurrently with the SES-50 group. Computational studies were performed to comprehend the interaction between SES and GABA A receptor subunits (α 2 and α 3 ). The results of our investigation revealed that SES dose-dependently and significantly (p < 0.05) reduced the number of square crosses, hole crosses, swings, grooming, and rearing along with a reduction of light residence time in animals. When combined with DZP, SES-50 significantly reduced all these parameters, while altering with FLU-0.1. The molecular docking analysis showed that the SES has a relatively good binding score (-5.03 ± 0.15 and -5.25 ± 0.23 kcal/mol) with GABA A receptor α 2 and α 3 subunits, respectively. The SES triggers anxiolytic effects via GABA A receptor α 2 and α 3 subunit interactions. Furthermore, precise and comprehensive preclinical research must be considered to validate potential SES targets for anxiolytic impact, clinical trial efficacy, and safety., (© 2024 Wiley Periodicals LLC.)

Background: Soyo-san (Xiaoyao-san; SYS), a traditional herbal medicine formula, has been used for treating mood disorders, especially depression and anxiety. Modified SYS (mSYS) is formulated by adding or removing herbs to SYS, and is mainly used in cases of mood disorders with comorbid diseases such as diabetes, digestive disorders, and anorexia. However, there has been no detailed comparative analysis of the differences in efficacy and underlying neurological mechanisms between SYS and mSYS., Purpose: This review aimed to investigate the present scientific evidence regarding the effects of SYS and mSYS on depression and anxiety in animal models based on behavioral improvements and changes in biomarker levels., Methods: The PubMed, Embase, Scopus, and Medline databases were searched for all depression- and anxiety-model animal studies that used SYS and mSYS. The types of animals, methods for inducing depression or anxiety, publication trends, target diseases, types and proportions of herbs, and significant behavioral and biomolecular changes induced by SYS and mSYS treatment were analyzed., Results: A total of 1,120 studies were identified, of which 57 studies were finally included in this review. Behavioral or environmental stress was mainly used to induce depression or anxiety in rodent models. SYS treatment improved body weight, food intake, and depression- and anxiety-like behaviors. The proportions of the herbs in the original SYS formulation were mostly fixed, whereas the types and proportions of herbs used in mSYS formulations were quite diverse. mSYS had a wider range of target diseases than SYS, and it has been used not only for depression and anxiety, but also cancer and stroke. Changes in biomarker levels in the hippocampus of the brain have been studied most extensively for both SYS and mSYS. Both SYS and mSYS are reported to regulate 5-hydroxytryptamine, brain-derived neurotrophic factor, and hypothalamic-pituitary-adrenal axis-related biomolecules in the brain, as well as changes in micro-organisms and metabolite levels in the serum and intestinal environment., Conclusions: SYS and mSYS improved depression- and anxiety-like behaviors by regulating neurotransmission, neuronal survival, and inflammation. Further research is needed to elucidate the clinical value of mSYS through various uses-related in-depth mechanistic studies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Anxiety disorders are the most prevalent psychiatric pathology with substantial cost to society, but the existing treatments are often inadequate. This has rekindled the interest in the GABA A -receptor (GABA A R) positive allosteric modulator (PAM) compounds, which have a long history in treatment of anxiety beginning with diazepam, chlordiazepoxide, and alprazolam. While the GABA A R PAMs possess remarkable anxiolytic efficacy, they have fallen out of favor due to a host of adverse effects including sedation, motor impairment, addictive potential and tolerance development. A substantial effort was thus devoted to the design of GABA A R PAMs as anxiolytics with reduced sedative liabilities. Several non-benzodiazepine (BZD) GABA A PAMs progressed to clinical trials (bretazenil, abecarnil, alpidem, and ocinaplon) with alpidem obtaining regulatory approval as anxiolytic, but later withdrawn from market due to hepatotoxicity. Advances in molecular biology gave birth to a host of subtype selective GABA A R-PAMs which suffered from signs of sedation and motor impairment and only three compounds progressed to proof-of-concept studies (TPA-023, AZD7325 and PF-06372865). TPA-023 was terminated due to toxicity in preclinical species while AZD7325 and PF-06372865 did not achieve efficacy endpoints in patients. We highlight a new compound, KRM-II-81, that is an imidazodiazepine selective for GABA A R containing α2/3 and β3 proteins. In preclinical studies KRM-II-81 produced anxiolytic-like effects but with minimal sedation, respiratory depression, and abuse liability. Thus, KRM-II-81 is a newly discovered, non- BZD anxiolytic compound, which targets a selective population of GABA A R for improved therapeutic gain and reduced side effects., Competing Interests: Declaration of competing interest Authors report no conflict of interest with the exception that Rok Cerne and Arnold Lippa are associated with RespireRx Pharmaceuticals Inc. that has licensed KRM-II-81 for development., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Anxiety can be a protective emotion when animals face aversive conditions, but is commonly associated with various neuropsychiatric disorders when pathologically exacerbated. Drug repurposing has emerged as a valuable strategy based on utilizing the existing pharmaceuticals for new therapeutic purposes. Ketamine, traditionally used as an anesthetic, acts as a non-competitive antagonist of the glutamate N-methyl-d-aspartate (NMDA) receptor, and shows potential anxiolytic and antidepressant effects at subanesthetic doses. However, the influence of ketamine on multiple behavioral domains in vertebrates is not completely understood. Here, we evaluated the potential modulatory effect of ketamine on the spatio-temporal exploratory dynamics and homebase-related behaviors in adult zebrafish using the open field test (OFT). Animals were exposed to subanesthetic concentrations of ketamine (0, 2, 20, and 40 mg/L) for 20 min and their locomotion-, exploration- and homebase-related behaviors were assessed in a single 30-min trial. Our data revealed that acute ketamine (20 and 40 mg/L) induced hyperlocomotion, as verified by the increased total distance traveled. All concentrations tested elicited circling behavior, a stereotyped-like response which gradually reduced across the periods of test. We also observed modulatory effects of ketamine on the spatio-temporal exploratory pattern, in which the reduced thigmotaxis and homebase activity, associated with the increased average length of trips, suggest anxiolytic-like effects. Collectively, our findings support the modulatory effects of ketamine on the spatio-temporal exploratory activity, and corroborate the utility of homebase-related measurements to evaluate the behavioral dynamics in zebrafish models., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

β-carboline compounds display a therapeutic property for treating depression and anxiety behaviors. Imipramine and citalopram play an important role in the modulation of anxiety and depression behaviors. We investigated the effects of norharmane, imipramine, and citalopram on anxiety- and depression-like effects and their interactions. Elevated plus maze and forced swimming test were used for the assessment of anxiety- and depression-like behaviors in male mice. The results revealed that intraperitoneal (i.p.) administration of norharmane (10 mg/kg) increased percentage of open arm time (%OAT) in the elevated plus maze test and decreased immobility time in the forced swimming test, proposing anxiolytic- and antidepressant-like effects. Injection of imipramine (5 mg/kg; i.p.) enhanced %OAT and decreased immobility time, suggesting anxiolytic- and antidepressant-like effects. Moreover, norharmane potentiated the anxiolytic- and antidepressant-like responses induced by imipramine by increasing %OAT and decreasing immobility time. The results revealed additive anxiolytic- and antidepressant-like effects between norharmane and imipramine in mice. Alone, the administration of citalopram (5 mg/kg; i.p.) enhanced %OAT and reduced immobility time, causing anxiolytic- and antidepressant-like effects. When citalopram and norharmane were coinjected, norharmane augmented the anxiolytic- and antidepressant-like effects induced by citalopram by increasing %OAT and reducing immobility time. These results indicated additive anxiolytic- and antidepressant-like effects between norharmane and antidepressant drugs such as imipramine and citalopram on the modulation of anxiety and depression processes in mice., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Anxiety disorders are characterized by intense feelings of worry and fear, which can significantly interfere with daily functioning. Current treatment options primarily include selective serotonin reuptake inhibitors, benzodiazepines, non-benzodiazepine anxiolytics, gabapentinoids, and beta-blockers. Neuropeptides have shown an important role in the regulation of complex behaviours, such as psychopathology and anxiety-related reactions. Neuropeptides have a great deal of promise to advance our understanding of and ability to help people with anxiety disorders. This review focuses on the expanding role of neuropeptides in anxiety management, particularly examining the impact of substance P, neuropeptide Y, corticotropin-releasing hormone, arginine-vasopressin, pituitary adenylate cyclase-activating polypeptide, and cholecystokinin. Furthermore, the paper discusses the neuropeptides that are becoming more and more recognized for their impact on anxiety-related reactions and their potential as therapeutic targets., Competing Interests: Declaration of competing interest None of the authors has any conflict of interest to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Understanding the reasons why people consume alcohol is a critical health issue. Alcohol produces a variety of effects, including a reduction in stress or negative emotional states termed an anxiolytic effect. The anxiolytic effect of alcohol is an often-reported reason for why people begin consuming the drug. However, several factors concerning the stress-reducing effect of alcohol need to be investigated. For example, research has demonstrated that both age and sex are factors that impact alcohol's anxiolytic effect producing differential outcomes in aged female rats compared to aged male rats. In light of these findings, the current commentary highlights critical questions in need of research with the goal of better understanding how age and sex interact to influence the anxiolytic effect of alcohol. For example, the central nucleus of the amygdala has been identified as a critical brain region mediating the anxiolytic effect of drugs, but additional research is needed to understand how aging alters the neurological functioning of the central nucleus of the amygdala in both females and males. Furthermore, specific receptor isoforms, such as GABA A receptor α2, have been shown to be critical for anxiolysis and understanding how aging and sex alter receptor isoform expression by brain region is needed. Finally, age and sex interact to alter allopregnanolone levels in brain and differential neurosteroid levels may mediate alcohol's unique anxiolytic effect in aged female rats compared to aged male rats. Given the increasing age of the population in most countries and the increasing alcohol consumption levels in females compared to males, investigating the interaction of sex and age on alcohol's anxiolytic effect has great promise to discover critical answers to what are currently unasked questions., (Copyright © 2024. Published by Elsevier Inc.)

Anxiety disorders represent one of the most common and debilitating illnesses worldwide. However, the development of novel therapeutics for anxiety disorders has lagged compared to other mental illnesses. A growing body of research suggests the gut microbiota plays a role in the etiopathology of anxiety disorders and may, therefore, serve as a novel target for their treatment through the use of probiotics. The use of dietary supplements like probiotics is increasing and their interaction with pharmacotherapies is not well understood. Utilizing the chick social-separation stress test, the primary aim of this study was to evaluate the commercially-available multi-strain probiotic found in VSL#3 for potential anxiolytic-like and/or antidepressant-like effects in the stress-vulnerable Black Australorp genetic line. A secondary aim was to evaluate the interaction between probiotics and the SSRI fluoxetine. Animals were treated with either saline, probiotics, fluoxetine, or probiotics + fluoxetine for 8 days prior to exposure to a 90-min isolation stressor that produces both a panic-like (i.e., anxiety-like) state followed by a state of behavioral despair (i.e., depression-like). The 8-day probiotic regimen produced anxiolytic-like effects but did not attenuate behavioral despair. Fluoxetine failed to significantly alter behavior in either of the two phases. Moreover, the combination of fluoxetine with probiotics attenuated the anxiolytic-like effects of probiotics. The fluoxetine + probiotics combination had no effect on behavioral despair. The results of the current study align with other preclinical studies and some clinical trials suggesting probiotics may offer beneficial effects on anxiety. Investigations examining the anxiolytic-like mechanism of probiotics are needed before any conclusions can be made. Additionally, as the use of probiotics becomes more popular, research on the interactions between probiotic-microbiota and psychotropic medications is necessary., Competing Interests: Declaration of competing interest The authors of this study have no conflicts of interest and hold no financial benefit from the publication of this manuscript., (Published by Elsevier Inc.)

Valproic acid or sodium valproate is a widely used drug in the treatment of epilepsy, although it also appears to have anxiolytic and sedative properties derived from its agonistic action on the GABAergic system. To analyze these potential effects of the drug, we conducted three experiments with rats using procedures designed to assess anxiety in rodents. In the first experiment, with a fear conditioning procedure, three groups of male rats were included that received either 100 mg/kg or 300 mg/kg of valproate or an equivalent volume of saline solution. In Experiment 2, recording spontaneous activity in an open field, we compared the effects of valproic acid (300 mg/kg) on male and female rats. In the third experiment, we analyzed the effect of valproic acid using a novelty-induced hypophagia test and tested again for potential differences as a function of the sex of the animals. The results showed an anxiolytic effect restricted to the 300 mg/kg dose of the drug in Experiment 1. Such an effect was restricted to the female sample in Experiment 2, but in the third experiment affected both sexes. As for the sedative effect, it was observed in all experiments irrespective of the sex of the rats. These findings hold significant implications for the treatment of anxiety disorders since valproate may offer a novel therapeutic approach for anxiety-related conditions with distinct benefits and fewer side effects. However, clinical studies are needed to validate the translation of these findings from animal models to human patients., (© 2024 The Author(s). Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

The sedative and hypnotic properties of 5,7,3',4',5'-pentamethoxyflavone (PMF), a monomer extracted from the leaves of Murraya paniculata (L.) Jack, have been reported. However, the role of PMFs in the development of anxiety remains uncertain. An anxiety model was developed using chronic unpredictable mild stimulation (CUMS). Kunming mice were randomly allocated to the following groups: control, CUMS, PMF (50 mg/kg), PMF (100 mg/kg), and diazepam (3 mg/kg). The anxiolytic effects of PMFs were evaluated using elevated plus maze (EPM) test and open field test (OFT). Enzyme-linked immunosorbent assay (ELISA) kits were used to analyze the serum levels of corticosterone (CORT), 5-hydroxytryptamine (5-HT), gamma-aminobutyric acid (GABA), and cyclic adenosine monophosphate (cAMP) in the hippocampus. High-throughput-16S rRNA sequencing was performed to investigate its effect on the composition of the gut microbiota. Subsequently, western blotting was performed to assess the expression of GABAergic synaptic-associated proteins. PMF effectively mitigated CUMS-induced anxiety-like behavior. Further examination revealed that PMF treatment ameliorated dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis and increased 5-HT and GABA levels in the hippocampus. Notably, the ability of PMF to maintain the stability of GABAergic synapses by enhancing the species composition of the gut microbiota and acting on the adenosine a2a receptor (A 2A R)/gephyrin/gamma-aminobutyric acid A receptor alpha 2 (GABRA2) pathway revealed a previously unrecognized mechanism for the anxiolytic effect of PMF. These findings suggest that PMF enhances the expression of A 2A R, preserves GABAergic synaptic stability, and reduces anxiety by modulating the microbiota composition. Thus, it holds promise as an anxiolytic agent., (© 2024 John Wiley & Sons, Ltd.)

Anxiety is a part of the human condition and has been managed by psychoactive substances for centuries. The current medical need and societal demand for anxiolytic medicines has not abated. The present overview provides a brief historical introduction to the discovery of modern age anxiolytics that include the benzodiazepines together with a discussion of the continuing medical need for new antianxiety medications. The paper also discusses the use and impact of behavioral pharmacology in the preclinical development of anxiolytics. The review then highlights the diversity of mechanisms for creating a new generation of anxiolytics through mechanisms beyond the potentiation of GABA A receptors and the blockade of monoamine uptake. A discussion then follows on the behavioral specificity of action of anxiolytics that includes the concept of creating an anxioselective drug, one that targets anxiety without producing untoward effects that include sedation and dependence. The use of anxiolytics in the treatment of other conditions such as substance use disorder is also briefly reviewed. Finally, a brief summary of the current status of anxiolytic drug development is provided. The review concludes with the idea that despite a host of anxiolytic drugs, the lack of efficacy in some patients and the side-effects and safety issues associated with some of these medications demands alternative medicines. Current preclinical and clinical research is ongoing with the goal of identifying such compounds., Competing Interests: Declaration of competing interest The authors have no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Despite the widespread use and perceived efficacy of cannabidiol (CBD) as an anxiolytic, few controlled studies have evaluated the effects of CBD on anxiety-relevant indications, and only one has done so in the context of trauma-related symptoms. The current study was designed to address this gap in the literature. Participants were 42 trauma-exposed individuals (M age = 23.12 years, SD age = 6.61) who endorsed elevated stress. They were randomly assigned to take 300 mg of oral CBD or placebo daily for 1 week. Acute (i.e., following an initial 300 mg dose) and repeated (i.e., following 1 week of daily 300 mg dosing) effects of CBD were evaluated in relation to indicators of anxious arousal (i.e., anxiety, distress, heart rate) in response to idiographic trauma script presentation. The results of the current study suggest that relative to placebo, 300 mg CBD did not significantly reduce anxiety, B = 13.37, t(37) = 1.71, p = .096, d = 0.09, Bayes factor (BF 10 ) = 0.54; distress, B = 15.20, t(37) = 1.31, p = .197, d = 0.07, BF 10 = 0.51; or heart rate, B = -1.09, t(36) = -0.32, p = .755, d = 0.02, BF 10 = 0.29, evoked by idiographic trauma script presentation in the context of acute or repeated administration. These data suggest that CBD may not effectively reduce trauma-relevant emotional arousal; however, more work is needed to confidently assert such claims due to the small sample size. The current study extends the groundwork for additional studies in this important area., (© 2024 International Society for Traumatic Stress Studies.)

Early handling (EH), the brief separation of pups from their mother during early life, has been shown to exert beneficial effects. However, the impact of EH in a high anxiety background as well as the role of brain mitochondria in shaping EH-driven responses remain elusive.Here, we used a high (HAB) vs. normal (NAB) anxiety-related behavior mouse model to study how EH affects pup and dam behavior in divergent anxiety backgrounds. We also investigated EH-induced effects at the protein and mRNA levels in adult male HAB mice in the hypothalamus, the prefrontal cortex, and the hippocampus by examining the same mitochondrial/energy pathways and mitochondrial dynamics mechanisms (fission, fusion, biogenesis, and mitophagy) in all three brain regions.EH exerts anxiolytic effects in adult HAB but not NAB male mice and does not affect HAB or NAB maternal behavior, although basal HAB vs. NAB maternal behaviors differ. In adult HAB male mice, EH does not impact oxidative phosphorylation (OXPHOS) and oxidative stress in any of the brain regions studied but leads to increased protein expression of glycolysis enzymes and a correlation of anxiety-related behavior with Krebs cycle enzymes in HAB mice in the hypothalamus. Intriguingly, EH alters mitochondrial dynamics by increasing hypothalamic DRP1, OPA1, and PGC1a protein levels. At the mRNA level, we observe altered, EH-driven mitochondrial dynamics mRNA signatures which predominantly affect the prefrontal cortex.Taken together, our results show that EH exerts anxiolytic effects in adulthood in high anxiety and modulates mitochondrial dynamics pathways in a brain region-specific manner., Competing Interests: Declarations. Ethics Approval: Animal work was carried out in accordance with the European Communities Council Directives 2010/63/EU and approved by the local authorities. Consent to Participate: Not applicable. Consent for Publication: Not applicable. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s).)

Stachys lavandulifolia Vahl known as "mountain tea", is a perennial flowering plant belonging to the Lamiaceae family and is widespread in Iran, Armenia, Azerbaijan, Iraq, Turkey and Turkmenistan. S. lavandulifolia is widely used in traditional medicine for its analgesic, anti-inflammatory and anxiolytic properties. This plant has different chemical compounds classes including terpenoids, iridoids, flavonoids and phenylethanoids that have been isolated from the aerial parts of it. This review covers the plant botany, traditional medicinal uses and chemical composition of S. lavandulifolia , along with its biological and pharmacological activities including clinical trial data. The information of this review article was obtained from different scientific databases such as Google scholar, Science Direct, Hindawi, SID, Scopus, PubMed, and ACS as well as traditional Persian books. Pharmacological and clinical studies, especially Anxiolytic activity and anti-inflammatory on the plant are relatively low, so these studies are suggested in the future. Also, phytochemical investigation on root of the plant is necessary.

Low doses of general anesthetics like ketamine and dexmedetomidine have anxiolytic properties independent of their sedative effects, but the underlying mechanisms remain unclear. We discovered a population of GABAergic neurons in the oval division of the bed nucleus of the stria terminalis that are activated by multiple anesthetics and the anxiolytic drug diazepam (ovBNST GA ). The majority of ovBNST GA neurons express neurotensin receptor 1 (Ntsr1) and form circuits with brain regions known to regulate anxiety and stress responses. Optogenetic activation of ovBNST GA or ovBNST Ntsr1 neurons significantly attenuated anxiety-like behaviors in both naive animals and mice with inflammatory pain, while inhibition of these cells elevated anxiety. Activation of these neurons decreased heart rate and increased heart rate variability, suggesting that they reduce anxiety by modulating autonomic responses. Our study identifies ovBNST GA /ovBNST Ntsr1 neurons as a common neural substrate mediating the anxiolytic effect of low-dose anesthetics and a potential therapeutic target for treating anxiety-related disorders., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Casein hydrolysates have been proven to exert varying sleep-enhancing and anxiolytic effects due to their distinct release of potential peptides. However, their underlying sleep-enhancing mechanisms at the metabolic level remain unclear. This study aims to investigate the potential sleep-enhancing mechanism of casein hydrolysates through an integrated approach of untargeted and targeted metabolomics in CUMS-induced anxiety mice for the first time. The results showed seven potential biomarkers were identified and screened using orthogonal partial least-squares discriminant analysis, random forest model, and pathway analysis, including ornithine, l-proline, l-prolinamide, inhibitory neurotransmitters gamma-aminobutyric acid, 5-HIAA, fumaric acid, and 4-oxoglutaramate. Moreover, casein hydrolysates exerted sleep-enhancing effects through multiple metabolic pathways, mainly including the GABAergic system, tryptophan metabolism, and cAMP response signaling pathway, which was validated by targeted metabolomics and vital protein expressions. It was interesting that casein hydrolysates with diverse representative peptide compositions exhibited varying activity, which could be attributed to distinct alterations in metabolites via different pathways.

There has been a recent renewal of interest in the therapeutic potential of serotonergic psychedelics. Here, we uncover the essential role of ventral hippocampus (vHpc) GABAergic interneurons in the anxiolytic effect evoked by the serotonergic psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI). Integrating anatomical, pharmacological, and genetic approaches, we show that 5-HT 2A receptors in the CA1/subiculum (CA1/sub) region of the vHpc are required for the anxiolytic action of DOI. In vivo electrophysiology and opto-tagging experiments indicate that DOI enhances the firing rate of hippocampal fast-spiking parvalbumin (PV)-positive interneurons, most of which express the 5-HT 2A receptors. Restoration of 5-HT 2A receptors in PV-positive interneurons in a loss-of-function background reinstated the anxiolytic responses evoked by DOI in the vHpc CA1/sub region. Collectively, our results localize the acute anxiolytic action of a serotonergic psychedelic to 5-HT 2A receptors in the ventral hippocampus and specifically identify PV-positive fast-spiking cells as a cellular trigger for the psychedelic-induced relief of anxiety-like behavior., Competing Interests: Declaration of interests A.C.K. has been a scientific advisor or consultant for Boehringer Ingelheim, Empyrean Neuroscience, Freedom Biosciences, Biohaven Pharmaceuticals, and Psylo. A.C.K. has received research support from Intra-Cellular Therapies. These duties had no influence on the content of this article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Affective and psychotic disorders are highly prevalent and severely debilitating mental illnesses that often remain untreated or treatment-resistant. Sulpiride is a common antipsychotic (neuroleptic) drug whose well-established additional (e.g., antidepressant) therapeutic effects call for further studies of a wider spectrum of its CNS effects. Here, we examined effects of acute 20-min exposure to sulpiride (50-200 mg/L) on anxiety- and depression-like behaviors, as well as on brain monoamines, in adult zebrafish (Danio rerio). Overall, sulpiride exerted overt anxiolytic-like effects in the novel tank test and showed tranquilizing-like effects in the zebrafish tail immobilization test, accompanied by lowered whole-brain dopamine and its elevated turnover, without affecting serotonin or norepinephrine levels and their turnover. Taken together, these findings support complex behavioral pharmacology of sulpiride in vivo and reconfirm high sensitivity of zebrafish-based screens to this and, likely, other related clinically active neuroleptics., Competing Interests: Declarations Ethical Approval Animal experiments were approved by the Institutional IACUC and fully adhered to the National and Institutional guidelines and regulations on animal experimentation, as well as the 3Rs principles of humane animal experimentation. Competing Interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Psychedelics hold promise as alternate treatments for neuropsychiatric disorders. However, the neural mechanisms by which they drive adaptive behavioral effects remain unclear. We isolated the specific neurons modulated by a psychedelic to determine their role in driving behavior. Using a light- and calcium-dependent activity integrator, we genetically tagged psychedelic-responsive neurons in the medial prefrontal cortex (mPFC) of mice. Single-nucleus RNA sequencing revealed that the psychedelic drove network-level activation of multiple cell types beyond just those expressing 5-hydroxytryptamine 2A receptors. We labeled psychedelic-responsive mPFC neurons with an excitatory channelrhodopsin to enable their targeted manipulation. We found that reactivation of these cells recapitulated the anxiolytic effects of the psychedelic without driving its hallucinogenic-like effects. These findings reveal essential insight into the cell-type-specific mechanisms underlying psychedelic-induced behavioral states.

Anxiety disorders are one of the most prevalent mental health conditions worldwide, imposing a significant burden on individuals affected by them and society in general. Current research endeavors aim to enhance the effectiveness of existing anxiolytic drugs and reduce their side effects through optimization or the development of new treatments. Several anxiolytic novel drugs have been produced as a result of discovery-focused research. However, many drug candidates that show promise in preclinical rodent model studies fail to offer any substantive clinical benefits to patients. This review provides an overview of the diagnosis and classification of anxiety disorders together with a systematic review of anxiolytic drugs with a focus on their targets, therapeutic applications, and side effects. It also provides a concise overview of the constraints and disadvantages associated with frequently administered anxiolytic drugs. Additionally, the study comprehensively reviews animal models used in anxiety studies and their associated molecular mechanisms, while also summarizing the brain circuitry related to anxiety. In conclusion, this article provides a valuable foundation for future anxiolytic drug discovery efforts., Competing Interests: Declaration of competing interest Regarding the competing interest statement, I stated, “The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.” In the current stage, this study was supported by the Provincial Education Department Project (23NSFSC2480), the Research Fund for Inheritance and Innovation Development of CDUTCM (CCCXFH202204), the National Natural Science Foundation General Project (82074316) and the Research and Development Fund Project of the Institute of Basic Theory of Traditional Chinese Medicine, China Academy of Chinese Medical Sciences (KJX202404). The authors have participated sufficiently in the work to take public responsibility for all or part of the content., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Aims: We aimed to investigate the anxiolytic effect of darbepoetin alpha (DEPO), an erythropoietin derivative, in a neuroinflammation model regarding different behaviors and biological pathways., Methods: Forty adult male Wistar albino rats were divided into four groups (control, LPS, DEPO, and DEPO + LPS). The rats were treated with 5 µg /kg DEPO once a week for four weeks, after which neuroinflammation was induced with 2 mg/kg lipopolysaccharide (LPS). The elevated plus maze, open-field, and light‒dark box tests were conducted to assess anxiety levels. Harderian gland secretions were scored via observation. Tumor necrosis factor alpha (TNF-α), Interleukin-1-beta (IL-1β), brain-derived growth factor (BDNF), serotonin, cortisol, total antioxidant/oxidant (TAS/TOS), and total/free thiol levels were measured in the prefrontal cortex, striatum, and serum., Results: DEPO had a potent anxiolytic effect on both DEPO and DEPO + LPS groups. Compared to the control group, DEPO administration caused an increase in serotonin and BDNF levels and decreased basal cortisol and TNF-α levels in naive rats. IL-1β did not alter after DEPO administration in naive rats. Prophylactic DEPO treatment remarkably downregulated cortisol, IL-1β, and TNF-α in the DEPO + LPS group. In addition, prophylactic DEPO administration significantly attenuated the decrease in serotonin and BDNF levels in the DEPO + LPS group. Furthermore, DEPO ameliorated excessive harderian gland secretion in the DEPO + LPS group. Compared with those in the control group, the free thiol content in the serum increased after DEPO administration. No similar effect was seen in the DEPO + LPS group receiving prophylactic DEPO. TAS showed no difference among all experimental groups. DEPO administration increased TOS and OSI in the serum and prefrontal cortex but not in the striatum. This effect was not seen in the DEPO + LPS group., Conclusion: Darbepoetin alpha had an anxiolytic effect on many physiological mechanisms in a neuroinflammation model and naive rats., Competing Interests: Declarations Competing interests The authors declare no competing interests. Ethical approval and consent to participate All procedures were carried out under the approval of the Ankara University Experimental Animals Ethics Committee, and the approval reference number is 2020-2-10. Consent to publication Not applicable. Conflict of interest The authors declare that they have no conflicts of interest., (© 2024. The Author(s).)

The effects of tyrosol and nano-tyrosol on the modulation of anxiety-like behavior and memory processes were evaluated in streptozotocin-induced diabetic rats. Male diabetic rats were orally treated with 1 ml of saline, nano-niosome, tyrosol, and nano-tyrosol (20 mg/dl) for 30 days. Anxiety-like behavior and memory process were evaluated by an elevated plus-maze (EPM) test-retest paradigm. The results showed that a single intraperitoneal (i.p.) administration of streptozotocin (50 mg/kg) raised blood glucose. While daily intragastric administration of tyrosol and nano-tyrosol reduced blood glucose. Induction of type II diabetes produced a distorted cellular arrangement whereas treatment with tyrosol and nano-tyrosol showed a typical cellular arrangement in the liver. Furthermore, induction of type II diabetes decreased %OAT (%open-arm time) but daily intragastric application of tyrosol (20 mg/dl) and nano-tyrosol (20 mg/dl) enhanced %OAT and %OAE (%open-arm entry) in the EPM when compared to the saline groups, showing anxiogenic- and anxiolytic-like effects, respectively. Also, induction of type II diabetes increased %OAT while daily intragastric administration of tyrosol (20 mg/dl) and nano-tyrosol (20 mg/dl) decreased %OAT and %OAE in the EPM in comparison to the saline groups, displaying impairment and improvement of emotional memory, respectively. Interestingly, nano-tyrosol exhibited the highest significant effect rather than tyrosol. Upon these results, we proposed the beneficial effects of tyrosol and nano-tyrosol on the modulation of anxiety-like behavior and memory processes in streptozotocin-induced diabetic rats., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Gyrophoric acid (GA) is a secondary metabolite of various lichens. It exhibits various biological activities in vitro, but only one study has been carried out in vivo. Because our previous study showed that GA stimulates neurogenesis in healthy rats, the current study aimed to explore the potential of GA during stress-induced depressive-like states in male Wistar rats. In the experiment, pregnant females were used. In the last week of pregnancy, females were subjected to restraint stress. After birth, progeny aged 60 days were stressed repeatedly. The males were divided into three groups: control animals (CTR; n = 10), males with a depression-like state (DEP; n = 10), and GA-treated animals (GA; n = 10). GA males were treated with GA (per os 10 mg/kg) daily for one month, starting from the 60th postnatal day. Our results indicate that GA acts as an antioxidant, as shown by a lowered ROS level in leukocytes ( p < 0.01). Moreover, it prolonged the time spent in open arms in the elevated plus maze ( p < 0.001). Concomitantly, the stimulation of proliferative activity in hippocampal regions was seen (hilus p < 0.01; subgranular zone p < 0.001) when compared with DEP males. Additionally, the number of mature neurons in the CA1 region of the hippocampus increased markedly ( p < 0.01), indicating the role of GA in the maturation process of neurons. Thus, our study points to the potential anxiolytic/antidepressant activity of GA. However, future studies are needed in this complex area.

Background: The study aims to explore the potential antianxiety effect of Froriepia subpinnata, a native plant in northern Iran, and it is considered an antiflatulent, appetizing, antiseptic, antispasmodic, and diuretic. Despite its widespread use in diets and its reputation for calming effects, no prior research has specifically investigated its antianxiety properties., Methods: Rats were subjected to a variety of stressors for 24 days. Rats were treated with the F. subpinnata extract (100, 200, and 400 mg/kg, orally) for 14 days starting from the 10th day of stress. Then behavioral tests (elevated plus-maze, open field, sucrose preference, Morris water maze, passive avoidance) were examined. Real-time PCR was used to investigate changes in the expression of candidate genes of stress response and memory. Oxidative stress markers and corticosterone levels in serum were also measured., Results: Chronic stress reduced performance in a variety of tests of anxiety and memory, and treatment with the F. subpinnata extract dose-dependently improved the behavioral deficits caused by chronic stress. At the dose of 200 mg/kg, the F. subpinnata extract mitigated the effect of stress on the expression of several genes, such as those encoding dopamine D 1 and D 2 receptors, glutamate NMDA, and AMPA receptor subunits (Grin1 and Gria1, respectively), glucocorticoid and mineralocorticoid receptors, cholecystokinin (CCK) and CCK B receptor, neuropeptide Y, and the GABA A receptor alpha 2 subunit. Also, the expression of two genes, TrkB and BDNF, was significantly affected by the extract, demonstrating meaningful decreasing changes. Furthermore, treatment with the extract led to a decrease in oxidative stress and an elevation in cortisol levels in stressed animals., Conclusion: In this study, we provide the first evidence of the antistress and antianxiety effects of F. subpinnata extract, along with its potential procognitive impact on memory., (© 2024 The Author(s). Brain and Behavior published by Wiley Periodicals LLC.)

Background: Gabapentin is often administered PO for preappointment or in-hospital anxiolysis in cats. A previous study reported mild changes on the neurologic examination after administration., Objectives: Investigate the effects of gabapentin on anxiety, sedation, compliance, and neurologic examination in 2 age groups of cats., Animals: Thirty-one young cats and 12 geriatric cats perceived by their owners to be healthy and neurologically normal., Methods: Prospective double-blinded clinical crossover study. Assessment of baseline sedation and anxiety was performed before initial neurologic examinations and after gabapentin administration (100 mg/cat). Assessments were repeated 90 to 120 minutes after administration. Ease of handling pregabapentin and postgabapentin was assessed in the younger cats. All examinations were performed by a board-certified veterinary neurologist and scoring of examinations was performed by a different, masked board-certified neurologist., Results: Sixteen cats (50%) in the younger cohort and 6 cats (50%) in the geriatric cohort exhibited an increase in their overall neurologic examination score postgabapentin administration, mainly through new or progressive postural reaction deficits and gait changes. Anxiety and sedation scores were significantly changed in the geriatric population (P < .01, P = .004, respectively); however, only sedation scores were significantly increased in the younger cats after gabapentin administration (P = .004)., Conclusions and Clinical Importance: All study participants showed mild neurologic changes after gabapentin administration, most markedly noted in the geriatric population. Dose reduction of gabapentin for preappointment anxiolysis and neurologic examination in geriatric patients should be considered., (© 2024 The Author(s). Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Background: Cannabidiol (CBD) impacts brain regions implicated in anxiety reactivity and stress reactivity (e.g., amygdala, anterior cingulate cortex (ACC), anterior insula (AI)); however, placebo-controlled studies are mixed regarding CBD's anxiolytic effects. We previously reported that CBD expectancy alone can alter subjective, physiological, and endocrine markers of stress/anxiety; however, it is unclear whether these findings reflect altered brain reactivity. This study evaluated whether CBD expectancy independently alters amygdala resting-state functional connectivity (rsFC) with the ACC and AI following acute stress., Method: Thirty-eight (20 females) healthy adults were randomly assigned to receive accurate or inaccurate information regarding the CBD content of a CBD-free oil administered during a single experimental session. Following a baseline resting state MRI scan, participants administered their assigned oil sublingually, engaged in a stress task (serial subtraction with negative feedback) inside the scanner, and underwent another resting state MRI scan. Amygdala rsFC with the ACC and AI was measured during each scan, and the subjective state was assessed at six time points. Outcomes were analyzed using ANCOVA., Results: CBD expectancy (vs CBD-free expectancy) was associated with significantly weaker rsFC between the left amygdala and right ACC ( p  = 0.042), but did not systematically alter amygdala-AI rsFC ( p- values > 0.05). We also replicated our previously reported CBD expectancy effects on subjective stress/anxiety in the scanner context., Conclusion: CBD placebo effects may be sufficient to alter neural responses relevant to its purported anxiolytic and stress-relieving properties. Future work is needed to replicate these results and determine whether CBD expectancy and pharmacology interact to alter neural anxiety reactivity and stress reactivity., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Long-term inflammation can cause chronic pain and trigger patients' anxiety by sensitizing the central nervous system. However, effective drugs with few side effects for treating chronic pain-induced anxiety are still lacking. The anxiolytic and anti-inflammatory effects of ruscogenin (RUS), an important active compound in Ophiopogon japonicus, were evaluated in a mouse model of chronic inflammatory pain and N9 cells. RUS (5, 10, or 20 mg/kg/day, i.g.) was administered once daily for 7 days after CFA injection; pain- and anxiety-like behaviors were assessed in mice. Anti-inflammatory effect of RUS (0.1, 1, 10 μM) on N9 microglia after LPS treatment was evaluated. Inflammatory markers (TNF-α, IL-1β, IL-6, CD86, IL-4, ARG-1, and CD206) were measured using qPCR. The levels of IBA1, ROS, NF-κB, TLR4, P-IKK, P-IκBα, and P65, MAPKs (ERK, JNK, and P38), NLRP3 (caspase-1, ASC, and NLRP3) were detected by Western blotting or immunofluorescence staining. The potential target of RUS was validated by molecular docking and adeno-associated virus injection. Mice in CFA group exhibited allodynia and anxiety-like behaviors. LPS induced neuroinflammation in N9 cells. Both CFA and LPS increased the levels of IBA1, ROS, and inflammatory markers. RUS (10 mg/kg in vivo and 1 μM in vitro) alleviated these alterations through NF-κB/MAPKs/NLRP3 signaling pathways but had no effect on pain hypersensitivity. TLR4 strongly interacted with RUS, and TLR4 overexpression abolished the effects of RUS on anxiety and neuroinflammation. RUS exerts anti-inflammatory and anxiolytic effects via TLR4-mediated NF-κB/MAPKs/NLRP3 signaling pathways, which provides a basis for the treatment of chronic pain-induced anxiety., (© 2024 John Wiley & Sons, Ltd.)

Background: Depression and anxiety disorders are prevalent psychiatric conditions, and currently utilized chemical drugs typically come with significant adverse effects. China boasts a wealth of medicinal and food herbs known for their safe and effective properties., Purpose: This study aimed to develop novel formulations with improved antidepressant and anxiolytic effects derived from medicinal and food herbs., Study Design: Screening combinations with antidepressant and anxiolytic effects using techniques such as network pharmacology and validating their effects in vitro and in vivo experiments., Methods: Utilizing network pharmacology and molecular docking, we identified the top ten medicinal herbs with anxiolytic and antidepressant potential. Herbs with cytoprotective effects and non-toxic characteristics were further screened to formulate the herbal blends. Subsequently, we established a PC12 cell injury model and a chronic unpredictable mild stress (CUMS) model in mice to assess the effects of our formulations., Results: Ten medicinal herbs were initially screened, and six of them were deemed suitable for formulating the blend, namely Gancao, Dazao, Gouqizi, Sangye, Huangqi, and Jinyinhua (GDGSHJ). The GDGSHJ formulation reduced Lactate Dehydrogenase (LDH) leakage, decreased apoptosis, and demonstrated a favorable antidepressant and antianxiety effect in the CUMS mouse model. Besides, GDGSHJ led to the upregulation of serum 5-Hydroxytryptamine (5-HT) content and brain tissue 5-HT, Gamma-aminobutyric acid (GABA), and Dopamine (DA) levels. It also downregulated the expression of SLC6A4 and SLC6A3 genes in the mouse hippocampus while upregulating HTR1A, DRD1, DRD2, and GABRA1 genes., Conclusion: Our formulation exhibited robust antidepressant and antianxiety effects without inducing substantial toxicity. This efficacy appears to be mediated by the expression of relevant genes within the hippocampus of mice. The formulation achieved this effect by balancing 5-HT levels in the serum and DA, GABA, and 5-HT levels within brain tissue., Competing Interests: Declaration of competing interest The authors have no financial interest or other potential conflict of interests., (Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

The gut microbiome is a vast, variable, and largely unexplored component of human biology that sits at the intersection of heritable and environmental factors, and represents a rich source of novel chemistry that is already known to be compatible with the human body. This alone would make it a promising place to search for new therapeutics, but recent work has also identified gut microbiome abnormalities in patients with a number of psychiatric disorders, including anxiety disorders-suggesting that not only treatments, but cures may lie therein. Here, we'll discuss two known "para-endogenous" anxiolytics-γ-hydroxybutyrate and the neurosteroid allopregnanolone-which have recently been discovered to be produced by the microbiome., (Copyright © 2024. Published by Elsevier Inc.)

Defective β-catenin signaling is accompanied with compensatory neurogenesis process that may pave to anxiety. β-Catenin has a distinct role in alleviating anxiety in adolescence; however, it undergoes degradation by the degradation complex Axin and APC. Vilazodone (VZ) is a fast, effective antidepressant with SSRI activity and 5-HT 1A partial agonism that amends somatic and/or psychic symptoms of anxiety. Yet, there is no data about anxiolytic effect of VZ on anxiety-related neurogenesis provoked by stress-reduced β-catenin signaling. Furthermore, females have specific susceptibility toward psychopathology. The aim of the present study is to uncover the molecular mechanism of VZ relative to Wnt/β-catenin signaling in female rats. Stress-induced anxiety was conducted by subjecting the rats to different stressful stimuli for 21 days. On the 15th day, stressed rats were treated with VZ(10 mg/kg, p.o.) alone or concomitant with the Wnt inhibitor: XAV939 (0.1 mg/kg, i.p.). Anxious rats showed low β-catenin level turned over by Axin-1 with unanticipated reduction of APC pursued with elevated protein levels of neurogenesis-stimulating proteins: c-Myc and p Thr183 -Erk likewise gene expressions of miR-17-5p and miR-18. Two weeks of VZ treatment showed anxiolytic effect figured by alleviation of hippocampal histological examination. VZ protected β-catenin signal via reduction in Axin-1 and elevation of APC conjugated with modulation of β-catenin downstream targets. The cytoplasmic β-catenin turnover by Axin-1 was restored by XAV939. Herein, VZ showed anti-anxiety effect, which may be in part through regaining the balance of the reduced β-catenin and its subsequent exaggerated response of p-Erk, c-Myc, Dicer-1, miR-17-5p, and miR-18., (© 2024. The Author(s).)

Background: Current treatment of major depressive disorder is facing challenges, including a low remission rate, late onset of efficacy, and worsening severity due to comorbid symptoms such as psychosis and cognitive dysfunction. Serotonin (5-HT) neurotransmission is involved in a wide variety of psychiatric diseases and its potential as a drug target continues to attract attention., Objectives: The present study elucidates the effects of a novel 5-HT modulator, DSP-6745, on depression and its comorbid symptoms., Results: In vitro radioligand binding and functional assays showed that DSP-6745 is a potent inhibitor of 5-HT transporter and 5-HT 2A , 5-HT 2C , and 5-HT 7 receptors. In vivo, DSP-6745 (6.4 and 19.1 mg/kg as free base, p.o.) increased the release of not only 5-HT, norepinephrine, and dopamine, but also glutamate in the medial prefrontal cortex. The results of in vivo mouse phenotypic screening by SmartCube® suggested that DSP-6745 has a behavioral signature combined with antidepressant-, anxiolytic-, and antipsychotic-like signals. A single oral dose of DSP-6745 (6.4 and 19.1 mg/kg) showed rapid antidepressant-like efficacy in the rat forced swim test, even at 24 h post-dosing, and anxiolytic activity in the rat social interaction test. Moreover, DSP-6745 (12.7 mg/kg, p.o.) led to an improvement in the apomorphine-induced prepulse inhibition deficit in rats. In the marmoset object retrieval with detour task, which is used to assess cognitive functions such as attention and behavioral inhibition, DSP-6745 (7.8 mg/kg, p.o.) enhanced cognition., Conclusions: These data suggest that DSP-6745 is a multimodal 5-HT receptor antagonist and a 5-HT transporter inhibitor and has the potential to be a rapid acting antidepressant with efficacies in mitigating the comorbid symptoms of depression., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Depression and anxiety are prevalent neuropsychiatric conditions among patients with Parkinson's disease (PD), which may manifest prior to motor symptoms. As levodopa, a prominent treatment for PD motor symptoms, provides few benefits for mood-related abnormalities, tackling non-motor symptoms is particularly important. AdipoRon (Ad), an adiponectin agonist, has demonstrated neuroprotective effects by suppressing neuroinflammatory responses and activating the AMPK/Sirt-1 signaling pathway. This study looked at the potential advantages and underlying mechanisms of intranasal Ad in a rat model of PD induced by 6-hydroxydopamine (6-OHDA). We found that Ad at doses of 1 and 10 µg for 21 days exhibited anxiolytic- and antidepressant effects in the open field (OF) test, elevated plus maze (EPM), sucrose splash test, and forced swimming test in a PD model caused by a unilateral 6-OHDA injection into the medial forebrain bundle (MFB). The Ad also lowered the levels of corticosterone in the blood, decreased inflammasome components (NLRP3, caspase 1, and IL-1β), and increased Sirt-1 protein levels in the prefrontal cortex (PFC) of PD rats. We conclude that Ad ameliorates anxious and depressive-like behaviors in the PD rat model through stimulating the AMPK/Sirt-1 signaling and blocking the NLRP3 inflammasome pathways in the PFC., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The present experiment used the trapped rat model to explore whether pharmacological manipulation of distress affects the likelihood of helping behavior. 120 Sprague-Dawley rats (30 male pairs and 30 female pairs) completed 12 consecutive, daily trials assessing helping behavior. During an individual trial, a trapped rat was placed in a restrainer in the center of an open field, while its cagemate could move around freely and possibly open the restrainer by lifting a door. Trapped rats received an intraperitoneal injection of either 1) physiological saline, 2) the anxiolytic midazolam (1.5 mg/kg), or 3) the anxiogenic yohimbine (2.5 mg/kg) 30 min prior to the start of each trial. Dependent variables measured were: 1) door opening latency (sec), 2) percentage of trials in which a door opening occurred, and 3) the number of free rats classified as "openers." Based on emotional contagion theory, we predicted that 1) free rats paired with midazolam-subjects would show attenuated helping behavior (e.g., higher door opening latency) compared to controls, and conversely 2) free rats paired with yohimbine-subjects would show enhanced helping behavior. First, a significant sex-difference was observed, in that more females were classified as openers than males. This supports previous evidence that females express higher altruistic motivation and experience stronger emotional contagion than males. Second, midazolam-treatment significantly attenuated helping behavior. From trials 4-12, free rats paired with midazolam-subjects expressed slower door opening latencies compared to controls. Third, yohimbine-treatment significantly increased helping behavior (e.g., reduced door opening latencies) - but only on trials 1-3; by trials 9-12, this pattern was reversed. These results are consistent with emotional contagion theory and indicate that intensity of distress directly modulates altruistic motivation through vicarious state-matching., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Anxiety and epilepsy are common worldwide and represent a primary global health concern. Fisetin, a flavonoid isolated from Bauhinia pentandra, has a wide range of biological activities may be a promising alternative to combat diseases related to the central nervous system (CNS). The present study aimed to investigate the anxiolytic and anticonvulsant effects of fisetin on adult zebrafish. Furthermore, molecular docking simulations were performed to improve the results. Fisetin did not present toxicity and caused anxiolytic behavior and delayed seizures in animals. This effect may occur through serotonin neurotransmission at 5-HT 3A and/or 5-HT 3B receptors. Molecular docking simulations showed that fisetin interacts with the orthosteric site of the 5-HT 3A receptor with strong H-bond interactions with the Trp156 residue, with a strong contribution from the catechol ring, a behavior similar to that of the antagonist co-crystallized inhibitor granisetron (CWB). Fisetin may be a promising alternative to combat diseases related to the central nervous system., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Objectives: To study the pharmacological interactions between agmatine and gamma aminobutyric acid (GABA) modulatory agents in the regulation of anxiety-like behavior in rats., Materials and Methods: Male Wistar rats were treated drugs per se or in combination and 15 min after last injection were subjected to elevated plus-maze (EPM) test. Anxiety-like behavior was evaluated by measuring behavioral conventional readout, open arm activity (duration and/or entries) for 5-minute duration., Results: Acute intra-central amygdala (CeA) injection of agmatine (0.1-0.6 μmol/site/rat), muscimol (0.25-1 nmol/site/rat), diazepam (5-20 μg/site/rat) and allopregnanolone (2-8 μg/site/rat) increased open arm entries of the rats in EPM suggesting anxiolytic effect in dose dependent manner. Moreover, the anxiolytic effect at subeffective dose of agmatine (0.1 μmol/site/rat) was potentiated by subeffective dose of muscimol (0.25 nmol/site/rat), diazepam (5 μg/site/rat) and allopregnanolone (4 μg/site/rat). Whereas, pretreatment with GABA A receptor antagonist, bicuculline (10 ng/site/rat) blocked the anxiolytic effect of agmatine and its synergistic effect of agmatine plus muscimol. Similarly, benzodiazepine (BZD) receptor antagonist, flumazenil (15 μg/site/rat) and GABA allosteric modulator antagonist, RO 15-45 13 (10 μg/site/rat) reduced the anxiolytic effect of agmatine, given alone and with diazepam and allopregnanolone, respectively., Conclusion: These results indicated that anxiolytic effect of agmatine is medicated via GABAergic mechanisms, probably conciliated by the GABA A receptor subtypes. Modulation of interplay between agmatine and GABA A receptor activity might be a pertinent solution for the regulation of anxiety.

Ethnopharmacological Relevance: Sugarcane (Saccharum officinarum L.) is reported by traditional medicine as tonic, stimulating and beneficial in increasing resistance to fatigue. Previous preclinical studies in rats using aqueous extract of sugarcane leaves (AE) revealed pharmacological effects on the central nervous and cardiovascular systems involving the participation of dopaminergic pathways. This neurotransmission system is also related to motor, emotional and cognitive activities, which could, in part, justify the ethnopharmacological information., Aim of Study: The present study aimed to investigate the motor, emotional and cognitive activities of rats submitted to AE treatment using behavioral tests in order to correlate the pharmacological effects with the therapeutic benefits postulated by traditional medicine. Additionally, the chemical profile of AE was evaluated by HPLC-UV/Vis, and the presence of shikimic acid, vitexin, and ferulic acid, as possible chemical markers, was investigated through comparisons of chemical parameters with the authentic patterns, and a UV-Vis scan of known spectra., Material and Methods: Rats received water (1.5 mL/kg, p.o.) and AE (0.5, 10 and 500 mg/kg, p.o.) in the absence and presence of haloperidol (0.5 mg/kg, i.p.), 90 min before open field; rotarod; elevated plus maze and inhibitory avoidance tests for investigation of motor; emotional and cognitive responses. As a positive control was used apomorphine (0.25 mg/kg, s.c.). The chemical profile of AE was evaluated by HPLC-UV/Vis and the presence of shikimic acid, vitexin and ferulic acid, as possible chemical markers, was investigated through comparisons with the retention times, an increase of the integral of the peak area determined by co-injection of AE with the authentic patterns, and a UV-Vis scan of known spectra., Results: In open field, it revealed that AE increased locomotion; reduced rearing but did not change freezing and grooming. Besides, AE increased motor performance in rotarod and reduced anxiety in elevated plus maze. A relation dose-response was observed in these tests where the lowest dose of AE was more effective in developing pharmacological responses. Previous administration of haloperidol inhibited the responses of AE. Inhibitory avoidance test revealed that AE did not modify fast-learning and associative memory., Conclusions: Sugarcane induced psychostimulant, anxiolytic-like effects, and improvement of motor performance in rats, with the involvement of dopaminergic pathways. The present study points to AE as a potential adaptogen but, in addition to behavioral assessments, metabolic and molecular aspects, that involve the participation of a variety of regulatory systems, will be investigated in futures studies. Phytochemical analyses showed that AE is a complex matrix and revealed shikimic acid, vitexin, and ferulic acid as potential chemical markers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In recent years, buspirone has been co-administered with sertraline to resolve sexual disorders caused by sertraline. Therefore, the present study was conducted to investigate the interaction effect of two antidepressants and anxiolytic drugs, sertraline and buspirone, on human serum albumin (HSA) using spectroscopic and molecular docking techniques. Fluorescence emission spectroscopy and molecular docking were used to calculate the binding affinity and determine the best binding sites for these two drugs. Additionally, UV-visible and circular dichroism spectroscopy were performed to investigate the effect of these drugs on the conformational changes of HSA. The results showed that both drugs have a strong ability to quench the fluorescence of HSA through a static mechanism, and cause structural changes in HSA. It was also found that binding of sertraline and buspirone to HSA is spontaneous (ΔG° <) and hydrophobic interactions, van der Waals forces and hydrogen bonds play a significant role in these interactions in the ternary system. In addition, molecular docking data showed that both drugs bind with high affinity to the Trp residue in subdomain IIA. The binding constants (K b ) for (HSA-SRH)-BSH and (HSA-BSH)-SRH were equal to 6.30 and 3.99, respectively, at 298 K. This study demonstrates that the presence of the second drug (buspirone/sertraline) affects the interaction and binding affinity of the first drug (sertraline/buspirone) to human serum albumin., (© 2024. The Author(s).)

Background: There is renewed interest in the use of ancient herbal remedies for their potential health benefits, particularly in the psychological domain. One herb that is receiving growing attention is lemon balm ( Melissa officinalis L.) which has received considerable interest for its influence on the brain. Lemon balm boasts an array of phytochemicals, including rosmarinic acid, citral, oleanolic acid, and ursolic acid, which are believed to underpin these effects on psychological well-being. Pharmacological evidence from animal and cellular work reveals that lemon balm and its components may modulate several brain signalling pathways, including GABAergic, cholinergic, and serotonergic systems., Results/conclusions: Although further robust randomised controlled trials using lemon balm are required, existing research indicates that lemon balm holds promise as a calming agent exhibiting both anxiolytic and anti-depressant properties and can elicit cognitive and sleep-quality enhancement.

Ethnopharmacological Relevance: Rosmarinus officinalis L. (Rosemary) is a popular herb with reported effectiveness against diarrhea, anxiety and constipation, albeit with limited pharmacological evidence., Aim of the Study: The current study was aimed at evaluating the therapeutic potential, possible pharmacological mechanisms of action and active constituents of hydro-ethanolic extract of rosemary (Rs.Cr), as potential anti-diarrheal, laxative and anxiolytic agent., Method: Rs.Cr was analyzed through reverse-phase high pressure liquid chromatography (RP-HPLC). Laxative, antidiarrheal, and anxiolytic activities were assessed using in vivo models. Spasmogenic and spasmolytic mechanisms were studied on isolated guinea pig ileum and rabbit jejunum tissues, respectively. Possible role of diosmetin, one of the active constituents of Rs.Cr was also evaluated., Results: RP-HPLC analysis revealed presence of diosmetin, rutin and apigenin in Rs.Cr. Laxative effect was seen at low doses, which was partially reversed in atropinized mice. The spasmogenic mechanism was mediated by cholinergic and histaminergic receptors stimulation. At higher doses, antidiarrheal activity was evident, with reduction in gastrointestinal motility and secretions using charcoal meal and enteropooling assays, respectively. Rs.Cr also showed dose-dependent anxiolytic effect. The antispasmodic mechanisms were mediated by anti-muscarinic and K + channel opening-like effect (predominant K ATP -dependent). Diosmetin exhibited antidiarrheal and antispasmodic activities, but spasmogenic effect was not seen., Conclusion: Rosemary leaves have dual antidiarrheal and laxative effects, and as well as anxiolytic activity. In addition, the possible modulation of muscarinic and histaminergic receptors, and K ATP channels show it as potential herb to be explored for irritable bowel syndrome. Diosmetin is possibly one of its constituents that contributes to its antidiarrheal activity., Competing Interests: Declaration of competing interest The authors declare no competing interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: To explore the effect and anxiolytic mechanism of a natural remedy called Fructus gardeniae (FG)., Methods: The elevated-plus maze (EPM) test was used to confirm the anxiolytic effect of FG. The potential and anxiolytic components, targets, and route processes of FG were investigated using the network pharmacology method in conjunction with metabolomics and molecular docking technologies., Results: FG could greatly enhance the proportion of time and times of opening arms, according to the EPM data. As to the metabolomics findings, a total of 61 distinct metabolites were found, mainly involved in glycine, serine, and threonine metabolism as well as alanine, aspartate, and glutamate metabolism. The primary active ingredients of FG, nicotiflorin, jasminodiol, and crocetin, demonstrated substantial binding affinities with monoamine oxidase A (MAOA), monoamine oxidase A (ACHE), malate dehydrogenase 2 (MDH2), glutamate decarboxylase 2 (GAD2), glutamate decarboxylase 1 (GAD1), and nitric oxide synthase (NOS1), according to the findings of network pharmacology and molecular docking., Conclusion: FG exerts an anxiolytic action via targeting MAOA, ACHE, MDH2, GAD2, GAD1, and NOS1, and regulating the metabolism of glycine, serine, and threonine as well as alanine, aspartic acid, and glutamic acid., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society.)

The phytoestrogens daidzein and genistein are ubiquitous in human food. This study aimed to elucidate their anxiety-liked effects, their effects on the reproductive organs, and the molecular mechanism behind any anxiety-liked effects in intact adult male Wistar rats. These phytoestrogens are of interest due to their posited health benefits, particularly for female, but with some effect on males as well. This study comprised two experiments: (1) Male Wistar rats received either a vehicle, daidzein, or genistein (0.25, 0.50, or 1.00 mg/kg) by subcutaneously injection for four weeks. They were then tested for anxiety-liked behaviors. Then, the brain monoamines in anxiolytic rats were determined; (2) The modulation of gamma aminobutyric acid receptors by phytoestrogens was further analyzed by administration of diazepam to phytoestrogen-treated rats before behavioral tests. In the first experiment, the biological parameters measured, including body weight, daily food intake and reproductive organ weights were unaffected by either genistein or daidzein. However, anxiolytic-like effect was observed in the low-dose daidzein (0.25 mg/kg) group. Higher doses of daidzein or genistein of all doses had no effect. Further, the low-dose daidzein did not alter brain monoamine levels. In the second experiment, the anxiolytic-like behavior of daidzein-treated rats receiving diazepam did not differ from that of the rats treated with just diazepam or just daidzein. In conclusion, 4-week exposure to daidzein or genistein had no negative effects on the reproductive organs, body weight, food intake, anxiogenic-like behavior, or monoaminergic and diazepam-modulated GABAergic neurotransmissions of intact male rats. However, beneficial anxiolytic-like effects were apparent after low-dose treatment with daidzein., Competing Interests: Declaration of Competing Interest Authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Pregabalin is an antiepileptic drug that binds to the alpha-2/delta unit at presynaptic voltage-dependent calcium channels. We aimed to investigate the effect of acute and chronic pregabalin administration on anxiety and depression-like behaviors., Methods: Fifty-six male Wistar albino rats were divided into seven groups: control, vehicle, and five different dose groups (5, 10, 30, 60, and 100 mg/kg). Pregabalin was administered for two weeks. Depression-like behaviors were evaluated by Forced swimming test. Anxiety-like behavior (ALB) was evaluated by Open field test (OFT), Elevated Plus Maze (EPM), and light-dark box. Subjects underwent the forced swimming test (FST) after the first dose, while the open field test (OFT), elevated plus maze (EPM), and light-dark box (LDB) were performed after two weeks of treatment. Further sucrose preference test was conducted to evaluate anhedonia until the end of the experiment., Results: In the forced swimming test, depression-like behaviors increased after acute single-dose administration of 10, 30, 60, 100 mg/kg pregabalin. According to OFT results, chronic 100 mg/kg pregabalin showed anxiolytic effects by decreasing grooming, and freezing behaviors. In addition, 100 mg/kg chronic pregabalin administration significantly increased the time spent in the central region, the number of entries to the center, and the unsupported rearing number without causing any change in locomotor activity. According to EPM results, both chronic 60 and 100 mg/kg pregabalin treatments showed anxiolytic effects by increasing open arm time and head dipping behavior. In addition, 60 and 100 mg/kg chronic pregabalin administration significantly decreased stretch attend posture. All pregabalin administrations between 5 and 100 mg/kg displayed anxiolytic effects in the LDB. Sucrose preference was above 65% for the duration of all experiments and subjects did not show anhedonia., Conclusion: Acute pregabalin treatment triggered depression-like behaviors. Anhedonia, which may be associated with depression, was not observed during chronic treatment. Moreover, chronic treatment with pregabalin revealed potent anxiolytic effects in different behavior patterns and doses for all tests of unconditional anxiety. In particular, 100 mg/kg chronic pregabalin administration decreased anxiety-like behaviors in all experiment setups. Although the anxiolytic effect was demonstrated in chronic treatment, acute treatment of pregabalin induced depression-like behaviors, and thus in clinical practice should be done with caution, especially in patients with anxiety-depression comorbidity., (© 2024. The Author(s).)

In humans, adverse physical and/or psychological traumas in childhood may predispose to developing psychiatric disorders in adulthood, including panic disorder. To model early life adversity in mice, we subjected male and female C57BL/6 J mice to a limited bedding and nesting (LBN) protocol between postnatal days 2-9 and investigated its effect on responsiveness to panicogenic challenges in adulthood. Panic-like escape behaviour was assessed during exposure to a high concentration of CO 2 (20%) or in the beetle mania task (BMT), used to model respiratory and non-respiratory-related types of panic respectively. Neonatal exposure to LBN increased panic-like jumping during the CO 2 challenge in male but not female mice. In an initial pharmacological validation of the BMT as a panic-inducing paradigm, undirected jumping and horizontal escape behaviours were reduced significantly by the panicolytic alprazolam (0.05 and 0.1mg.kg -1 i.p.) whilst tolerance to the close proximity of the aversive robo-beetle increased. The anxiolytic diazepam (1 mg.kg -1  i.p.) reduced only the number of horizontal escape attempts. In both sexes, previous experience of LBN significantly enhanced the number of horizontal escape episodes, indicating a pro-panic phenotype. Directed escape to access a safe ledge on the wall of the test arena, which was seen only in males, was also reduced significantly following LBN. These findings indicate that early life adversity produced by fragmented and unpredictable maternal care promotes a sex-specific increase in susceptibility to panic-like behaviour in adulthood. Whilst non-respiratory-related panic-like behaviour was enhanced in both sexes, females were resilient to respiratory-related challenges., (© 2024 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Mice of two strains selected for successful solution of "object permanence" test and for lack of such solution demonstrated the differential reaction to injections of two drugs. The effects of injections of atomoxetine. which blocks the noradrenaline reuptake, and of 'non-benzodiazepine" anxiolytic afobazol was different. The success of solutions increased in mice selected for this test "non-solution": and decreased or was inefficient in mice, selected for successful solution of object permanence cognitive test., (© 2024. Pleiades Publishing, Ltd.)