Tail Suspension Test In Mice Research Articles

PACAP/VIP in the prefrontal cortex mediates the rapid antidepressant effects of zhizichi decoction

Ethnopharmacological relevanceZhizichi decoction (ZZCD) is a traditional Chinese medicine formula that consists of Gardenia jasminoides J.Ellis (GJ) and Semen Sojae Praeparatum. It is used to treat insomnia and emotion-related disorders, such as irritability. Previous studies have found that GJ has a rapid antidepressant effect. The study found that ZZCD is safer than GJ at the same dosage. Consequently, ZZCD is a superior drug with quicker antidepressant effects than GJ. The rapid antidepressant effects of ZZCD were examined in this study, along with the components that make up this effect. It was determined that the activation of prefrontal Pituitary Adenylate Cyclase Activating Polypeptide (PACAP)/Vasoactive Intestinal Polypeptide (VIP) is essential for ZZCD's rapid antidepressant effects. AimThis study identified and discussed the rapid antidepressant effects and biological mechanisms of ZZCD. Materials and methodsThe tail suspension test (TST) and the forced swimming test (FST) were used to screen the effective dosage of ZZCD (0.67 g/kg, 1 g/kg, 4 g/kg). The effective dosage of ZZCD (1 g/kg) was tested in the TST conducted on Institute of Cancer Research (ICR) mice that were treated with lipopolysaccharide (LPS) at a concentration of 0.1 mg/mL. To confirm the expression of c-Fos, PACAP, and VIP in the prefrontal cortex (PFC), immunohistochemistry tests were conducted on mice following intragastric injection of ZZCD. Chemical characterization analysis and HPLC quality control analysis were conducted using UHPLC-Q-Obitrap-HRMS and chromatographic analysis. ResultsThe results showed that an acute administration of ZZCD (1 g/kg) decreased the immobility time of Kunming (KM) mice in TST and FST. Depressive behaviors in TST-induced ICR mice treated with LPS (0.1 mg/mL) were reversed by ZZCD (1 g/kg). The results of immunohistochemical experiments showed that ZZCD (1 g/kg) activated neurons in the PFC and PACAP/VIP in the PFC. In this study, 22 substances in ZZCD were identified. Five primary distinctive fingerprint peaks—geniposide, genistin, genipin-1-β-D-gentiobioside, glycitin, and daidzin—were found among the ten common peaks. ConclusionZZCD (1 g/kg) had significant rapid antidepressant effects. PACAP/VIP in the PFC was found to mediate the rapid antidepressant effects of ZZCD.

Antidepressant-like effects of Cimicifuga dahurica (Turcz.) Maxim. via modulation of monoamine regulatory pathways

Sheng-ma is recorded in the Compendium of Materia Medica and mainly originates from the rhizomes of Cimicifuga dahurica (Turcz.) Maxim. (CD), Cimicifuga heracleifolia Kom. and Cimicifuga foetida L. The alcoholic extract of Cimicifuga foetida L. (Brand name: Ximingting®) has been approved for the treatment of perimenopausal symptoms accompanying hot flash, depression and anxiety in China. However, there's no further study about the antidepressant-like effects of C. dahurica (CD). The aim of this study is to investigate the antidepressant-like effect of CD extracted by 75% ethanol and its possible mechanisms.The neuro-protective effects of CD on injured PC12 cells induced by corticosterone was measured firstly. Then, forced swim test (FST), tail suspension test (TST), reserpine-induced hypothermia, 5-hydroxytryptophan (5-HTP) induced head twitch response in mice and chronic unpredictable mild stress (CUMS) on sucrose preference tests were executed. Moreover, the potential mechanisms were explored by measuring levels of monoamine neurotransmitter in mice frontal cortex and hippocampus, testing monoamine oxidase enzyme A (MAO-A) activities in the brains of CUMS-exposed mice. Results showed that CD (60, 120 mg/kg) can significantly decreased the immobility period in FST and TST in mice without affecting locomotor activity. CD (30 mg/kg, 60 mg/kg, 120 mg/kg) could significantly counteracted reserpine-induced hypothermia and increased the number of head-twitches in 5-HTP induced head twitch response. It was also found that the monoamine neurotransmitter levels in the hippocampus and frontal cortex were significantly increased in 60 mg/kg and 120 mg/kg CD treated mice. In addition, CD (60 and 120 mg/kg) significantly inhibited MAO-A after 6-week CUMS exposure. CD can effectively produce an antidepressant-like effect, which involved with modulation of monoamine regulatory pathways.

Development and pharmacological evaluation of liposomes and nanocapsules containing paroxetine hydrochloride

Depression is one of the most common psychiatric disorders. Nanotechnology has emerged to optimize the pharmacological response. Therefore, the aim of this work was to develop and characterize liposomes and nanocapsules containing paroxetine hydrochloride and evaluate their antidepressant-like effect using the open field and tail suspension tests in mice. Liposomes and nanocapsules were prepared using the reverse-phase evaporation and nanoprecipitation methods, respectively. The particle size of the formulation ranged from 121.81 to 310.73 nm, the polydispersity index from 0.096 to 0.303, the zeta potential from −11.94 to −34.50 mV, the pH from 5.31 to 7.38, the drug content from 80.82 to 94.36 %, and the association efficiency was 98 %. Paroxetine hydrochloride showed slower release when associated with liposomes (43.82 %) compared to nanocapsules (95.59 %) after 10 h. In Vero cells, in vitro toxicity showed a concentration-dependent effect for paroxetine hydrochloride nanostructures. Both nanostructures decreased the immobility time in the TST at 2.5 mg/kg without affecting the number of crossings in the open field test, suggesting the antidepressant-like effect of paroxetine. In addition, the nanocapsules decreased the number of groomings, reinforcing the anxiolytic effect of this drug. These results suggest that the nanostructures were effective in preserving the antidepressant-like effect of paroxetine hydrochloride even at low doses.

Electroacupuncture intervention alleviates depressive-like behaviors and regulates gut microbiome in a mouse model of depression

Electroacupuncture (EA) is a neuroregulatory therapy for depression. Nonetheless, the effects of EA on the gut microbiome in mice models of depression are not well established. Here, using a chronic unpredictable mild stress (CUMS) model in mice, we evaluated the antidepressant effects of EA and changes in gut microbiota with behavioral tests and 16S rRNA gene sequencing. The results found that EA increased the time spent in the center area of the open-field test and the percentage of sucrose preference and reduced the immobility time in the tail suspension test in CUMS-treated mice. Furthermore, the genus Lachnoclostridium, Ruminococcaceae_UCG-002 and Rikenellaceae_RC9_gut_group were enriched in the CUMS group, which was positively correlated with depressive-like behaviors. Whereas phylum Actinobacteria and genus Allobaculum, Bifidobacterium, Dubosiella, Rikenella and Ileibacterium were enriched in the EA and CUMS + EA groups, all of which were negatively correlated with depressive-like behaviors. This study characterizes gut microbiota under EA treatment and provides new insights into the association of anti-depressive-like effects of EA and gut microbiota.

Dopaminergic Modulation and Computational ADMET Insights for the Antidepressant-like Effect of N-(3-(Phenylselanyl)prop-2-yn-1-yl)benzamide.

The compound N-(3-(phenylselanyl)prop-2-yn-1-yl)benzamide (SePB), which combines a selenium atom and a benzamide nucleus in an organic structure, has demonstrated a fast antidepressant-like effect in mice. This action is influenced by the serotonergic system and represents a promising development in the search for novel antidepressant drugs to treat major depressive disorder (MDD), which often resists conventional treatments. This study aimed to further explore the mechanism underlying the antidepressant-like effect of SePB by investigating the involvement of the dopaminergic and noradrenergic systems in the tail suspension test (TST) in mice and evaluating its pharmacokinetic profile in silico. Preadministration of the dopaminergic antagonists haloperidol (0.05 mg/kg, intraperitoneally (i.p.)), a nonselective antagonist of dopamine (DA) receptors, SCH23390 (0.01 mg/kg, subcutaneously (s.c.)), a D1 receptor antagonist, and sulpiride (50 mg/kg, i.p.), a D2/3 receptor antagonist, before SePB (10 mg/kg, intragastrically (i.g.)) prevented the anti-immobility effect of SePB in the TST, demonstrating that these receptors are involved in the antidepressant-like effect of SePB. Administration of the noradrenergic antagonists prazosin (1 mg/kg, i.p.), an α1-adrenergic antagonist, yohimbine (1 mg/kg, i.p.), an α2-adrenergic antagonist, and propranolol (2 mg/kg, i.p.), a β-adrenergic antagonist, did not block the antidepressant-like effect of SePB on TST, indicating that noradrenergic receptors are not involved in this effect. Additionally, the coadministration of SePB and bupropion (a noradrenaline/dopamine reuptake inhibitor) at subeffective doses (0.1 and 3 mg/kg, respectively) produced antidepressant-like effects. SePB also demonstrated good oral bioavailability and low toxicity in computational absorption, distribution, metabolism, excretion, and toxicity (ADMET) analyses. These findings suggest that SePB has potential as a new antidepressant drug candidate with a particular focus on the dopaminergic system.

Gynura procumbens and selected metabolites: Amelioration of depressive-like behaviors in mice and risperidone-induced hyperprolactinemia in rats

Gynura procumbens (Lour.) Merr., utilized in traditional Chinese medicine, is known for its liver-protective, liver-soothing, and depression-alleviating properties. This research examines the antidepressant and anti-hyperprolactinemia potentials of an ethanol extract from G. procumbens stems (EEGS) and specific metabolites. To model depression and hyperprolactinemia, chronic unpredictable mild stress (CUMS) was induced in mice and risperidone was administered to rats, respectively. Treatments involved administering low (5 mg/kg), medium (25 mg/kg), and high (125 mg/kg) doses of EEGS and certain metabolites to both models. Behavioral assessments were conducted in the CUMS-induced mice, while the CA3 neuronal damage in mice and histopathological alterations in rat mammary glands were evaluated using Nissl and Hematoxylin & Eosin staining techniques, respectively. EEGS decreased immobility times in the forced swimming and tail suspension tests in mice, enhancing their exploration of the central zone. It elevated the serum levels of 5-hydroxytryptamine, norepinephrine, estradiol, luteinizing hormone (LH), and testosterone in mice. Moreover, EEGS restored the neuronal cell arrangement in the CA3 area, reduced interleukin-1beta mRNA production, and increased the expression of interleukin-10 and beta-catenin mRNA. In the context of risperidone-induced hyperprolactinemia, EEGS lowered blood prolactin levels, reduced the dimensions of rat nipples, and enhanced LH, progesterone, and dopamine levels, alongside mitigating mammary hyperplasia. Among the EEGS selected metabolites, the combined effect of chlorogenic acid and trans-p-coumaric acid was found to be more effective than the action of each compound in isolation. Collectively, the findings indicate that EEGS and its selected metabolites offer promising antidepressant benefits while counteracting hyperprolactinemia.

Antidepressant-Like Effect of the Polymethoxylated Flavone Tangeretin from Citrus Peels: The Role of Serotonergic Mechanisms

Objective: Depression is a mood disorder characterized by a set of emotional, cognitive, physical and behavioral symptoms. Low response rate to antidepressant treatment in patients with depression, late onset of action, side effects due to long-term drug use, and pharmacogenetic variations limit the effectiveness and tolerability of these drugs and lead to compliance problems in patients. Therefore, studies on the discovery and development of new antidepressant drugs continue, and molecules of natural origin are becoming the focus of attention of researchers. Tangeretin, which is commonly found in citrus peels and has a pentamethoxyflavone structure, is an important member of flavonoids. Since it lacks a glycoside structure, it is easily absorbed from the intestines and can easily pass through the blood-brain barrier due to its lipophilic structure. Previous studies indicating that tangeretin may be effective on the central nervous system suggest that it may be possible for this phytochemical to have an effect on mood. Based on this idea, this study aimed to investigate the possible antidepressant-like effects of tangeretin and to elucidate the pharmacological mechanisms mediating this effect. Methods: Male Balb/c mice of the same age, weighing 30-35 g, were used for the experiments. The antidepressant-like effect of tangeretin (10, 20 ve 40 mg/kg, p.o.) was examined by tail suspension and modified forced swimming tests, while its effect on the motor coordination of experimental animals was evaluated using the Rota-rod method. Results: The data obtained revealed that doses of 10 and 20 mg/kg tangeretin decreased the immobility time of mice in tail suspension test and immobility number of mice in modified forced swimming tests compared to control animals not receiving tangeretin. These findings indicated that tangeretin showed an antidepressant-like activity comparable to the reference drug fluoxetine (30 mg/kg) when administered at doses of 10 and 20 mg/kg. Tangeretin, at the same doses, did not alter the climbing number of mice in modified forced swimming tests, but significantly increased their swimming number. The 40 mg/kg dose of this flavonoid did not cause a statistically significant effect in either test. While α-methyl-para-tyrosine methyl ester (an inhibitor of catecholamine synthesis; 100 mg/kg i.p.) and ondansetron (a 5-HT3 receptor antagonist; 0.3 mg/kg i.p.) pretreatments did not change the antidepressant-like activity induced by 20 mg/kg dose of this flavonoid in the tail suspension tests; pretreatment of p-chlorophenylalanine methyl ester (an inhibitor of serotonin synthesis; 100 mg/kg i.p., administered for 4-consecutive days), NAN-190 (a 5-HT1A receptor antagonist; 0.5 mg/kg i.p.) and ketanserin (a 5-HT2A/2C receptor antagonist; 1 mg/kg i.p.), reversed this activity. These findings indicated that tangeretin has antidepressant-like activity mediated by the serotonergic system and that 5-HT1A and 5-HT2A/5-HT2C serotonergic receptor subtypes participate in this effect. Conclusion: The findings of this study suggest that tangeretin may be a useful drug candidate in the treatment of depression. However, it is clear that for tangeretin to be considered an antidepressant agent, the antidepressant-like activity presented in this preclinical study must be confirmed by well-designed clinical studies conducted on various groups of patients with depressive disorders.

Nebulized and intraperitoneal ketamine have equivalent antidepressant-like effect in the forced swim and tail suspension tests in mice

Major depressive disorder (MDD) is a debilitating illness that affects millions of people worldwide. Currently available antidepressants often take weeks to months to reach their full effect, which leads to an increased risk of suicidal behavior in patients with MMD. Intranasally, esketamine has emerged as an alternative to current antidepressants because of its rapid onset and long-lasting effects in patients with MDD. Animal models are useful for the initial pharmacological screening and for a better understanding of the mechanisms underlying the effects of new drugs with potential against MDD. There is a lack of data on alternative routes of drug administration, either oral or injectable, that can be used in preclinical studies. This study aimed to test whether ketamine has antidepressant-like effects in mice when administered via nebulization using a low-cost apparatus. When mice whose depressive-like behavior was induced by corticosterone were treated with nebulized ketamine at concentrations of 1.3, 2.6, and 5.2 mg/mL, immobility was reduced by 38.6 %, 62.0 %, and 61.1 %, respectively, in the forced swimming test (FST) and 43.6 %, 42.1 %, and 57.9 %, respectively, in the tail suspension test (TST). When depression-like behavior was induced by dexamethasone, nebulization with ketamine reduced immobility by 79.7 %, 49.2 %, and 44.4 % in the FST and 80.9 %, 71.4 %, and 80.4 %, respectively, in the TST. When depression-like behavior was induced by the association between dexamethasone and unpredictable chronic mild stress (UCMS) exposure, immobility was reduced by 26.1 %, 55.3 %, and 19.1 % in FST. Mice treated with nebulized ketamine did not show significant changes in the distance covered or in the time spent moving in the open field test. The efficacy of intraperitoneal and nebulized ketamine is equivalent, which shows that nebulization can be an alternative inexpensive route of drug administration for behavioral studies in rodents.

Engeletin alleviates depression-like phenotype by increasing synaptic plasticity via the BDNF-TrkB-mTORC1 signalling pathway.

Major depressive disorder (MDD) is a severe mental disorder associated with high rates of morbidity and mortality. Current first-line pharmacotherapies for MDD are based on enhancement of monoaminergic neurotransmission, but these antidepressants are still insufficient and produce significant side-effects. Consequently, the development of novel antidepressants and therapeutic targets is desired. Engeletin, a natural Smilax glabra rhizomilax derivative, is a compound with proven efficacy in treating ischemic stroke, yet its therapeutic effects and mechanisms for depression remain unexplored. The effects of engeletin were assessed in the forced swimming test (FST) and tail suspension test (TST) in mice. Engeletin was also investigated in the chronic restraint stress (CRS) mouse model of depression with fluoxetine (FLX) as the positive control. Changes in prefrontal cortex (PFC) spine density, synaptic plasticity-linked protein expressions and the brain-derived neurotrophic factor (BDNF)-tyrosine kinase B (TrkB)- mammalian target of rapamycin complex 1 (mTORC1) signalling pathway after chronic stress and engeletin treatment were then investigated. The TrkB and mTORC1 selective inhibitors, ANA-12 and rapamycin, respectively, were utilized to assess the engeletin's antidepressive mechanisms. Our data shows that engeletin exhibited antidepressant-like activity in the FST and TST in mice without affecting locomotor activity. Furthermore, it exhibited efficiency against the depression of CRS model. Moreover, it enhanced the BDNF-TrkB-mTORC1 pathway in the PFC during CRS and altered the reduction in dendritic spine density and levels of synaptic plasticity-linked protein induced by CRS. In conclusion, engeletin has antidepressant activity via activation of the BDNF-TrkB-mTORC1 signalling pathway and upregulation of PFC synaptic plasticity.

Experimental evaluation of anxiolytic and antidepressant activities of methanolic extract of Triticum aestivum (wheatgrass) in albino mice

Background: Anxiety and depression are common psychiatric conditions. The present study was carried out to find antianxiety and antidepressant activity of methanolic extract of Triticum aestivum (wheat grass) in mice. Materials and methods: The methanolic extract of Triticum aestivum (META) was screened for antianxiety activity by elevated plus maze (EPM) and light and dark box (LDB) and for antidepressant activity by forced swim test (FST) and tail suspension test (TST) in mice. Animals were divided into four groups having six animals in each group. Group I served as control and received gum acacia aqueous suspension 10 ml/kg, Groups II and III served as test groups and received META 200 and 400 mg/kg, respectively, Group IV served as standard group and received diazepam 1 mg/kg for antianxiety activity and fluoxetine (20 mg/kg) for antidepressant activity once daily for thirty days. Result: META 200 and 400 mg/kg showed significant (P < 0.01) dose-dependent increase in entries and stay in the open arms in EPM and entries and stay in the light compartment in LDB as compared to control. Antianxiety effect of META at dose of 400 mg/kg was comparable (P > 0.05) with diazepam 1mg/kg. META 200 and 400 mg/kg also produced dose-dependent significant (P < 0.01) antidepressant effect, indicated by reduction in the immobility time as compared to control in both FST and TST. The antidepressant activity of META at dose of 400 mg/kg was comparable (P > 0.05) with fluoxetine 20 mg/kg. Conclusion: Results of our study suggested that META possess dose-dependent significant antianxiety and antidepressant activities.

Study of Central Nervous System Depressant and Behavioral Activity of Ethanolic Extract of Clitoria Annuain Albino Rats

Objective: The objective was to evaluate depressant effects on central nervous system (CNS) and behavioral effects of ethanol extract of clitoria annua and to find the phytochemical responsible for these activities with possible mode of action. Materials & Method: The central nervous system (CNS) depressant activity of C. annua was evaluated by the classical models of depression as Rota rod method, Actophotometer test, tail suspension, and thiopental sodium induced sleeping time tests in Rat. The Rats were divided into Normal, Standard, and two test groups containing five rats each. The test groups received extract at the doses of 200, and 400 mg/kg body weight orally where as the Normal group received distilled water (0.1 ml/mice, p.o.). Diazepam (2 mg/kg, i.p.) was used as standard drug. Results: It is clear that the plant extract significantly decreased the locomotor activity of rats in Rota rod method and Actophotometer test when compared to the normal (p < 0.05). It is observed that the extract showed significantly (p < 0.05) increased in immobility time in tail suspension test in mice. In addition, the extract produced prolongs the sleeping time with onset of action in contrast to the normal group. Conclusions: The present work depicts the evaluation of possible CNS depressant activity of C. annua in mice models. EECA can be a safe and effective approach/alternative for the treatment of number of CNS depressant disorders. More extensive study is required to fractionate, purify, and identify the exact mechanism of action CNS Depressant activity present in ethanolic extract of Clitoria annua with its active ingredients.

Antidepressant-like Effect of 1-(2-(4-(4-Ethylphenyl)-1H-1,2,3-triazol-1-yl)phenyl)ethan-1-one in Mice: Evidence of the Contribution of the Serotonergic System.

Major depressive disorder (MDD) is a psychiatric disorder that affects a large portion of the population, with dysregulation of the serotonergic system, which is deeply involved in both the pathophysiology of MDD and mechanism of action of many antidepressants. Current pharmacological therapies do not meet the neurobiological needs of all depressed individuals, making the development of new antidepressants necessary. In recent decades, compounds containing triazoles have become promising due to their range of biological activities, including antidepressant activity. In this study, we evaluated the antidepressant-like effect of a hybrid containing triazole and acetophenone, 1-(2-(4-(4-ethylphenyl)-1H-1,2,3-triazol-1-yl)phenyl)ethan-1-one (ETAP) (0.5-5 mg/kg), in the forced swimming test (FST) and tail suspension test (TST) in mice, as well as the involvement of the serotonergic system in this effect. Our findings demonstrated that ETAP exhibited an antidepressant-like effect from the dose of 1 mg/kg and that this effect is modulated by 5-HT2A/2C and 5-HT4 receptors. We also demonstrated that this effect may be related to inhibition of monoamine oxidase A activity in the hippocampus. Additionally, we evaluated the in silico pharmacokinetic profile of ETAP, which predicted its penetration into the central nervous system. ETAP exhibited a low potential for toxicity at a high dose, making this molecule interesting for the development of a new therapeutic strategy for MDD.

(099) Dual Effect of a Serotonin and Dopamine Reuptake Inhibitor (IP2018), and the Search for a Depressive Rat Model with Erectile Dysfunction

Abstract Introduction In patients with major depressive disorder, up to 68% present with comorbid sexual dysfunction, which resolves in only 5% to 30% of patients treated with antidepressants. Several groups of antidepressants negatively affect sexual function. Objective The present study investigated whether a newly developed amine transport inhibitor, IP2018, improves depression and erectile function in the same dose range. Methods The dose-dependent effect of IP2018 in two different mouse models for depression, the mouse forced swim test (mFST) and mouse tail suspension test (mTST), is reported. In male Wistar, Sprague Dawley and the depressive rats (Flinders Sensitive Line (FSL) and Flinders Resistant Line (FRL)), increases in intracavernosal pressure (ICP) and mean arterial pressure (MAP) were measured, and the ratio ICP/MAP was used as a measure of erectile function. We investigated whether IP2018 induces changes in ICP or flow and whether IP2018 facilitates suboptimal increases in ICP induced by cavernosal nerve electrical stimulation. The late IP2018 procedure was performed in the rest of the rats to evaluate their erectile function. Results We found that infusion of IP2018 dose-dependently improved mFST and was more potent than citalopram. At the same time, higher doses of IP2018 were required to obtain effect in the mTST model, and IP2018 was equipotent to citalopram. Infusion of low doses of IP2018 dose-dependently increased the number and the duration of spontaneous erections. At the highest dose of IP2018, the increases in the number and duration of spontaneous erections were similar to the effect of the lowest dose, and the increases in flow were 5 times higher. IP2018 (1-30 μM) caused small relaxations in isolated corpus cavernosum strips. FSL and FRL rats showed a diminished ICP/MAP compared to Sprague Dawley control rats. Conclusions IP2018 is more potent or has a similar effect to the well-known antidepressant drug citalopram in mouse models for depression. The potent effect of IP2018 on erectile function in anaesthetized rats suggests that IP2018 in the same dose range has positive effects on both depression and erectile function. FSL/FRL rats appear to allow the study of drug effects on both depression and sexual function in one animal model. Disclosure Yes, this is sponsored by industry/sponsor: Initiator Pharma A/S Clarification Industry funding only - investigator initiated and executed study Any of the authors act as a consultant, employee or shareholder of an industry for: Initiator Pharma A/S

Antidepressant effect of 4-Butyl-alpha-agarofuran via HPA axis and serotonin system

Depression is a leading cause of disability worldwide and the psychiatric diagnosis most commonly associated with suicide. 4-Butyl-alpha-agarofuran (AF-5), a derivative of agarwood furan, is currently in phase III clinical trials for generalized anxiety disorder. Herein, we explored the antidepressant effect and its possible neurobiological mechanisms in animal models. In present study, AF-5 administration markedly decreased the immobility time in mouse forced swim test and tail suspension test. In the sub-chronic reserpine-induced depressive rats, AF-5 treatment markedly increased the rectal temperature and decreased the immobility time of model rats. In addition, chronic AF-5 treatment markedly reversed the depressive-like behaviors in chronic unpredictable mild stress (CUMS) rats by reducing immobility time of forced swim test. Single treatment with AF-5 also potentiated the mouse head-twitch response induced by 5-hydroxytryptophan (5-HTP, a metabolic precursor to serotonin), and antagonized the ptosis and motor ability triggered by reserpine. However, AF-5 had no effect on yohimbine toxicity in mice. These results indicated that acute treatment with AF-5 produced serotonergic, but not noradrenergic activation. Furthermore, AF-5 reduced adrenocorticotropic hormone (ACTH) level in serum and normalized the neurotransmitter changes, including the decreased serotonin (5-HT) in hippocampus of CUMS rats. Moreover, AF-5 affected the expressions of CRFR1 and 5-HT2C receptor in CUMS rats. These findings confirm the antidepressant effect of AF-5 in animal models, which may be primarily related to CRFR1 and 5-HT2C receptor. AF-5 appears to be promising as a novel dual target drug for depression treatment.

Gap junction is essential for the antidepressant effects of fluoxetine.

Fluoxetine has been used as the first line for the therapy of depression. However, lack of therapeutic efficacy and time lag still limit the application of fluoxetine. Gap junction dysfunction is a potentially novel pathogenic mechanism for depression. To clarify the mechanism underlying these limitations, we investigated whether gap junction was related to the antidepressant effects of fluoxetine. After chronic unpredictable stress (CUS), animals showed decreases in gap junction intracellular communication (GJIC). Treatment with fluoxetine 10 mg/kg significantly improved GJIC and anhedonia of rats until six days. These results indicated that fluoxetine improved gap junction indirectly. Furthermore, to test the role of gap junction on antidepressant effects of fluoxetine, we blocked gap junction using carbenoxolone (CBX) infusion in the prefrontal cortex. CBX dampened fluoxetine-induced decrease in immobility time of mice in tail suspension test (TST). Our study suggested that gap junction dysfunction blocks antidepressant effects of fluoxetine, contributing to understanding the mechanism underlying the time lag of fluoxetine.

ANTIDEPRESSANT-LIKE ACTIVITY OF METHANOLIC EXTRACT OF WITHANIA QARAITICA IN MICE

Objective: The goal of the present study was to assess the antidepressant-like action of Withania qaraitica in two behavioral animal models, the forced-swimming test (FST) and tail suspension test (TST) in mice. Methods: Withania qaraitica methanolic extract was prepared by the maceration. The antidepressant activity was measured by the forced-swimming test (FST) using C57BL/6 mice and the tail suspension test (TST) using BALB/c mice. Mice were divided into three groups: control (DMSO), standard (citalopram and desipramine), and Withania qaraitica methanolic extract (n = 6 per group). Drugs were injected (1 ml/100 g) intraperitoneally (i. p.). Data were evaluated using analysis of variance, followed by LSD post-hoc tests, where *p<0.001 was considered significantly different from the vehicle control. The data are expressed as mean±SEM. Results: In both the FST and the TST, antidepressant-positive controls citalopram and desipramine significantly reduced the time of immobility compared to vehicle control (p<0.001). The methanolic extract of Withania qaraitica at the dose of 40 mg/kg significantly reduced the immobility times with respect to vehicle control as well as lower doses of the same extract (10 and 20 mg/kg) in FST (p<0.001). In a similar fashion, the methanolic extract of Withania qaraitica at the dose of 40 mg/kg significantly decreased the duration of immobility in TST (p<0.005). Conclusion: The current results show the antidepressant-like activity of Withania qaraitica in mice. This observation warrants additional studies to identify the underlining mechanism by which Withania qaraitica produces antidepressant-like effects.

Nanoencapsulation of Vaccinium ashei Leaf Extract in Eudragit® RS100-Based Nanoparticles Increases Its In Vitro Antioxidant and In Vivo Antidepressant-like Actions.

Depression is a major psychiatric disorder in Brazil and worldwide. Vaccinium ashei (V. ashei) leaves are cultivation by-products with high bioactive compound levels. Here, a hydroalcoholic extract of V. ashei leaves (HEV) was associated with Eudragit® RS100-based nanoparticles (NPHEV) to evaluate the in vitro antioxidant and in vivo antidepressant-like effects. Interfacial deposition of the preformed polymer method was used for NPHEV production. The formulations were evaluated regarding physicochemical characteristics, antioxidant activity (DPPH radical scavenging and oxygen radical absorbance capacity), and antidepressant-like action (1-25 mg/kg, single intragastric administration) assessed in forced swimming and tail suspension tests in male Balb-C mice. The NPHEV presented sizes in the nanometric range (144-206 nm), positive zeta potential values (8-15 mV), polydispersity index below 0.2, and pH in the acid range. The phenolic compound content was near the theoretical values, although the rutin presented higher encapsulation efficiency (~95%) than the chlorogenic acid (~60%). The nanoencapsulation improved the HEV antioxidant effect and antidepressant-like action by reducing the immobility time in both behavioral tests. Hence, Eudragit® RS100 nanoparticles containing HEV were successfully obtained and are a promising alternative to manage depression.

Beneficial effects of arthrocen on neuroinflammation and behavior like depression in stroke in a murine model.

Stroke is a considerable reason for death, disability, socioeconomic loss, and depression in the world. Notably, many attempts to the reduction of the complications of poststroke injuries like depression have failed so far. In this study, we aimed to evaluate the anti-inflammatory effect of arthrocen, avocado/soybean unsaponifiables (ASU), in the poststroke injuries like depression improvement in a mice model. We examined the antidepressant-like effect of arthrocen using the forced swimming test and tail suspension test in mice subjected to stroke. Furthermore, immunohistochemistry of proinflammatory cytokines, IL-10 and TNF-α, and neural cell count were performed in the ischemic brain hippocampus of mice. Oral arthrocen reduced significantly (p< .001) the immobility time in the forced swimming test and tail suspension test in the stroke animals. Also, immunohistochemistry analysis of the hippocampus indicated significantly (p< .01) the reduction of IL-10 and TNF-α cytokines production. Nissl staining showed a significant (p< .0001) increase in the number of viable neurons in stroke mice receiving arthrocen. In conclusion, our data revealed the antidepressant activity of arthrocen in the stroke mice which may be the result of its anti-inflammatory and neuroprotective role.

Synthesis and antidepressant activity of novel 1-(1-benzoylpiperidin-4-yl) methanamine derivatives selectively targeting SSRI/5-HT1A

A series of novel 1-(1-benzoylpiperidin-4-yl) methanamine derivatives were synthesized and evaluated for the serotonin reuptake inhibitory abilities and binding affinities to the 5-HT1A receptor. The metabolic stabilities of these compounds were measured in vitro using human or mouse liver microsomes and the antidepressant activities were explored In vivo using the forced swimming test (FST) and tail suspension test (TST) in mice. The results indicated that the compound 12a exhibited strongest serotonin reuptake inhibition (IC50 = 8.2 nM) and marked 5-HT1A receptor affinity (Ki = 0.069 nM), which were significantly superior to lead compounds Ⅰ and Ⅱ. Meanwhile, compound 12a showed good metabolic stability in vitro and exhibited potential antidepressant-like effects in the FST and TST in mice.

The antidepressant-like effect of guanosine involves the modulation of adenosine A1 and A2A receptors.

Guanosine has been considered a promising candidate for antidepressant responses, but if this nucleoside could modulate adenosine A1 (A1R) and A2A (A2AR) receptors to exert antidepressant-like actions remains to be elucidated. This study investigated the role of A1R and A2AR in the antidepressant-like response of guanosine in the mouse tail suspension test and molecular interactions between guanosine and A1R and A2AR by docking analysis. The acute (60min) administration of guanosine (0.05mg/kg, p.o.) significantly decreased the immobility time in the tail suspension test, without affecting the locomotor performance in the open-field test, suggesting an antidepressant-like effect. This behavioral response was paralleled with increased A1R and reduced A2AR immunocontent in the hippocampus, but not in the prefrontal cortex, of mice. Guanosine-mediated antidepressant-like effect was not altered by the pretreatment with caffeine (3mg/kg, i.p., a non-selective adenosine A1R/A2AR antagonist), 8-cyclopentyl-1,3-dipropylxanthine (DPCPX - 2mg/kg, i.p., a selective adenosine A1R antagonist), or 4-(2-[7-amino-2-{2-furyl}{1,2,4}triazolo-{2,3-a}{1,3,5}triazin-5-yl-amino]ethyl)-phenol (ZM241385 - 1mg/kg, i.p., a selective adenosine A2AR antagonist). However, the antidepressant-like response of guanosine was completely abolished by adenosine (0.5mg/kg, i.p., a non-selective adenosine A1R/A2AR agonist), N-6-cyclohexyladenosine (CHA - 0.05mg/kg, i.p., a selective adenosine A1 receptor agonist), and N-6-[2-(3,5-dimethoxyphenyl)-2-(methylphenyl)ethyl]adenosine (DPMA - 0.1mg/kg, i.p., a selective adenosine A2A receptor agonist). Finally, docking analysis also indicated that guanosine might interact with A1R and A2AR at the adenosine binding site. Overall, this study reinforces the antidepressant-like of guanosine and unveils a previously unexplored modulation of the modulation of A1R and A2AR in its antidepressant-like effect.