Anxiolytic Behavior Research Articles

CTCF in parvalbumin-expressing neurons regulates motor, anxiety and social behavior and neuronal identity

CCCTC-binding factor (CTCF) is a regulator of chromatin organization and has direct effects on gene transcription. Mutations in CTCF have been identified in individuals with neurodevelopmental conditions. There are wide range of behaviors associated with these mutations, including intellectual disabilities, changes in temperament, and autism. Previous mice-model studies have identified roles for CTCF in excitatory neurons in specific behaviors, particularly in regards to learning and memory. However, the role of CTCF in inhibitory neurons is less well defined. In the current study, specific knockout of CTCF in parvalbumin-expressing neurons, a subset of inhibitory neurons, induced a specific behavioral phenotype, including locomotor abnormalities, anxiolytic behavior, and a decrease in social behavior. The anxiolytic and social abnormalities are detected before the onset of locomotor abnormalities. Immunohistochemical analysis revealed a disbalance in parvalbumin-expressing and somatostatin-expressing cells in these mice. Single nuclei RNA sequencing identified changes in gene expression in parvalbumin-expressing neurons that are specific to inhibitory neuronal identity and function. Electrophysiology analysis revealed an enhanced inhibitory tone in the hippocampal pyramidal neurons in knockout mice. These findings indicate that CTCF in parvalbumin-expressing neurons has a significant role in the overall phenotype of CTCF-associated neurodevelopmental deficits.

Peroxiredoxin 6 Overexpression Induces Anxiolytic and Depression-Like Behaviors by Regulating the Serotonergic Pathway in Mice.

Peroxiredoxin 6 (PRDX6) is a bifunctional protein with both glutathione peroxidase and calcium-independent phospholipase activity. Recently, we reported that PRDX6 plays an important role in dopaminergic neurodegeneration in Parkinson’s disease. However, the relationship between PRDX6 function and emotional behavior remains elusive. In the present study, we examined depression- and anxiety-like behaviors in PRDX6-overexpressing transgenic (PRDX6-Tg) mice using the forced swim test, tail suspension test, open field paradigm, and elevated plus-maze. PRDX6-Tg mice exhibited depression-like behaviors and low anxiety. In particular, female PRDX6-Tg mice exhibited anxiolytic behavior in the open field test. Furthermore, the serotonin content in the cortex and 5-hydroxytryptophan-induced head twitch response were both reduced in PRDX6-Tg mice. Interestingly, levels of dopa decarboxylase expression in the cortex were decreased in male PRDX6-Tg mice but not in female mice. Our findings provide novel insights into the role of PRDX6 in 5-HT synthesis and suggest that PRDX6 overexpression can induce depression-like behaviors via downregulation of the serotonergic neuronal system.

Sex- and Genotype-Dependent Nicotine-Induced Behaviors in Adolescent Rats with a Human Polymorphism (rs2304297) in the 3′-UTR of the CHRNA6 Gene

In human adolescents, a single nucleotide polymorphism (SNP), rs2304297, in the 3′-UTR of the nicotinic receptor subunit gene, CHRNA6, has been associated with increased smoking. To study the effects of the human CHRNA6 3′-UTR SNP, our lab generated knock-in rodent lines with either C or G SNP alleles. The objective of this study was to determine if the CHRNA6 3′-UTR SNP is functional in the knock-in rat lines. We hypothesized that the human CHRNA6 3′-UTR SNP knock-in does not impact baseline but enhances nicotine-induced behaviors. For baseline behaviors, rats underwent food self-administration at escalating schedules of reinforcement followed by a locomotor assay and a series of anxiety tests (postnatal day (PN) 25-39). In separate cohorts, adolescent rats underwent 1- or 4-day nicotine pretreatment (2×, 30 μg/kg/0.1 mL, i.v.). After the last nicotine injection (PN 31), animals were assessed behaviorally in an open-field chamber, and brain tissue was collected. We show the human CHRNA6 3′-UTR SNP knock-in does not affect food reinforcement, locomotor activity, or anxiety. Further, 4-day, but not 1-day, nicotine exposure enhances locomotion and anxiolytic behavior in a genotype- and sex-specific manner. These findings demonstrate that the human CHRNA6 3′-UTR SNP is functional in our in vivo model.

Impaired initial development and behavior in zebrafish exposed to environmentally relevant concentrations of widely used pesticides

Pesticides reach water bodies through different routes, either owing to incorrect packaging disposal, direct application to control macrophytes, leaching from fields, or natural degradation processes. In the aquatic environment, adverse effects in non-target species that come in contact with these substances are poorly understood. Currently, the most used pesticides are glyphosate (GBH) and 2,4-dichlorophenoxyacetic acid-based herbicides (DBH), as its presence in water bodies is already known, we used environmental concentrations and our exposure time comprised the entire period of organogenesis (3-120 h post-fertilization). We evaluated the response of embryos in their early development with the parameters of mortality, hatching, spontaneous movement, and heart rate; and it's through behavior the open field test and aversive stimulus, as well as biochemical analyzes of acetylcholinesterase activity (AChE), catalase (CTL) and superoxide dismutase (SOD) as a possible mechanism of action. Exposure to GBH decreased survival, caused hypermobility and anxiolytic behavior, negatively affected the anti-predatory behavior of the larvae, and increases acetylcholinesterase activity, whereas exposure to DBH caused only slight hypermobility in the larvae and increases acetylcholinesterase activity. These changes may compromise the perpetuation of the species, the search for partners/food, and facilitate the action of predators, which can result in serious ecological consequences.

Comparative assessment of organic and inorganic tea leaf extract feeding on anxiety behaviour status of colchicine-induced rat model of Alzheimer's disease.

Tea (Camellia sinensis), having anti-inflammatory, antioxidant, and free radical scavenging properties, may be beneficial to prevent the symptoms of neurodegenerative disorders like Alzheimer's disease (AD). In this present study, field experiments using the productive tea clone (TV25) with four nutrient management treatments were conducted during 2015 to 2017 in the research farm of Agricultural and Food Engineering Department, Indian Institute of Technology Kharagpur. The four nutrient management treatments were no application of fertilizer (control), organic fertilizer (OF), inorganic fertilizer (IF), and integration of OF and IF (IF + OF). The contents of different catechins of tea leaves grown under these treatments were measured using High Performance Liquid Chromatography. Tea leaf samples of these treatments were fed to the intracerebroventricular (ICV) colchicine administered rats. The animal study was double-blinded and randomized. Assessment of anxiety status was done for the rat model in an elevated open field with a novel object in two intervals (14-day and 21-day study). Anxiolytic behaviour with the lower corticosterone (CORT) level (82ng/ml) was observed in ICV colchicine administered rat models of AD. After feeding of organically and inorganically grown tea extract (10, 20, and 30mg/kg) for 14days and 21days, it was found that the anxiolytic behaviour decreased with the increased concentration of serum CORT. However, organic tea showed greater increase in CORT level (216.1ng/ml) as compared to inorganic tea (214ng/ml). Thus, this study showed organic tea may act as a favourable agent or adjuvant in the improvement of the anxiolytic behaviour in rat model of AD.

The Slack Channel Regulates Anxiety-Like Behaviors via Basolateral Amygdala Glutamatergic Projections to Ventral Hippocampus.

Anxiety disorders are a series of mental disorders characterized by anxiety and fear, but the molecular basis of these disorders remains unclear. In the present study, we find that the global Slack KO male mice exhibit anxious behaviors, whereas the Slack Y777H male mice manifest anxiolytic behaviors. The expression of Slack channels is rich in basolateral amygdala (BLA) glutamatergic neurons and downregulated in chronic corticosterone-treated mice. In addition, electrophysiological data show enhanced excitability of BLA glutamatergic neurons in the Slack KO mice and decreased excitability of these neurons in the Slack Y777H mice. Furthermore, the Slack channel deletion in BLA glutamatergic neurons is sufficient to result in enhanced avoidance behaviors, whereas Kcnt1 gene expression in the BLA or BLA-ventral hippocampus (vHPC) glutamatergic projections reverses anxious behaviors of the Slack KO mice. Our study identifies the role of the Slack channel in controlling anxious behaviors by decreasing the excitability of BLA-vHPC glutamatergic projections, providing a potential target for anxiolytic therapies.SIGNIFICANCE STATEMENT Anxiety disorders are a series of mental disorders characterized by anxiety and fear, but the molecular basis of these disorders remains unclear. Here, we examined the behaviors of loss- and gain-of-function of Slack channel mice in elevated plus maze and open field tests and found the anxiolytic role of the Slack channel. By altering the Slack channel expression in the specific neuronal circuit, we demonstrated that the Slack channel played its anxiolytic role by decreasing the excitability of BLA-vHPC glutamatergic projections. Our data reveal the role of the Slack channel in the regulation of anxiety, which may provide a potential molecular target for anxiolytic therapies.

GABAA receptor participation in anxiolytic and anticonvulsant effects of (E)-3-(furan-2-yl)-1-(2hydroxy-3,4,6-trimethoxyphenyl)prop-2-en-1-one in adult zebrafish

Anxiety is a mental disorder that affects 25% of patients with epilepsy, and treatments for anxiety and seizures involve the use of benzodiazepines, a class of drugs that have many adverse effects such as decreased motor coordination, drowsiness, and sedation. Thus, new types of drugs with minimal side effects are of immediate requirement. Chalcones comprise a class of compounds with important therapeutic potential and have recently been investigated for their potential as anxiolytic and anticonvulsant agents. Therefore, this study aimed to evaluate the anxiolytic and anticonvulsant effects of the synthetic chalcone (E)-3-(furan-2-yl)-1-(2hydroxy-3,4,6-trimethoxyphenyl)prop-2-en-1-one (FURCHAL) using adult zebrafish as an animal model. Anxiolytic potential was assessed using the light/dark test and the anticonvulsant effect in 3-stage pentylenetetrazol (PTZ)-induced seizure tests. The mechanisms of the anxiolytic effect were analyzed using γ-aminobutyric acid (GABA) and the serotoninergic system. The anxiolytic effect of FURCHAL was verified by a reduction in fish locomotion, similar to diazepam (DZP), which may involve the GABAA receptor, as there was no reversal in the anxiolytic behavior of animals treated with FURCHAL by serotonergic antagonists. In addition, pretreatment with flumazenil blocked the anticonvulsant effect of FURCHAL and DZP at all three stages, indicating that FURCHAL also has anticonvulsant effects and that the presence of the α,β unsaturated aromatic system and heterocyclic moiety in FURCHAL provided greater affinity for the GABAA receptors. Molecular docking revealed that the interactions involved in the formation of the protein-binding complex FURCHAL-GABAA are formed by three H-bonds involving the oxygen atoms of FURCHAL, and notably, complexes operated in the same region of the DZP site. Thus, this study adds new evidence and highlights that FURCHAL can potentially be used to develop compounds with anxiolytic and anticonvulsant properties.

Structural and spectroscopic analysis, ADMET study, and anxiolytic-like effect in adult zebrafish (Danio rerio) of 4′-[(1E,2E)-1-(2-(2′,4′-dinitrophenyl)hydrazone-3-(4-methoxyphenyl)allyl)aniline

Benzodiazepines (GABA receptor agonists) and serotonin reuptake inhibitors (SSRIs) are the drugs of choice for the treatment of anxiety. However, they have considerable adverse effects, so it is important to discover new anxiolytic agents. In this work, the 4′-[(1E,2E)-1-(2-(2′,4′-dinitrophenyl)hydrazone-3-(4-methoxyphenyl)allyl)aniline (HYDRAZDN) was synthesized and characterized by 1H and 13C NMR, 2D-NMR, ATR-FTIR, FT-Raman, and UV–Vis spectroscopy, and their structural and spectroscopic proprieties were evaluated by quantum chemistry theoretical calculations. Properties such as drug-likeness and pharmacokinetics were also estimated. The anxiolytic-like effect of the compound was also evaluated using adult zebrafish (Danio rerio). The results showed that the HYDRAZDN compound caused a reduction in zebrafish locomotor activity and induced maximum permanence of zebrafish in the clear zone at a dose of 40 mg/kg, an effect similar to the effect of positive control diazepam (DZP: 40 mg/kg). To identify the mechanism of action of the anxiolytic effect of this compound, we used flumazenil, an antagonist at the benzodiazepine binding site at GABAA receptors. The treatment with the highest dose of HYDRAZDN (40 mg/kg) and DZP (40 mg/kg) caused anxiolytic behavior in the animals that spent most of their time in the dark region of the aquarium. This effect was reduced by flumazenil, indicating that anxiolytic activity of the synthesized hydrazone occurs through the GABAergic system.

Exposure to acetochlor impairs swim bladder formation, induces heat shock protein expression, and promotes locomotor activity in zebrafish (Danio rerio) larvae

Acetochlor is one of the most widely used herbicides in the world, however, there are few data on the sub-lethal effects of acetochlor on early developmental stages of fish. To address this, we measured survival, deformity, swim bladder formation, embryo oxygen consumption rates, reactive oxygen species (ROS) levels, transcripts (related to swim bladder formation, oxidative damage response, and apoptosis) and behavior responses following exposure to acetochlor (0.001 µM up to 125 µM). Exposure to acetochlor at concentrations 50 µM and above exerted 100% mortality after 3 dpf, and significantly reduced the size of the swim bladder (25 µM). In embryos, basal respiration, oligomycin-induced ATP production, and maximal respiration were decreased 30–60% following a 24 h exposure to 125 μM acetochlor. Acetochlor did not affect ROS levels up to 25 µM in larvae with acute exposure. Acetochlor at 25 µM increased mRNA levels of bax1, hsp70, and hsp90a by ~4-fold in larval zebrafish. In both the visual motor response and light-dark preference test, 25 µM acetochlor increased locomotor activity of larval fish. At lower exposure concentrations, 100 and 1000 nM acetochlor increased the mean time spent in the dark zone, suggesting promotion of anxiolytic behavior. This study presents a comprehensive evaluation of sublethal effects of acetochlor, spanning molecular responses to behavior, which can be used to refine risk assessment decisions for aquatic environments.

The zebrafish (Danio rerio) anxiety test battery: comparison of behavioral responses in the novel tank diving and light\u2013dark tasks following exposure to anxiogenic and anxiolytic compounds

RationaleTriangulation of approaches (i.e., using several tests of the same construct) can be extremely useful for increasing the robustness of the findings being widely used when working with behavioral testing, especially when using rodents as a translational model. Although zebrafish are widely used in neuropharmacology research due to their high-throughput screening potential for new therapeutic drugs, behavioral test battery effects following pharmacological manipulations are still unknown.MethodsHere, we tested the effects of an anxiety test battery and test time following pharmacological manipulations in zebrafish by using two behavioral tasks: the novel tank diving task (NTT) and the light–dark test (LDT). Fluoxetine and conspecific alarm substance (CAS) were chosen to induce anxiolytic and anxiogenic-like behavior, respectively.ResultsFor non-drug-treated animals, no differences were observed for testing order (NTT → LDT or LDT → NTT) and there was a strong correlation between performances on the two behavioral tasks. However, we found that during drug treatment, NTT/LDT responses are affected by the tested order depending on the test time being fluoxetine effects higher at the second behavioral task (6 min later) and CAS effects lower across time.ConclusionsOverall, our data supports the use of baseline behavior assessment using this anxiety test battery. However, when working with drug exposure, data analysis must carefully consider time-drug-response and data variability across behavioral tasks.

Behavioral, neuroplasticity and metabolic effects of 7,8-dihydroxy-4-methylcoumarin associated with physical activity in mice.

The search for strategies to develop resilience against metabolic and neuropsychiatric disorders has motivated the clinical and experimental assessment of early life interventions such as lifestyle-based and use of unconventional pharmacological compounds. In this study, we assessed the effects of voluntary physical activity and 7,8-Dihydroxy-4-methylcoumarin (DHMC), independently or in combination, over mice physiological and behavioral parameters, adult hippocampal and hypothalamic neurogenesis, and neurotrophic factors expression in the hypothalamus. C57Bl/6J mice were submitted to a 29-day treatment with DHMC and allowed free access to a running wheel. We found that DHMC treatment alone reduced fasting blood glucose levels. Moreover, physical activity showed an anxiolytic effect in the elevated plus maze task and DHMC produced additional anxiolytic behavior, evidenced by reduced activity during the light cycle in the physical activity group. Although we did not find any differences in hypothalamic or hippocampal adult neurogenesis, DHMC increased gene expression levels of VEGF, which was correlated to the reduced fasting glucose levels. In conclusion, our data emphasize the potential of physical activity in reducing development of neuropsychiatric conditions, such as anxiety, and highlights DHMC as an attractive compound to be investigated in future studies addressing neuropsychiatric disorders associated with metabolic conditions.

RNA-seq co-expression network analysis reveals anxiolytic behavior of mice with Efnb2 knockout in parvalbumin+\u2009neurons

Anxiety disorders are the most common psychiatric disorders, and the change in the activity of the prefrontal cortex (PFC) is considered as the underlying pathological mechanism. Parvalbumin-expressing (PV+) inhibition contributes to the overall activity of the PFC. However, the molecular mechanism underlying the excitation-inhibition imbalance of PV+ neurons in the PFC is unknown. Efnb2 is a membrane-bound molecule that plays an important role in the nervous system through binding the Eph receptor. To investigate whether the loss of Efnb2 in PV+ affects anxiety, we examined the behavior of wild type and Efnb2 in PV+ neurons knockout (KO) mice. We monitored the defensive responses to aversive stimuli of elevated plus maze (EPM) and found that KO mice exhibited obvious fearless and anxiolytic behaviors. To further investigate the underlying regulatory mechanism, we performed RNA sequencing, analyzed the differentially expressed genes (DEGs), and constructed the weighted gene co-expression network analysis (WGCNA). The WGCNA identified 12 characteristic modules. Among them, the MEgreen module showed the most significant correlation with KO mice of EPM stimuli. The Gene Ontology enrichment and the Kyoto Encyclopedia of Genes and Genomes enrichment analysis revealed that this was related to the distal axon, Ras signaling pathway and insulin signaling pathway. Furthermore, the whole-cell voltage clamp recordings also proved that Efnb2 gene knock-out could affect synaptic function. Together with the transcriptomic analysis of mice with Efnb2 knockout on PV+ neurons, our findings suggest that Efnb2 gene in the PV+ neuron of PFC may be a crucial factor for fear and anxiety, which provide an insight into anxiety pathophysiology.

Cognitive deficits in episodic ataxia type 2 mouse models.

Episodic ataxia type 2 (EA2) is a rare autosomal dominant disorder characterized by motor incoordination, paroxysmal dystonia, vertigo, nystagmus and more recently cognitive deficits. To date over 100 mutations in the CACNA1A gene have been identified in EA2 patients leading to a loss of P/Q-type channel activity, dysfunction of cerebellar Purkinje cells and motor incoordination. To determine if the cerebellum is contributing to these cognitive deficits, we examined two different EA2 mouse models for cognition impairments where CACNA1A was removed specifically from cerebellar Purkinje or granule cells postnatally. Both mutant mouse models showed anxiolytic behavior to lighted, open areas in the open field and light/dark place preference tests but enhanced anxiousness in the novel suppressed feeding test. However, EA2 mice continued to show augmented latencies in the light/dark preference test and when the arena was divided into two dark zones in the dark/dark preference test. Moreover, increased latencies were also displayed in the novel object recognition test, indicating that EA2 mice are indecisive and anxious to explore new territories and objects and may have memory recognition deficits. Exposure to a foreign mouse led to deficiencies in attention and sniffing as well as in social and genital sniffing. These data suggest that postnatal removal of the P/Q type calcium channel from the cerebellum regulates neuronal activity involved in anxiety, memory, decision making and social interactions. Our EA2 mice will provide a model to identify the mechanisms and therapeutic agents underlying cognitive and psychiatric disorders seen in EA2 patients.

A role of noradrenergic receptors in anxiolytic-like effect of high CRF in the rat frontal cortex

Corticotropin releasing factor (CRF) is a neuropeptide widely distributed in the brain as a hormonal modulator and neurotransmitter. The best known behavioral function of CRF is activation of stress and anxiety via the hypothalamus and limbic structures but the role of CRF in the cortex is still poorly understood. Our previous studies have shown anxiolytic-like effects of high doses of CRF injected into the Fr2 frontal cortex and involvement of CRF1 receptors (R) in that effect. These results seemed to be controversial as most other studies suggested anxiogenic and not anxiolytic effects of CRF1R stimulation. Since stress is associated with adrenergic system, in the present study, we focused on participation of alpha1 and alpha2 or beta adrenergic receptors in the anxiolytic-like effect of CRF. Moreover, we verified whether these effects of CRF in the Fr2 were really connected with CRF1R.Male Wistar rats were bilaterally microinjected with CRF in a dose of 0.2 μg/1 μl/site or with the specific agonist of CRF1R, stressin 1 (0.2–0.0125 μg/1 μl/site) into the Fr2 area. The elevated plus maze (EPM) test was performed 30 min later to assess the anxiolysis. An involvement of noradrenergic receptors in the CRF induced anxiolytic-like effect in the Fr2 was studied by pretreatment with the alpha1 antagonist prazosin, alpha2 agonist clonidine, alpha2 antagonist RS 79948 or beta antagonist propranolol, 20–30 min before CRF. The influence on anxiety was assessed in the EPM test. The results show that anxiolytic behavior after CRF microinjection into the Fr2 area seems to be mainly connected with the CRF1R activation because a similar effect was observed after stressin 1 administration and it was blocked by CRF1R antagonist. The results observed after administration of noradrenergic ligands indicated that anxiolytic effects of CRF in the Fr2 engaged the alpha1 and alpha2 adrenergic receptors but not beta receptors.

Anxiolytic-like and antidepressant-like effects of ethanol extract of Terminalia chebula in mice

Terminalia chebula (T.chebula) fruit is referred as “King of Medicines” in Tibet and is listed as a key plant in “Ayurvedic Materia Medica” due to its diverse pharmacological activity. The present study was aimed to investigate the comorbid antidepressant-like and anxiolytic-like effects of ethanol extract from T.chebula fruit using experimental behavioral tests in mice. In addition, the study explored the effects of extract on monoamine oxidase –A (MAO-A) levels in mouse brain. Two doses of the T.chebula extract (100 or 200 mg/kg, p.o.) were treated continuously for fifteen days to mice. Regarding antidepressant-like effects, the treatment of T.chebula extract at both dose (100 or 200 mg/kg, p.o.) levels resulted with significant (p < 0.001) reduction in duration of immobility time and increase in swimming time as compared to control group in forced swimming test. Moreover, both doses declined the duration of immobility time in the tail suspension test and increased the number of crossing in the center area using open-field test. Additionally, the dose 200 mg/kg treatment showed a significant reduction (p < 0.05) in MAO-A activity in mouse brain. For anxiolytic activity, both doses significantly (p < 0.001) improved the time spent in open arm and the number of head dips in elevated plus maze test. The higher duration of time spent in light chamber and higher number of crossing between the light and dark chambers by extract treatment in light-dark box test also supported the anxiolytic behavior. The obtained results supported the antidepressant-like and anxiolytic-like effects of ethanol extract of T.chebula in mice.

Antagonization of monoamine reuptake transporters by agmatine improves anxiolytic and locomotive behaviors commensurate with fluoxetine and methylphenidate

BackgroundAgmatine (AGM) is known for its protective effects including neuroprotection, nephroprotection, gastroprotection, cardioprotection, and glucoprotection. Studies have validated the neuroprotective role of AGM as antidepressant, anxiolytic, locomotive, and antipsychotic agent in psychopathologies. Fluoxetine (FLX) is the most extensively prescribed antidepressant while methylphenidate (MPD) is the most frequently prescribed psychoactive stimulant for ADHD (attention deficit hyperactivity disorder) treatment worldwide. The mechanism of action of FLX and MPD involves reuptake inhibition of serotonin and dopamine and norepinephrine at presynaptic transporters. Present study was designed to determine the safety and efficacy of AGM administration along with conventional antidepressant and psychostimulative drugs. The study also aimed to establish underlying mechanism of action of AGM at monoamine reuptake transporters.ResultsAGM significantly ameliorated locomotion in activity box and open field while anxiolytic behaviors in light/dark transition box and EPM were also improved (p<0.01). The growth and appetite of animals were enhanced along with antidepressive behavior in FST (p<0.01). Moreover, co-administration of AGM with FLX or MPD improved rats’ behaviors as compared to single AGM administration.ConclusionPresent study determined the significant anxiolytic, locomotor, and antidepressive effects of AGM compared with FLX and MPD. The study also showed improved behaviors of rats treated with combined doses of AGM with FLX or MPD along with food intake and body weights. This study has also proposed the potential mechanism of action of AGM at monoamine receptors that may lead to inhibition of monoamine reuptake transporters that may lead to increase in 5-HT, D, and NE concentrations at synaptic level.

The Potential of Parsley Polyphenols and Their Antioxidant Capacity to Help in the Treatment of Depression and Anxiety: An In Vivo Subacute Study.

Depression and anxiety are major mental health problems in all parts of the world. These illnesses are associated with a number of risk factors, including oxidative stress. Psychotropic drugs of a chemical nature have demonstrated several side effects that elevated the impact of those illnesses. Faced with this situation, natural products appear to be a promising alternative. The aim of this study was to evaluate the anxiolytic and antidepressant effects of the Petroselinum sativum polyphenols in vivo, as well as its correlated antioxidant properties in vitro. Anxiolytic activity of the extract (50 and 100 mg/kg) was evaluated using the open field and the light-dark chamber tests, while the antidepressant activity was evaluated using the forced swimming test. The antioxidant activity of the extract was evaluated by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical test and the FRAP (iron-reducing capacity) test. The phenolic extract showed very powerful anxiolytic and antidepressant-like effects, especially at a dose of 100 mg/kg, decreasing the depressive behavior in mice (decreased immobility time) and also the anxiolytic behavior (tendency for discovery in the center and illuminated areas) better even than those of paroxetine and bromazepam (classic drugs) concomitant with those results the extract also showed an important antioxidant capacity. These preliminary results suggest that Petroselinum sativum exhibits anxiolytic and antidepressant potential for use as a complement or independent phytomedicine to treat depression and anxiety.

Grewia asiatica Berry Juice Diminishes Anxiety, Depression, and Scopolamine-Induced Learning and Memory Impairment in Behavioral Experimental Animal Models.

Grewia asiatica L. fruit natively called phalsa is a popular berry of Pakistan and widely consumed in the form of fresh juices and carbonated drinks in the summer season. The berry is enriched with antioxidants such as phenols, flavonoids, anthocyanins, and vitamin C. Scientifically, it is the least explored berry in terms of neuromodulatory activities, and therefore, in the designed study, chronically fed rats with the different dilutions (5%−30%) of fruit juice were subjected to behavioral assessment for anxiety, depression, and cognition (spatial memory) followed by biochemical analysis of isolated brains. Results revealed a prominent impact of 20 and 30% dilutions of fruit exudate as treated animals showed anxiolytic behavior to central zone (P < 0.05) of open field test (OFT) and open arms of elevated plus maze (EPM) (P < 0.05) in anxiety models. Overall, immobility of rats treated with a higher concentration of exudate in forced swim test (FST) was reduced (P < 0.05) presenting antidepressant-like activity. Moreover, in learning and memory experimental models, the treated animals reversed scopolamine-induced amnesic effects as evident from improved step-through latencies (P < 0.05 vs. scopolamine; passive avoidance test), spontaneous alternation behavior (P < 0.05 vs. scopolamine; Y-maze test), discrimination index (P < 0.05 vs. scopolamine; novel object recognition test), and escape latencies (P < 0.05 vs. scopolamine; Morris water maze). Biochemical studies of isolated brains from treated rats demonstrated significantly elevated levels of superoxide dismutase and glutathione peroxidase (P < 0.05), whereas levels of acetylcholinesterase and malondialdehyde level (P < 0.05) were reduced, indicating its potential to reduce oxidative damage in the brain and modulation with the cholinergic system. The outcomes of studies support the benefits of phytoconstituents possessed by G. asiatica fruit in the amelioration of neurological disorders that could be due to their antioxidative capacity or due to interaction with GABAergic, serotonergic, and cholinergic systems in the brain.

Induction of anxiolytic, antidepressant and analgesic effects by Shiff base of (E)-3-(1H-imidazol-4-yl)-2-((2-oxoindolin-3-ylidene)amino)propanoic acid derivatives in diabetic rats.

Diabetes mellitus is a metabolic disorder with several psychological problems such as anxiety, depression, and pain sense. This study aimed to evaluate the effect of Schiff base on the modulation of anxiety, depression, and pain behaviors in diabetic rats. Anxiety, depression, and pain behaviors were evaluated by elevated plus maze (EPM), forced swim test (FST), and hot-plate test, respectively. The results indicated that induction of diabetes decreased time spent in open arms (OAT) in the EPM whereas injection of insulin (1ml/kg), glibenclamide (5mg/kg), and Schiff base II (100mg/kg) increased OAT in the EPM. So, induction of diabetes in rats caused an anxiogenic effect that this effect reversed by drug treatment. Interestingly, co-treatment of insulin and glibenclamide along with an ineffective dose of Schiff base II potentiated anxiolytic behavior in diabetic rats. Furthermore, induction of diabetes increased immobility time in the FST but administration of insulin (1ml/kg), glibenclamide (5mg/kg), and Schiff base II (25, 50, and 100mg/kg) decreased immobility time in the FST which indicated depressant effect in diabetic rats without drug-treatment and antidepressant effect in diabetic rats with drug-treatment. Additionally, induction of diabetes decreased latency in the hot-plate test while injection of insulin (1ml/kg), glibenclamide (5mg/kg), Schiff base I (50mg/kg), and Schiff base II (25, 50, and 100mg/kg) enhanced latency in the hot-plate test which revealed hyperalgesic effect in diabetic rats without drug-treatment and analgesic effect in diabetic rats with drug-treatment. Consequently, induction of diabetes-induced anxiogenic, depressant, and hyperalgesia effects that administration of insulin, glibenclamide, Schiff bases I, and II reversed these effects.

Duplicated dnmt3aa and dnmt3ab DNA Methyltransferase Genes Play Essential and Non-Overlapped Functions on Modulating Behavioral Control in Zebrafish.

DNA methylation plays several roles in regulating neuronal proliferation, differentiation, and physiological functions. The major de novo methyltransferase, DNMT3, controls the DNA methylation pattern in neurons according to environmental stimulations and behavioral regulations. Previous studies demonstrated that knockout of Dnmt3 induced mouse anxiety; however, controversial results showed that activation of Dnmt3 causes anxiolytic behavior. Thus, an alternative animal model to clarify Dnmt3 on modulating behavior is crucial. Therefore, we aimed to establish a zebrafish (Danio rerio) model to clarify the function of dnmt3 on fish behavior by behavioral endpoint analyses. We evaluated the behaviors of the wild type, dnmt3aa, and dnmt3ab knockout (KO) fish by the novel tank, mirror biting, predator avoidance, social interaction, shoaling, circadian rhythm locomotor activity, color preference, and short-term memory tests. The results indicated that the dnmt3aa KO fish possessed abnormal exploratory behaviors and less fear response to the predator. On the other hand, dnmt3ab KO fish displayed less aggression, fear response to the predator, and interests to interact with their conspecifics, loosen shoaling formation, and dysregulated color preference index ranking. Furthermore, both knockout fishes showed higher locomotion activity during the night cycle, which is a sign of anxiety. However, changes in some neurotransmitter levels were observed in the mutant fishes. Lastly, whole-genome DNA methylation sequencing demonstrates a potential network of Dnmt3a proteins that is responsive to behavioral alterations. To sum up, the results suggested that the dnmt3aa KO or dnmt3ab KO fish display anxiety symptoms, which supported the idea that Dnmt3 modulates the function involved in emotional control, social interaction, and cognition.