Utilization of antidepressants, anxiolytics, and hypnotics during the COVID-19 pandemic.

Since the onset of the COVID-19 pandemic, there have been concerns over the mental health impact of COVID-19. This is a review of the utilization of antidepressants, anxiolytics, and hypnotics since the COVID-19 pandemic was declared on March the 11th 2020. A number of reports so far have been based on large prescription databases for administrative use at the national or regional level, but mainly in high-income countries. We found studies reporting increased prescription rates of antidepressants, anxiolytics, and hypnotics during March 2020, which has been interpreted as hoarding of such medications. In the following months, most studies of antidepressant prescription rates did not display a clear pattern of change compared with prepandemic trends. In later phases of the pandemic small increases in utilization of antidepressants, with higher than predicted prescription rates, have been the most consistent finding, especially in youth. In most high-income countries, there were increasing trends in utilization of antidepressants also before 2020, which needs to be considered when estimating utilization during the pandemic, whereas for anxiolytics and hypnotics, the prepandemic patterns of prescriptions were more varying. Overall, after March 2020 we could not find any distinct changes in the utilization of anxiolytics and hypnotics during the COVID-19 pandemic. Most studies did not contain information about the prevalence of indicated psychiatric disorders in the studied populations. More studies are needed about the long-term effects of COVID-19, particularly regarding utilization of antidepressants. Research relating antidepressant utilization with the prevalence of major depression and anxiety disorders would promote a better understanding of how well antidepressant prescription rates reflect the needs of the population.

Repeated finasteride administration promotes synaptic plasticity and produces antidepressant- and anxiolytic-like effects in female rats.

Finasteride is used in female-pattern hair loss, hirsutism, and polycystic ovarian syndrome. It inhibits 5α-reductase, which is an important enzyme in the biosynthesis of neurosteroids. The effects of finasteride treatment on mental health in female patients as well as the effects of repeated/chronic finasteride administration in female rodents are still unknown. Accordingly, in our study, we administered finasteride (10, 30, or 100 mg/Kg, s.c.) for 6 days in female rats and evaluated behavior, plasma steroid levels, and synaptic plasticity. Depression-like behavior was evaluated using forced swim test (FST) and splash test. Anxiety-like behavior was evaluated using novelty-suppressed feeding task (NSFT), elevated plus maze (EPM), open field test (OFT), and light-dark test (LDT). Plasma steroid levels were assessed using ELISA and synaptic plasticity by field potential recordings. We observed that finasteride decreased total immobility duration in FST, indicating antidepressant-like effect and decreased the latency to first bite in NSFT, showing anxiolytic-like effect. We also found a significant increase in plasma estradiol and a significant decrease in plasma corticosterone level. Furthermore, field potential recordings showed that finasteride increased hippocampal long-term potentiation. These results indicate that repeated finasteride administration in female rats may have antidepressant- and anxiolytic-like effect, which might be mediated by enhanced estradiol levels or decreased corticosterone levels. Further studies are required to validate the molecular mechanisms underlying the effects of finasteride in female rats. Understanding the mechanisms will help us in developing novel neurosteroid-based therapeutics in the treatment of neuropsychiatric disorders in women.

The application of drug behavior management methods in the treatment of dental fear and oral diseases in children: A review.

Oral behavior management methods include basic behavior management methods and drug behavior management methods. In many cases, dental treatment that cannot be done simply through basic behavior management is not possible. The uncooperative behavior of children with dental fear in oral treatment has increased the demand for medication based behavior management methods. Drug sedation can provide more effective analgesic and anti-anxiety effects, thereby helping to provide comfortable, efficient, and high-quality dental services. This article will review the drug sedation methods selected in clinical treatment of pediatric dental fear in recent years, as well as the safety and effectiveness of commonly used drugs, in order to provide guidance for dental professionals in clinical practice.

Nitric Oxide (NO) Synthase Inhibitors: Potential Candidates for the Treatment of Anxiety Disorders?

Close to 19% of the world population suffers from anxiety. Current medications for this chronic mental disorder have improved treatment over the last half century or more, but the newer anxiolytics have proved disappointing, and enormous challenges remain. Nitric oxide (NO), an intra- and inter-cellular messenger in the brain, is involved in the pathogenesis of anxiety. In particular, excessive NO production might contribute to its pathology. This implies that it might be useful to reduce nitrergic activity; therefore, molecules aiming to downregulate NO production such as NO synthase inhibitors (NOSIs) might be candidates. Here, it was intended to critically review advances in research on these emerging molecules for the treatment of anxiety disorders. Current assessment indicates that, although NOSIs are implicated in anxiety, their potential anti-anxiety action remains to be established.

Baseline symptom severity and efficacy of Silexan in patients with anxiety disorders: A symptom-based, patient-level analysis of randomized, placebo-controlled trials.

The influence of baseline severity on the efficacy of Silexan, a proprietary essential oil from Lavandula angustifolia, in anxiety disorders has not been investigated in a pooled dataset. We report on an individual patient data analysis of all five double-blind, randomized, placebo-controlled trials with Silexan in anxiety disorders. Eligible participants received Silexan 80 mg/d or placebo for 10 weeks. Analyses were based on the Hamilton Anxiety Rating Scale (HAMA), its psychic and somatic anxiety subscores, and the Clinical Global Impressions (CGI) scale. To correlate baseline severity with outcome, patients were segregated into mild, moderate, and severe cases. Altogether 1,172 patients (Silexan, n = 587; placebo, n = 585) were analyzed. For the HAMA total score, we found a significant association between the score at baseline and the treatment effect of Silexan versus placebo at week 10 (p < 0.001). HAMA items from the somatic domain scored lower at baseline and showed less improvement than items from the psychic domain, particularly in patients with mild or moderate baseline symptoms. For CGI item 2 (global improvement), significant efficacy favoring Silexan were observed in mild, moderate, and severe baseline symptom severity. Although significant improvements were found for all subsets, the more severe the initial symptoms, the greater the treatment effects documented by the HAMA. Overall this analysis confirms that Silexan is an effective treatment option in early or mild stages of anxiety disorder. Given its favorable safety profile, Silexan can thus fill a therapeutic gap in the treatment of (subsyndromal) anxiety disorders.

Effect of high-intensity interval training on self-care and anxiety-like behaviors in naive rats.

Self-care behavior covers individual's health, life and well-being to maintain the necessary activities. The aim of this study is to examine the self-care and possible anxiolytic effects of high-intensity interval exercise (HIIT). Eight-week-old Wistar Albino male rats were divided into Control (n = 8), and Exercise (n = 8). Rat exercised for 38 min a day, 5 days a week, for 8 weeks The animals were then subjected to open field test and splash test, and the behaviors were video recorded. Student t test and Shapiro-Wilk test were used as statistical tests. In the exercise group, spray-induced grooming behavior increased significantly in terms of duration and frequency (p < 0.05), but no significant difference was observed in the latency of grooming (p > 0.05). In the open-field test, the total distance traveled, which is a locomotor activity parameter, did not change between the groups. Anxiolytic-like behaviors such as total rearing behavior, unsupported rearing, central time, and central region entries increased remarkably in the exercise group vs. control (p < 0.0001). Freezing as an anxiogenic behavior decreased in the exercise group positively (p < 0.0001). Intermittent high-intensity exercise improved and increased self-care behaviors. Further, the present study shows that HIIT has beneficial effects on different aspects of behaviors such as exploratory behaviors, increasing anxiolytic behaviors, and reducing anxiogenic behavior. The present study is a preclinical study that will pave the way for new studies.

Efficacy and safety of venlafaxine hydrochloride combined with tandospirone citrate for patients with vascular depression accompanied by somatic symptoms: An open-labeled randomized control trial.

AIMS: To explore the pharmacological treatment of vascular depression (VaDep) and whether the blood levels of neurotransmitters can reflect the VaDep severity. METHODS: VaDep patients with somatic symptoms were enrolled and randomly received venlafaxine + tandospirone (Combined Group) or venlafaxine (Monotherapy Group). The treatment efficacy was assessed by Hamilton Depression Scale (HAMD), Hamilton Anxiety Scale (HAMA), and Patient Health Questionnaire-15 (PHQ-15). The levels of blood monoamine neurotransmitters were measured by enzyme-linked immunosorbent assay. RESULTS: Both groups reported a progressive decrease in HAMD, HAMA, and PHQ-15 scores to below the baseline after the respective treatment. Compared with the Monotherapy Group, the Combined Group reported a significant decrease in HAMD score at week 2 and markedly lower HAMA and PHQ-15 scores at weeks 1, 2, 4, and 8. Both groups showed a decrease in the levels of blood monoamine neurotransmitters at weeks 4 and 8 when compared with the baseline. A strong positive association was evident between the plasma 5-HT levels and the HAMD score. CONCLUSION: The combined therapy rapidly acts on VaDep comorbid with anxiety and somatic symptoms and significantly alleviates the anxiety and somatic symptoms. The plasma levels of 5-HT may serve as potential objective candidates in evaluating VaDep severity and the efficacy of the undertaken treatment regimen.

The avBNSTGABA-VTA and avBNSTGABA-DRN pathways are respectively involved in the regulation of anxiety-like behaviors in parkinsonian rats.

The anteroventral bed nucleus of stria terminalis (avBNST) is a key brain region which involves negative emotional states, such as anxiety. The most neurons in the avBNST are GABAergic, and it sends GABAergic projections to the ventral tegmental area (VTA) and the dorsal raphe nucleus (DRN), respectively. The VTA and DRN contain dopaminergic and serotonergic cell groups in the midbrain which regulate anxiety-like behaviors. However, it is unclear the role of GABAergic projections from the avBNST to the VTA and the DRN in the regulation of anxiety-like behaviors, particularly in Parkinson's disease (PD)-related anxiety. In the present study, unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra pars compacta in rats induced anxiety-like behaviors, and decreased level of dopamine (DA) in the basolateral amygdala (BLA). Chemogenetic activation of avBNSTGABA-VTA or avBNSTGABA-DRN pathway induced anxiety-like behaviors and decreased DA or 5-HT release in the BLA in sham and 6-OHDA rats, while inhibition of avBNSTGABA-VTA or avBNSTGABA-DRN pathway produced anxiolytic-like effects and increased level of DA or 5-HT in the BLA. These findings suggest that avBNST inhibitory projections directly regulate dopaminergic neurons in the VTA and serotonergic neurons in the DRN, and the avBNSTGABA-VTA and avBNSTGABA-DRN pathways respectively exert impacts on PD-related anxiety-like behaviors.

Research Report: A Link between Sertraline Treatment and Susceptibility to (Mis)information.

Recent research revealed that several psycho-cognitive processes, such as insensitivity to positive and negative feedback, cognitive rigidity, pessimistic judgment bias, and anxiety, are involved in susceptibility to fake news. All of these processes have been previously associated with depressive disorder and are sensitive to serotoninergic manipulations. In the current study, a link between chronic treatment with the selective serotonin reuptake inhibitor (SSRI) sertraline and susceptibility to true and fake news was examined. Herein, a sample of 1162 participants was recruited via Prolific Academic for an online study. Half of the sample reported taking sertraline (Zoloft) for at least 8 weeks (sertraline group), and the other half confirmed not taking any psychiatric medication (control group). The sertraline group was further divided according to their daily dosage (50, 100, 150, and 200 mg/day). All participants completed a susceptibility to misinformation scale, wherein they were asked to determine the veracity of the presented true and fake news and their willingness to behaviorally engage with the news. The results were compared between those of the sertraline groups and the control group. The results showed that sertraline groups did not differ significantly in the assessment of the truthfulness of information or their ability to discern the truth. However, those taking sertraline appeared to have a significantly increased likelihood of behavioral engagement with the information, and this effect was observed for both true and fake news. The research presented here represents the initial endeavor to comprehend the neurochemical foundation of the susceptibility to misinformation. The association between sertraline treatment and increased behavioral engagement with information observed in this study can be explained in light of previous studies showing positive correlations between serotonin (5-HT) system activity and the inclination to engage in social behaviors. It can also be attributed to the anxiolytic effects of sertraline treatment, which mitigate the fear of social judgment. The heightened behavioral engagement with information in people taking sertraline may, as part of a general phenomenon, also shape their interactions with fake news. Future longitudinal studies should reveal the specificity and exact causality of these interactions.

Cannabidiol exhibits anxiolytic-like effects and antipsychotic-like effects in mice models.

Cannabidiol (CBD), a non-psychoactive compound derived from the cannabis plant, has been confirmed to induce anxiolytic-like and antipsychotic-like effects. However, the exact mechanisms remain unclear. This study substantiated CBD's interaction with the 5-HT1A receptor (5-HT1AR) in vitro (CHO cells expressing human 5-HT1AR) and in vivo (rat lower lip retraction test, LLR test). We then assessed the impact of CBD in mice using the stress-induced hyperthermia (SIH) model and the phencyclidine (PCP)-induced negative symptoms of schizophrenia model, respectively. Concurrently, we investigated whether WAY-100635, a typical 5-HT1AR antagonist, could attenuate these effects. Furthermore, the neurotransmitter changes through high-performance liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) were studied. Results revealed that CBD exhibits selective 5-HT1AR agonists-mediated effects in the rat lower lip retraction test, aligning with the robust agonistic (EC50 = 1.75 µM) profile observed in CHO cells. CBD at 3 mg/kg significantly reduced SIH (ΔT), a response that WAY-100635 abolished. Chronic administration of CBD at 100 mg/kg mitigated the increase in PCP-induced immobility time in the forced swim test (FST) and tail suspension test (TST). Moreover, it induced significant alterations in gamma-aminobutyric acid (GABA) and norepinephrine (NE) levels within the hippocampus (HPC). Thus, we concluded that the 5-HT1AR mediates CBD's anxiolytic-like effects. Additionally, CBD's effects on the negative symptoms of schizophrenia may be linked to changes in GABA and NE levels in the hippocampus. These findings offer novel insights for advancing the exploration of CBD's anxiolytic-like and antipsychotic-like effects.

Potential Mechanisms of Casein Hexapeptide YPVEPF on Stress-Induced Anxiety and Insomnia Mice and Its Molecular Effects and Key Active Structure.

The hexapeptide YPVEPF with strong sleep-enhancing effects could be detected in rat brain after a single oral administration as we previously proved. In this study, the mechanism and molecular effects of YPVEPF in the targeted stress-induced anxiety mice were first investigated, and its key active structure was further explored. The results showed that YPVEPF could significantly prolong sleep duration and improve the anxiety indexes, including prolonging the time spent in the open arms and in the center. Meanwhile, YPVEPF showed strong sleep-enhancing effects by significantly increasing the level of the GABA/Glu ratio, 5-HT, and dopamine in brain and serum and regulating the anabolism of multiple targets, but the effects could be blocked by bicuculline and WAY100135. Moreover, the molecular simulation results showed that YPVEPF could stably bind to the vital GABAA and 5-HT1A receptors due to the vital structure of Tyr-Pro-Xaa-Xaa-Pro-, and the electrostatic and van der Waals energy played dominant roles in stabilizing the conformation. Therefore, YPVEPF displayed sleep-enhancing and anxiolytic effects by regulating the GABA-Glu metabolic pathway and serotoninergic system depending on distinctive self-folding structures with Tyr and two Pro repeats.

A phase III multisite randomised controlled trial to compare the efficacy of cannabidiol to placebo in the treatment of cannabis use disorder: the CBD-CUD study protocol.

BACKGROUND: Cannabis use disorder (CUD) is increasingly common and contributes to a range of health and social problems. Cannabidiol (CBD) is a non-intoxicating cannabinoid recognised for its anticonvulsant, anxiolytic and antipsychotic effects with no habit-forming qualities. Results from a Phase IIa randomised clinical trial suggest that treatment with CBD for four weeks reduced non-prescribed cannabis use in people with CUD. This study examines the efficacy, safety and quality of life of longer-term CBD treatment for patients with moderate-to-severe CUD. METHODS/DESIGN: A phase III multi-site, randomised, double-blinded, placebo controlled parallel design of a 12-week course of CBD to placebo, with follow-up at 24 weeks after enrolment. Two hundred and fifty adults with moderate-to-severe CUD (target 20% Aboriginal), with no significant medical, psychiatric or other substance use disorders from seven drug and alcohol clinics across NSW and VIC, Australia will be enrolled. Participants will be administered a daily dose of either 4 mL (100 mg/mL) of CBD or a placebo dispensed every 3-weeks. All participants will receive four-sessions of Cognitive Behavioural Therapy (CBT) based counselling. Primary endpoints are self-reported cannabis use days and analysis of cannabis metabolites in urine. Secondary endpoints include severity of CUD, withdrawal severity, cravings, quantity of use, motivation to stop and abstinence, medication safety, quality of life, physical/mental health, cognitive functioning, and patient treatment satisfaction. Qualitative research interviews will be conducted with Aboriginal participants to explore their perspectives on treatment. DISCUSSION: Current psychosocial and behavioural treatments for CUD indicate that over 80% of patients relapse within 1-6 months of treatment. Pharmacological treatments are highly effective with other substance use disorders but there are no approved pharmacological treatments for CUD. CBD is a promising candidate for CUD treatment due to its potential efficacy for this indication and excellent safety profile. The anxiolytic, antipsychotic and neuroprotective effects of CBD may have added benefits by reducing many of the mental health and cognitive impairments reported in people with regular cannabis use. TRIAL REGISTRATION: Australian and New Zealand Clinical Trial Registry: ACTRN12623000526673 (Registered 19 May 2023).

Comparison of perception of stress and consumption of anxiolytics in hospital and out-hospital conditions: a cross-sectional study.

Background: The workplace is a place where medical workers are exposed to extreme stress, particularly during medical emergencies or events of epidemic or pandemic proportions. Anxiolytic therapy is often used to overcome professional challenges. Deepening knowledge about the prevalence of the use of anxiolytics and the perception of stress among medical workers enables the timely recognition of problems and the preparation of measures to improve the working conditions and quality of life of medical workers. The study's primary objective was to investigate whether there were differences in the usage of anxiolytics among healthcare professionals in and out of the hospital. In addition to the main objective, there are other objectives that have been established: To examine whether there are statistically justified differences in stress perceptions between hospital and outpatient healthcare professionals; 2. To examine the stress factors in the workplace in both hospital and outpatient settings. To compare the frequency of taking anxiolytics with respect to various variables (age, seniority, occupation and level of education); 4. determines the impact of working conditions on stress perception and life satisfaction in healthcare professionals. The design of research: Cross-sectional research. Materials and methods: The research involved 159 healthcare professionals in Slavonski Brod: 96 employees of the General Hospital "Dr. Josip Bencevic" and 63 employees of the Health Center and the Institute for Emergency Medicine of Brodsko-Posavina County. Respondents were able to participate in the study by filling out questionnaires online. The questionnaire was designed to be voluntary and anonymous and contained 53 questions. Results: Statistically significant differences were shown in the perception of stress, which is greater in hospital staff, than in the difference between stressors in the workplace, where hospital staff showed higher values in all categories, but three factors are more significant differences: "Organization of the workplace and financial issues," "Conflicts and communication at work" and "Professional and intellectual requirements." There are significant differences in the frequency of using anxiolytics with the assistance of a psychiatrist. Working conditions have a much greater impact on the perception of stress and life satisfaction in hospital staff, while in hospital staff only a weak link between the perception of stress and life satisfaction is expressed. Anxiolytics are consumed by 27.10% of hospital workers and 23.80% of outside-the-hospital workers. Conclusion: The consumption of anxiolytic drugs by healthcare professionals in hospital and outpatient conditions does not make a significant difference, but they do have statistically significant differences in their perception of stress.

Additive anxiolytic-like effect of citicoline and ACPA in the non-acute restraint stress (NARS) and acute restraint stress (ARS) mice.

The cannabinoid system plays a key role in stress-related emotional symptoms such as anxiety. Citicoline is a supplemental substance with neuroprotective properties that alleviates anxiety-related behaviors. There is a relation between the actions of cannabinoids and cholinergic systems. So, we decided to evaluate the effects of intracerebroventricular (i.c.v.) infusion of cannabinoid CB1 receptor agents on citicoline-produced response to anxiety-like behaviors in the non-acute restraint stress (NARS) and acute restraint stress (ARS) mice. For i.c.v. microinjection of drugs, a guide cannula was inserted in the left lateral ventricle. ARS was induced by movement restraint for 4 h. Anxiety-related behaviors were assessed using an elevated plus maze (EPM). The results showed that induction of ARS for 4 h decreased the percentage of time spent in the open arms (%OAT) and the percentage of entries to the open arms (%OAE) without affecting locomotor activity, showing anxiogenic-like behaviors. i.c.v. infusion of ACPA (1 µg/mouse) induced an anxiolytic-like effect due to the enhancement of %OAT in the NARS and ARS mice. Nonetheless, i.c.v. microinjection of AM251 (1 µg/mouse) decreased %OAT in the NARS and ARS mice which suggested an anxiogenic-like response. Intraperitoneal (i.p.) administration of citicoline (80 mg/kg) induced an anxiolytic-like effect by the augmentation of %OAT in the ARS mice. Furthermore, when ACPA and citicoline were co-administrated, ACPA potentiated the anxiolytic-like effect induced by citicoline in the NARS and ARS mice. On the other hand, when AM251 and the citicoline were co-injected, AM251 reversed the anxiolytic-like response induced by the citicoline in the NARS and ARS mice. The results of this research exhibited an additive effect between citicoline and ACPA on the induction of anxiolytic-like response in the NARS and ARS mice. Our results indicated an interaction between citicoline and cannabinoid CB1 receptor drugs on the control of anxiety-like behaviors in the NARS and ARS mice.

Psychotropic Medication Prescriptions and Large California Wildfires.

Importance: Wildfires, intensified by climate change, have known effects on physical health but their effects on mental health are less well characterized. It has been hypothesized that the residential proximity to a large wildfire can exacerbate underlying mental health conditions as evidenced by increased prescriptions of psychotropic medications. Objective: To evaluate the association between the occurrence of large wildfires and the prescription rates of psychotropic medications immediately following the start of the fire. Design, Setting, and Participants: This cohortstudy used an interrupted time-series analysis to compare psychotropic medication prescriptions in the 6 weeks before and after each of 25 wildfires. The setting was California counties within metropolitan statistical areas (MSAs) experiencing large wildfires from 2011 through 2018. Participants included individuals residing in California MSAs with prescriptions of psychotropic medications recorded in the Merative MarketScan Research Database (MarketScan) during the study period. Statistical analysis was performed for these 25 large wildfires occurring between September 2011 and November 2018. Exposure: Residential proximity to large wildfires that burned more than 25 000 acres occurring in a California county within an MSA. Main Outcomes and Measures: Prescriptions of psychotropic medications, including antidepressants, antipsychotics, anxiolytics, hypnotics, and mood-stabilizers, with statins as a negative control outcome. Results: For the study period, prescription data and patient-level attributes were extracted for 7 115 690 unique individuals (annual mean [range]: 889 461 [455 705-1 426 928] individuals) enrolled in MarketScan and residing in fire-affected MSAs. This study found a statistically significant increase in prescriptions of antidepressants (rate ratio [RR], 1.04 [95% CI, 1.01-1.07]), anxiolytics (RR, 1.05 [95% CI, 1.02-1.09]), and mood-stabilizing medications (RR, 1.06 [95% CI, 1.01-1.13]) in the fire period compared with the prefire baseline. However, the prescriptions of antipsychotics, hypnotics, and the negative control outcome, statins, showed no significant association. Conclusions and Relevance: In this cohort study of large California wildfires, the occurrence of wildfire was associated with increased mental health burden as reflected in increased prescription rates of certain psychotropic medications. The findings underscore the need for further scientific examination into the mental health effects of wildfires and the allocation of mental health resources in disaster responses. California experienced a substantial burden of wildfires from 2011 to 2018, and as wildfires become more intense and frequent in the context of anthropogenic climate change, it is increasingly important to understand and address their mental health effects.

Treatment with Glycyrrhiza glabra Extract Induces Anxiolytic Effects Associated with Reduced Salt Preference and Changes in Barrier Protein Gene Expression.

We have previously identified that low responsiveness to antidepressive therapy is associated with higher aldosterone/cortisol ratio, lower systolic blood pressure, and higher salt preference. Glycyrrhiza glabra (GG) contains glycyrrhizin, an inhibitor of 11ß-hydroxysteroid-dehydrogenase type-2 and antagonist of toll-like receptor 4. The primary hypothesis of this study is that food enrichment with GG extract results in decreased anxiety behavior and reduced salt preference under stress and non-stress conditions. The secondary hypothesis is that the mentioned changes are associated with altered gene expression of barrier proteins in the prefrontal cortex. Male Sprague-Dawley rats were exposed to chronic mild stress for five weeks. Both stressed and unstressed rats were fed a diet with or without an extract of GG roots for the last two weeks. GG induced anxiolytic effects in animals independent of stress exposure, as measured in elevated plus maze test. Salt preference and intake were significantly reduced by GG under control, but not stress conditions. The gene expression of the barrier protein claudin-11 in the prefrontal cortex was increased in control rats exposed to GG, whereas stress-induced rise was prevented. Exposure to GG-enriched diet resulted in reduced ZO-1 expression irrespective of stress conditions. In conclusion, the observed effects of GG are in line with a reduction in the activity of central mineralocorticoid receptors. The treatment with GG extract or its active components may, therefore, be a useful adjunct therapy for patients with subtypes of depression and anxiety disorders with heightened renin-angiotensin-aldosterone system and/or inflammatory activity.

Interaction between citalopram and omega-3 fatty acids on anxiety and depression behaviors and maintaining the stability of brain pyramidal neurons in mice.

This research was done to examine the combination of citalopram, an antidepressant drug, and omega-3 in a mice model of depression. Mice received citalopram (1 and 2 mg/kg) or omega-3 (10 and 20 mg/kg) daily over 30 days. Then, they were exposed to acute and chronic restraint stress to assess the possible increasing effect of omega-3 on the antidepressant and anxiolytic effects of citalopram. Elevated plus-maze (EPM) and forced swimming test (FST) were used to assess anxiety and depression symptoms in non-restraint stress (NRS), acute restraint stress (ARS), and chronic restraint stress (CRS) mice. The results indicated that induction of acute and chronic restraint stress reduced %OAT (Open arm time) and %OAE (Open arm entrance) in the EPM test but enhanced immobility time in the FST, showing anxiogenic- and depressive-like effects. These stresses reduced the stability of pyramidal neurons in the prefrontal cortex (PFC) and hippocampus. Aone and combination administration with citalopram and omega-3 induced anxiolytic- and antidepressant-like effects in NRS, ARS, and CRS mice. This combination usage increased the stability of pyramidal neurons in the PFC and hippocampus. These results suggested an interaction between citalopram and omega-3 upon the induction of anxiolytic- and antidepressant-like effects as well as augmentation of the ratio of pyramidal live to dark neurons in the PFC and hippocampus of the ARS and CRS mice.

A role for the cerebellum in motor-triggered alleviation of anxiety.

Physical exercise is known to reduce anxiety, but the underlying brain mechanisms remain unclear. Here, we explore a hypothalamo-cerebello-amygdalar circuit that may mediate motor-dependent alleviation of anxiety. This three-neuron loop, in which the cerebellar dentate nucleus takes center stage, bridges the motor system with the emotional system. Subjecting animals to a constant rotarod engages glutamatergic cerebellar dentate neurons that drive PKCδ+ amygdalar neurons to elicit an anxiolytic effect. Moreover, challenging animals on an accelerated rather than a constant rotarod engages hypothalamic neurons that provide a superimposed anxiolytic effect via an orexinergic projection to the dentate neurons that activate the amygdala. Our findings reveal a cerebello-limbic pathway that may contribute to motor-triggered alleviation of anxiety and that may be optimally exploited during challenging physical exercise.

Anxiolytic-like effects of YL-IPA08, a potent ligand for the translocator protein (18 kDa) via regulating the synaptic plasticity in hippocampus.

TSPO, translocator protein (18 kDa) ligands have demonstrated consistent antidepression and anxiolytic effects in several preclinical studies. This study aimed to examine whether YL-IPA08[N-ethyl-N-(2-pyridinylmethyl)-2-(3,4-ichlorophenyl) -7-methylimidazo [1,2-a] pyridine-3-acetamide hydrochloride], a potent and selective TSPO ligand synthesized by our institute, could alleviate anxiety-related behaviors induced by electric shock (ES) and investigate its underlying mechanism. As expected, we showed that chronic treatment with YL-IPA08 significantly reversed anxiety-related behaviors induced by electrical stimulation (0.5 mA, 12 times, duration 1s, interval 10s) exposure. Using the analysis of RNA-sequencing (RNA-seq) technology, it was found that the differential genes associated with the anxiolytic effect of YL-IPA08 were mainly related to synaptic plasticity. Furthermore, YL-IPA08 restored the decreased levels of brain-derived neurotrophic factor (BDNF), synapse-related protein (e.g. synapsin-1 and post-synaptic density95, PSD95), and the number of doublecortin (DCX) + neurons in the hippocampus of post-ES mice. In addition, YL-IPA08 also enhanced the dendritic complexity and dendritic spine density of hippocampal dentate gyrus (DG) granule neurons. Meanwhile, the induction of long-term potentiation (LTP) was significantly enhanced by YL-IPA08. In summary, the findings from the current study showed that YL-IPA08 exerted a clear anxiolytic effect, which might be partially mediated by promoting hippocampal neuroplasticity.

Line- and sex-dependent effects of juvenile stress on contextual fear- and anxiety-related behavior in high- and low-alcohol-preferring mouse lines.

Juvenile stress (JS) is a known risk factor for the development of alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD), both of which are frequently co-morbid. Data suggest there may be common, genetically-influenced biological responses to stress that contribute to the development of both AUD and PTSD. The present study investigated the impact of JS on contextual fear learning and extinction, as well as corticosterone (CORT) responses before and after JS, before and after contextual fear conditioning (CFC), and after fear extinction in male and female high-alcohol-preferring (HAP2) and low-alcohol-preferring (LAP2) mouse lines. We also measured unconditioned anxiety-related behavior in the light-dark-transition test before CFC. HAP2 and LAP2 mice did not differ in fear acquisition, but HAP2 mice showed faster fear extinction compared to LAP2 mice. No effects of JS were seen in HAP2 mice, whereas in LAP2 mice, JS reduced fear acquisition in males and facilitated fear extinction in females. Females showed greater fear-related behavior relative to males, regardless of subgroup. HAP2 males demonstrated more anxiolytic-like responses than LAP2 males and LAP2 females demonstrated more anxiolytic-like responses than LAP2 males in the light-dark transition test. HAP2 and LAP2 mice did not differ in CORT during the juvenile stage; however, adult LAP2 mice showed greater CORT levels than HAP2 mice at baseline and after CFC and extinction testing. These findings build upon prior work in these unique mouse lines that differ in genetic propensity toward alcohol preference and provide new information regarding contextual fear learning and extinction mechanisms theorized to contribute to co-morbid AUD and PTSD.