Novelty-suppressed Feeding Test Research Articles

Valeriana jatamansi jones improves depressive behavior in CUMS mice by modulating vitamin B12-related ileal homeostasis.

Valeriana jatamansi Jones (V. jatamansi) is a traditional Chinese medicine (TCM). It was recorded in Diannan Bencao, Compendium of Materia Medica and some local medical books and was described as useful in treating insomnia, distraction, poor mental health, vomiting and diarrhea. To investigate whether the antidepressant effect of V. jatamansi may operate through modulating vitamin B12-related ileal homeostasis using a chronic unpredictable mild stress (CUMS) mouse model. A CUMS-induced depression model was established in mice for five weeks, after which V. jatamansi extracts were administered for three weeks. At week eight, the forced swimming test and novelty-suppressed feeding test were conducted. H&E staining assessed ileal pathology, while 16S rDNA sequencing analyzed changes in ileal microbiota. Additionally, B12 in serum, cubilin (CUBN) and amnionless (AMN) in ileal tissue, methionine synthase (MS) and homocysteine (Hcy) in the hippocampus were measured using ELISA, and the correlations between them and ileal microbiota were explored. Mice in the model group exhibited significant depressive behavior. However, after treatment with V. jatamansi, immobility time and feeding latency were improved. H&E staining demonstrated the repairing effect of V. jatamansi on the ileum regarding tissue damage. The alpha and beta diversity of the ileal microbiota were regulated and converged to the normal group. Additionally, V. jatamansi modulated B12, CUBN, AMN, MS, and Hcy levels. Correlation analysis showed that there are certain correlations between a variety of microorganisms and B12-related factors. These findings suggest that the mechanism of V. jatamansi in treating depression may be through repairing depression-associated intestinal damage. This repair process may affect the intestinal absorption and microbial production of B12. By reversing the reduction of serum B12, V. jatamansi ultimately reduces the infiltration of Hcy into the CNS.

GW117 induces anxiolytic effects by improving hippocampal functions

GW117 functions as both an MT1/MT2 receptor agonist and a 5-HT2C receptor antagonist. This study aimed to investigate the anxiolytic effects of GW117 through behavioral assessments, including the open field test and novelty-suppressed feeding test (NSFT) within a chronic unpredictable mild stress (CUMS) model. GW117 was administered via oral gavage for 21 days to evaluate its sustained anxiolytic effects, with behavioral tests including the NSFT, the Vogel-conflict test, and the O-maze test. To explore the underlying mechanisms, we performed Western blot analyses to assess the expression levels of BCL2-Associated X (Bax), cleaved caspase-3, B-cell lymphoma-2 (Bcl-2), brain-derived neurotrophic factor (BDNF), and glial fibrillary acidic protein (GFAP). Additionally, BrdU labeling and immunofluorescence staining were used to examine changes in neuronal regeneration and astrocytogenesis. Our results demonstrated that GW117 produced significant anxiolytic effects across all behavioral assays, both in the CUMS model and during long-term administration. Mechanistic studies revealed that GW117 notably increased the expression of BDNF, GFAP, and Bcl-2, while reducing Bax and cleaved caspase-3 levels in the hippocampus of CUMS model rats. Furthermore, the populations of BrdU-positive and GFAP-positive cells were elevated. These findings suggest that GW117 exerts anxiolytic effects, potentially through enhancements in hippocampal function.

Vagal nerve stimulation dynamically alters anxiety-like behavior in rats.

Electrical vagal nerve stimulation (VNS), at currents designed to target sensory, interoceptive neurons, decreases anxiety-like behavior. We hypothesized that different VNS current intensities would differentially alter anxiety-like behavior through the activation of distinct brainstem circuits. Electrodes were implanted to stimulate the left vagus nerve and to record diaphragm muscle and electrocardiogram activity. The VNS current required to elicit the A-fiber-mediated Hering-Breuer Reflex (HBR) was determined for each animal. Based on this threshold, animals received either sham stimulation or VNS at 1.5 (mid-intensity VNS) or 3 (higher-intensity VNS) times the threshold for HBR activation. Anxiety-like behavior was assessed using the elevated plus maze, open field test, and novelty-suppressed feeding test. Additionally, a place preference assay determined whether VNS is rewarding or aversive. Finally, a c-Fos assay was performed to evaluate VNS-driven neuronal activation within the brainstem. Mid-intensity VNS reduced anxiety-like behavior in the elevated plus maze and open field test. Higher-intensity VNS was aversive during the place preference assay, confounding anxiety measures. Both intensities increased overall c-Fos expression in neurons within the nucleus of the solitary tract, but mid-intensity VNS specifically increased c-Fos expression in noradrenergic neurons within the nucleus of the solitary tract while decreasing it in the locus coeruleus. In contrast, higher-intensity VNS had no effect on c-Fos expression in noradrenergic neurons of either the nucleus of the solitary tract or locus coeruleus. Delivery of VNS induced reproducible, current intensity-dependent, effects on anxiety-like and aversive behavior in rats.

Sugemule-7 alleviates oxidative stress, neuroinflammation, and cell death, promoting synaptic plasticity recovery in mice with postpartum depression

Postpartum depression (PPD) profoundly impacts the mental and physical health of women globally and is an incurable psychological disorder. Traditional pharmacological treatments often have strong side effects and may adversely affect infant health through breastfeeding, underscoring the critical need for natural and gentle treatment strategies. Sugemule-7, a traditional Chinese medicine comprising multiple natural plant ingredients, represents a potentially safer and more effective alternative. To investigate its preventive effects on PPD, we established an animal model and administered the drug Sugemule-7. Our study demonstrated that varying doses of Sugemule-7 effectively alleviated depressive and anxiety-like behaviors in PPD mice, as assessed through a battery of tests, including the open field test, tail suspension test, sucrose preference test, forced swim test, novelty-suppressed feeding test, and elevated plus maze test. Furthermore, Sugemule-7 significantly improved oxidative stress levels in the serum, prefrontal cortex, and hippocampus of PPD-induced mice while also suppressing inflammatory responses and abnormal neuronal death in these brain regions. Transcriptomic sequencing of hippocampal and prefrontal cortex tissues supported our findings, revealing that differential gene expression is primarily involved in regulating synaptic plasticity. Overall, our study confirms the efficacy of Sugemule-7 in treating PPD at different concentrations, potentially alleviating depressive behaviors by enhancing synaptic plasticity, mitigating oxidative stress, reducing inflammation, and protecting neurons.

A stress-activated mid-insula to BNST pathway regulates susceptibility to abstinence-induced negative affect in female mice.

Stress is central to many neuropsychiatric conditions, including alcohol use disorder (AUD). Stress influences the initiation and continued use of alcohol, the progression to AUD, and relapse. Identifying the neurocircuits activated during stress, and individual variability in these responses is critical for developing new treatment targets for AUD, particularly to mitigate stress-induced relapse. Using a longitudinal approach, this study examined the relationship between sub-chronic stress exposure and negative affect during protracted abstinence following chronic ethanol exposure. Sub-chronic restraint stress heightened negative affect-like behavior in protracted abstinence. Interestingly, this was driven by a subset of "stress-susceptible" female mice. We examined the mid-insula, a hub in the brain's salience network, as a driver of this effect, given its role in emotional regulation and links to alcohol craving, consumption, and abstinence-induced negative affect. Mid-insula GCaMP fiber photometry revealed that GCaMP activity during stress exposure was positively correlated with activity during the novelty-suppressed feeding test (NSFT) two weeks into abstinence. A distinct subset of mice exhibited increasing activity during the consummatory phase, implicating the mid-insula as a neural basis for heightened negative affect in abstinence. Chemogenetic inhibition of mid-insula neurons projecting to the dorsal BNST during stress disrupted the emergence of stress susceptibility, highlighting this circuit as a key determinant of susceptibility to abstinence-induced negative affect. These outcomes were female-specific, addressing a critical gap in understanding AUD risk in women. Furthermore, female mice exhibited higher struggling behavior during stress than males. However, this effect was blocked by chemogenetic inhibition of the insula-BNST pathway during stress. By linking pre-alcohol stress response with abstinence outcomes, this work positions the insula-BNST pathway as a potential AUD circuit activity biomarker and therapeutic target.

Cichorium intybus L. Oligo-Polysaccharides (CIO) Exerts Antianxiety and Antidepressant Effects on Mice Experiencing Behavioral Despair and Chronic Unpredicted Mild Stress.

Cichorium intybus L. oligo-polysaccharides (CIOs), obtained from Cichorium intybus L., is a mixture of oligosaccharides and polysaccharides. This study explores the antianxiety and antidepressant effects and mechanisms of CIOs by using acute behavioral despair and chronic unpredictable mild stress mice models and measuring the levels of 5-HT and the expression of proteins related to the BDNF/ERK and PI3K/Akt/mTOR pathways. Moreover, 56 male C57BL/6N mice were used to test behavioral despair. They were randomized into seven groups (Control, Citalopram, CIO 12.5 mg/kg, CIO 25 mg/kg, CIO 100 mg/kg, and CIO 200 mg/kg) based on body weight; they were administered with the corresponding medication daily for 7 days; and behavioral tests were conducted on them (forced swimming test (FST) and tail suspension test (TST)) after 7 days. Seventy male C57BL/6N mice were adopted in the next part of the experiment and randomly divided into seven groups (Control, CUMS, Fluoxetine, MOO, CIO 25 mg/kg, and CIO 100 mg/kg) based on the sucrose preference index. Except for the control group, the other groups were subjected to 6 weeks of CUMS. From the fifth week of stress, the corresponding drugs were administered by gavage until the end of the behavioral tests. In the behavioral despair tests, the immobility time was significantly reduced in the FST and TST after the CIO (25 and 100 mg/kg) treatment of 7 days. After 6 weeks of chronic unpredicted mild stress (CUMS) treatment, CIO (25, 50, and 100 mg/kg) administration significantly reduced the number of buried beads in the marble burying test (MBT), decreased the latency in the novelty-suppressed feeding test (NSFT), and shortened the immobility time in the FST and TST. CIO administration significantly increased the sucrose preference index in the sucrose preference test (SPT). Additionally, CIO treatment increased hippocampal 5-HT levels while upregulating the expression of BDNF, P-PI3K/PI3K, P-ERK/ERK, P-Akt/Akt, and P-mTOR/mTOR. In summary, CIO exerted promising antidepressant effects in behavioral despair and antianxiety and antidepressant effects in CUMS-induced depressive mice. Moreover, CIO therapy was facilitated by increasing the 5-HT content, alleviating the damage of hippocampal neurons, and upregulating the BDNF/ERK and PI3K/AKT/mTOR cascade. Thus, CIO is a substance with the potential to treat anxiety and depression.

Characterizing the therapeutical use of ketamine for adolescent rats of both sexes: Antidepressant-like efficacy and safety profile.

While ketamine was approved for treatment-resistant depression in adult patients, its efficacy and safety profile for adolescence still requires further characterization. In this context, prior preclinical studies have shown that sub-anesthetic doses of ketamine during adolescence exert antidepressant-like effects in rodents in a dose- and sex-dependent manner. However, additional studies evaluating the short- and long-term safety profile of ketamine at the doses necessary to induce antidepressant-like effects are needed. The present study aimed at validating the dose- and sex-dependent antidepressant-like responses of adolescent ketamine while evaluated its safety profile in rats of both sexes. To do so, ketamine was administered (1, 5 or 10 mg/kg; vs. vehicle; 1 vs. 7 days) during adolescence in naïve or early-life stressed (i.e., maternal deprivation) rats of both sexes. Antidepressant-like responses were scored in the forced-swim or novelty-suppressed feeding tests, and safety was evaluated by measuring psychomotor- and reinforcing-like responses induced by ketamine. In addition, long-term safety was assessed in adulthood through cognitive performance, or addiction liability (induced by ketamine re-exposure in rats treated with ketamine in adolescence). The main results validated the potential use of ketamine as an antidepressant for adolescence, but at different dose ranges for each sex. However, some safety concerns emerged in adolescent female rats (i.e., signs of sensitization at the dose used as antidepressant) or adult male rats (i.e., addiction liability when re-exposed to ketamine in adulthood), suggesting that caution and further research are needed before ketamine could be safely used in the clinic as an antidepressant for adolescents.

Concurrent stress modulates the acute and post-acute effects of psilocybin in a sex-dependent manner.

There is renewed interest in psychedelics, such as psilocybin, as therapies for multiple difficult-to-treat psychiatric disorders. Even though psychedelics can induce highly pleasant or aversive experiences, depending on multiple personal and environmental factors, there is little research into how such experiences impact post-acute mood-altering actions. Here we aimed at offsetting this gap. First, we tested whether acute psilocybin effects differed between sexes. Adult male and female C57BL/6J mice received saline or psilocybin (5mg/kg;i.p.), and head-twitch response (HTR) frequency was quantified. Notably, while psilocybin increased HTR frequency in both sexes, the effect was greater in females. We then tested if stress exposure during acute drug effects impacted post-acute psilocybin actions. Following drug treatment, mice were returned to their homecage or restrained for 1h. Anxiety- and depressive-like behaviors were assessed starting 24h following drug administration, using the marble burying, novelty-suppressed feeding, and splash tests. Psilocybin induced anxiolytic-, but not antidepressant-like, which were fully blocked by stress in males, but only partially so in females. Lastly, we assessed the acute stress-psilocybin interaction on plasma corticosterone levels in a separate cohort of mice, treated as above. Both stress and psilocybin independently increased corticosterone levels, without additive or interactive effects being observed for either sex. Our data reveals the role of sex and peri-acute negative experiences in the acute and post-acute actions of psilocybin. These findings underline the importance of non-pharmacological factors, such as the quality of the psychedelic experience, in the mood-altering effects of psychedelics, holding significant for both their therapeutic and recreational use.

One-Week Maternal Separation Caused Sex-Specific Changes in Behavior and Hippocampal Metabolomics of Offspring Rats.

To investigate the effects of one-week maternal separation (MS) on anxiety- and depression-like behaviors in adolescent and adulthood as well as adult hippocampal metabolomics simultaneously in offspring female and male rats. In the MS group, newborn SD rats were separated from their mothers for 3 h per day from postnatal days (PND) 2 to 8. The open field test (OFT), elevated plus mazes (EPM), novelty suppressed feeding test (NSFT), and forced swimming test (FST) were conducted during adolescence and adulthood. Serum corticosterone, mRNA expression of hippocampal inflammatory cytokines, and hippocampal untargeted metabolomics of offspring adult rats were examined using an assay kit, qRT-PCR, and UPLC-Q-TOF/MS. Both MS female and male rats showed similar behaviors in OFT, EPM, NSFT, and SPT, except for the latency to feeding during adolescence and the open arm entries during adulthood, showed statistical significance only in MS female rats. Serum corticosterone and hippocampal pro-inflammatory cytokines IFN-γ were significantly elevated in both female and male rats, and IL-1β and TNF-α were significantly increased only in female rats. In hippocampal metabolism, the identification of differential metabolites displayed 53 and 37 in female rats and male rats, respectively (with 35 common metabolites), which were involved in 33 and 30 metabolic pathways with 28 common pathways. One-week MS induced sex-specific anxiety- and depression-like behaviors in female and male offspring rats during adolescence and adulthood, as well as sex-differentiated characteristics in the hippocampus inflammatory cytokines and metabolomics of adult MS rats. From the experimental data, the effects of MS on the female offspring rats were more severe than those of the male offspring rats.

Evaluation of a user-friendly CSDS cage apparatus for studying depressive-like behaviors in rodents.

Previously, a chronic social defeat stress (CSDS) model has been widely-adopted for assessing depressive-like behaviors in animals. However, there is still room for improvement in the CSDS model to safeguard study accuracy and the welfare of lab rodents. Our study team developed a novel, standardized apparatus to induce CSDS in rodents and assessed the model's practical adaptability. An innovative CSDS cage apparatus and water bottle was designed. To evaluate the effectiveness of the newly developed tools, a variety of animal models, including the tail suspension test (TST), sucrose preference test, forced swimming test (FST), novelty-suppressed feeding test, female urine sniffing test, and open field test (OFT), were adopted to assess depressive-like behaviors in mice. Fluoxetine treatment was also administered to observe the reversal effect, as part of the validation. The CSDS cage apparatus resulted in the manifestation of depressive-like behaviors in the model mice. Significant reductions in sucrose preference and urine sniffing time were observed, while the OFT revealed decreased central zone total distance, residence time, and frequency of entry. Moreover, increased immobility was found in the FST and TST. Fluoxetine treatment was found to successfully reverse the modeling effect. The CSDS cage apparatus was validated for enhanced usability and addressed the previous challenges of water bottle leakage and lab rodent welfare issues. The consistent results from multiple behavioral tests also supported real-world application of the apparatus, offering researchers a promising alternative to conventional rodent cages.

Hypoxanthine Produces Rapid Antidepressant Effects by Suppressing Inflammation in Serum and Hippocampus.

The occurrence and development of depression are closely related to disorders of the brain and peripheral substances. Abnormal metabolites in the blood affect the signal regulation function of the nerve center, which is one of the key factors for depression episodes. This study was focused on metabolites in serum and the mechanism of its antidepressant in the hippocampus. In the present study, serum metabolites in patients with depression were screened by metabolomic techniques. Various depressive mouse models and behavioral tests were used to assess its antidepressant effects. The expressions of inflammatory signaling were detected by using Western blot, ELISA, and immunofluorescence. We found that the metabolite hypoxanthine in the serum of patients with depression was significantly reduced, and the same result was also found in two mouse models of depression such as chronic unpredictable mild stress (CUMS) and social defeat stress (SD). By administering different doses of hypoxanthine (5, 10, 15 mg/kg), we found that only 15 mg/kg was able to significantly reduce the latency and increase food consumption in the novelty suppressed-feeding test (NSF), which was also able to reverse the depressive phenotypes of mice in the CUMS model after a single administration at 2 h later. Hypoxanthine obviously reduced the expressions of inflammation in serum and downregulated the expressions of MAPK and NLRP3-related pathways in the hippocampus in CUMS mice. Moreover, hypoxanthine also suppressed the activations of glial cells including GFAP and IBA-1 in hippocampal CA1, CA3, and dentate gyrus (DG). To sum up, hypoxanthine exerted antidepressant effect relying on the inhibition of peripheral and hippocampal inflammations by regulating MAPK, NLRP3-related pathways, and glial cells. This was the first time that we have found a disordered metabolite in patients with depression and further systematically demonstrated its efficacy and potential mechanism of antidepressants, providing new ideas for antidepressant drug development.

Unpredictable chronic mild stress induced anxio-depressive disorders and enterobacteria dysbiosis: Potential protective effects of Detariummicrocarpum

Ethnopharmacological relevanceDetarium microcarpum Guill. & Perr. is used traditionally in Far North Cameroun to treat stomach aches, anxiety, epilepsy, and other mental disorders. Aim of the studyEvaluate the anxiolytic and antidepressant-like effects of D. microcarpum (DM) in unpredictable chronic mild stress (UCMS) model of depression in male rats and its impact on fecal enterobacteria of stressed rats. Materials and methodsRats were handled daily (control) or subjected to the UCMS procedure for 42 days. Anxiety-like behaviors were assessed using the light and dark box test (LBD) and the open field test (OFT). Depressive-like behaviors were assessed using the forced swimming test (FST), the sucrose preference test (SPT), and the novelty suppressed feeding test (NSFT). Feces were then collected, followed by blood, brain, and duodenum sections after sacrifice. Monoamine levels, pro-inflammatory cytokines, oxidative stress factors, and nitrosative stress were assessed. Feces were introduced into Hectoen enteric agar for the identification of enterobacteria. An in vitro growth test was performed. ResultsThe DM ethanolic extract has significantly increased the time spent in the light box, in the LBD, and in the center area of the OFT. Moreover, the extract has significantly reduced the preference for sucrose in the SPT, the time of immobility in the FST, and the latency period to consume the pet in the NSFT. DM extract has significantly reduced serum cortisol levels. It also significantly decreased the pro-inflammatory cytokines TNF-α and Il-1β in both brain and duodenum homogenate. DM has increased the brain's serotonin, GABA, and dopamine levels. The DM extract also decreased the MDA and nitrite levels. It also increased the SOD and CAT activities in both brain and duodenal homogenate. Histologically, the DM extract restored the cell's density in hippocampi sections and prevented gut inflammation and peroxidation characterizing leaky gut syndrome. DM extract has no effect on the growth of enterobacteria species isolated in vitro. ConclusionThe ethanolic extract of DM would have anxiolytic and antidepressant effects via the modulation of the HPA axis, brain antioxidant enzyme activities, inflammation, and nitrosative stress. Moreover, it could act by preventing leaky gut syndrome.

Effects of ketamine on GABAergic and glutamatergic activity in the mPFC: biphasic recruitment of GABA function in antidepressant-like responses.

Major depressive disorder (MDD) is associated with disruptions in glutamatergic and GABAergic activity in the medial prefrontal cortex (mPFC), leading to altered synaptic formation and function. Low doses of ketamine rapidly rescue these deficits, inducing fast and sustained antidepressant effects. While it is suggested that ketamine produces a rapid glutamatergic enhancement in the mPFC, the temporal dynamics and the involvement of GABA interneurons in its sustained effects remain unclear. Using simultaneous photometry recordings of calcium activity in mPFC pyramidal and GABA neurons, as well as chemogenetic approaches in Gad1-Cre mice, we explored the hypothesis that initial effects of ketamine on glutamate signaling trigger subsequent enhancement of GABAergic responses, contributing to its sustained antidepressant responses. Calcium recordings revealed a biphasic effect of ketamine on activity of mPFC GABA neurons, characterized by an initial transient decrease (phase 1, <30 min) followed by an increase (phase 2, >60 min), in parallel with a transient increase in excitation/inhibition levels (10 min) and lasting enhancement of glutamatergic activity (30-120 min). Previous administration of ketamine enhanced GABA neuron activity during the sucrose splash test (SUST) and novelty suppressed feeding test (NSFT), 24 h and 72 h post-treatment, respectively. Chemogenetic inhibition of GABA interneurons during the surge of GABAergic activity (phase 2), or immediately before the SUST or NSFT, occluded ketamine's behavioral actions. These results indicate that time-dependent modulation of GABAergic activity is required for the sustained antidepressant-like responses induced by ketamine, suggesting that approaches to enhance GABAergic plasticity and function are promising therapeutic targets for antidepressant development.

The effects of amphetamine exposure on stress susceptibility in mice

Substance use disorders (SUDs) and their many psychiatric comorbidities, including major depression and anxiety disorders, are characterized by significant sex differences. Although the causes of SUDs and their psychiatric comorbidities remain unknown, stress has been heavily implicated in their etiology. Indeed, one leading hypothesis regarding the basis of clinically observed sex differences in psychopathology argues that differences in stress susceptibility and stress exposure play key roles. Consistent with this, differences in stress susceptibility and reactivity in females compared to males have been documented across multiple species. A wide range of environmental, genetic, and epigenetic factors are also thought to impact stress susceptibility, but whether there are sex differences in the effects of specific susceptibility factors remains understudied. Preclinical work suggests that a history of cocaine exposure can increase susceptibility to stress in males, but whether similar effects occur in females following stimulant exposure has not been established. The current work examined the impact of repeated amphetamine administration on subsequent susceptibility to mild sub-chronic stress in male and female mice. In addition to examining behavior, potential sex differences in the effects of stress and amphetamine on the expression of several genes were evaluated. Our results reveal several significant sex differences in the behavioral effects of amphetamine and stress in the elevated plus maze, forced swim test, and novelty-suppressed feeding test. However, in contrast to our initial hypothesis, a history of amphetamine did not lead to an overall increase in stress susceptibility across multiple tests in males or females.

Rapid reorganization of serotonin projections and antidepressant response to 5-HT1A-biased agonist NLX-101 in fluoxetine-resistant cF1ko mice

Selective serotonin (5-HT) reuptake inhibitors (SSRIs) like fluoxetine remain a first-line treatment for major depression, but are effective in less than half of patients and can take 4–8 weeks to show results. In this study, we examined cF1ko mice with genetically induced upregulation of 5-HT1A autoreceptors that reduces 5-HT neuronal activity. These mice display anxiety- and depression-related behaviors that did not respond to chronic fluoxetine treatment. We examined treatment with NLX-101, a biased agonist that preferentially targets 5-HT1A heteroreceptors. By testing different doses of NLX-101, we found that a dose of 0.2 mg/kg was effective in reducing depression-related behavior in cF1ko mice without causing hypothermia, a 5-HT1A autoreceptor-mediated response. After 1 h, this dose activated dorsal raphe 5-HT neurons and cells in the medial prefrontal cortex (mPFC), increasing nuclear c-fos labelling in cF1ko mice. In cF1ko mice but not wild-type littermates, 0.2 mg/kg NLX-101 administered 1 h prior to each behavioral test for two weeks reduced depressive behavior in the forced swim test, but increased anxiety-related behaviors in the open field, elevated plus maze, and novelty suppressed feeding tests. During this treatment, NLX-101 induced widespread increases in the density of 5-HT axons, varicosities, and especially synaptic and triadic structures, particularly in depression-related brain regions including mPFC, hippocampal CA1 and CA2/3, amygdala and nucleus accumbens of cF1ko mice. Overall, NLX-101 was rapid and effective in reducing depressive behavior in SSRI-resistant mice, but also induced anxiety-related behaviors. The increase in serotonin innervation induced by intermittent NLX-101 may contribute to its behavioral actions.

A Systematic Review and Meta-Analysis of Anxiety- and Depressive-Like Behaviors in Rodent Models of Neuropathic Pain

BackgroundEpidemiological studies have frequently shown the concurrence of chronic pain with symptoms of anxiety and depression, particularly in women. Animal models are useful to understand the complex mechanisms underlying comorbidities, but the wide range of methods employed and the wealth of evidence sometimes impedes effective translation and reproducibility. In this systematic review and meta-analysis, we aimed to synthesize the evidence regarding the influence of variables such as sex and species on anxiety- and depressive-like behaviors in rodent models of neuropathic pain. MethodsFollowing PROSPERO registration, we searched EMBASE, Scopus, and the Web of Science from their inception to November 24, 2023, identifying 126 studies that met the inclusion criteria. The Hedges’ g value for each experiment and study was calculated, and further subgroup and meta-regression analyses were performed. ResultsNeuropathic pain significantly reduced the time that rats and mice spent in the open arms of the elevated plus and zero mazes (g = −1.14), time spent in the center of the open field (g = −1.12), sucrose consumption in the sucrose preference test (g = −1.43), and grooming time in the splash test (g = −1.37) while increasing latency to feed in the novelty-suppressed feeding test (g = 1.59) and immobility in the forced swimming (g = 1.85) and tail suspension (g = 1.91) tests. Sex differences were observed, with weaker effects in female than in male rodents for several behavioral paradigms, and funnel plots identified positive publication bias in the literature. ConclusionsThis meta-analysis emphasizes the effect of neuropathic pain on anxiety- and depressive-like behaviors in rodents, highlighting the importance of investigating sex differences in future experimental studies.

Fast-acting antidepressant-like effects of ketamine in aged male rats

BackgroundThe aging process causes anatomical and physiological changes that predispose to the development of late-life depression while reduces the efficacy of classical antidepressants. Novel fast-acting antidepressants such as ketamine might be good candidates to be explored in the context of aging, especially given the lack of previous research on its efficacy for this age period. Thus, the aim of the present study was to characterize ketamine’s effects in older rats.MethodsThe fast-acting (30 min) and repeated (7 days) antidepressant-like effects of ketamine (5 mg/kg, ip) were evaluated in 14-month-old single-housed rats through the forced-swim and novelty-suppressed feeding tests. In parallel, the modulation of neurotrophic-related proteins (i.e., mBDNF, mTOR, GSK3) was assessed in brain regions affected by the aging process, prefrontal cortex and hippocampus, as well as possible changes in hippocampal cell proliferation.ResultsAcute ketamine induced a fast-acting antidepressant-like response in male aged rats, as observed by a reduced immobility in the forced-swim test, in parallel with a region-specific increase in mBDNF protein content in prefrontal cortex. However, repeated ketamine failed to induce antidepressant-like efficacy, but decreased mBDNF protein content in prefrontal cortex. The rate of hippocampal cell proliferation and/or other markers evaluated was not modulated by either paradigm of ketamine.ConclusionsThese results complement prior data supporting a fast-acting antidepressant-like effect of ketamine in rats, to further extend its efficacy to older ages. Future studies are needed to further clarify the lack of response after the repeated treatment as well as its potential adverse effects in aging.

A refined formula derived from Jiawei-Xiaoyao pill exerts rapid antidepressant-like effects in LPS-induced depression by reducing neuroinflammation and restoring neuroplasticity signaling

Ethnopharmacological relevanceJiawei-Xiaoyao Pill (JWX), a classic formula in traditional Chinese medicine, is derived from Xiaoyao Pill by adding significant amounts of Gardeniae Fructus (GF) and Moutan Cortex (MC). It is frequently used for the treatment of depression. JWX has been demonstrated to uniquely elicit rapid antidepressant-like effects within the prescribed dosage range. To date, GF has been shown to have rapid antidepressant-like effects, but a much higher dose is required than its proportion in JWX. It is assumed that the synergism of GF with a minimum number of other herbs in JWX serves as a refined formula that exerts these rapid antidepressant-like effects. Identification of a refined formula is important for prioritizing the herbs and ingredients to optimize the quality control of JWX. However, such a refined formula for JWX has not been identified yet. Aim of the studyHere we aimed to identify a refined formula derived from JWX for optimized rapid antidepressant-like effects. Since the neuroinflammation mechanism involving in depression treatment has not been previously investigated for JWX, we tested the mechanism for both JWX and the refined formula. Materials and methodsIndividual herbs (MC; ASR, Angelica Sinensis Radix; Bupleuri Radix; Paeonia Radix Alba) that show antidepressant-like responses were mixed with GF at the proportional dosage in JWX to identify the refined formula. Rapid antidepressant-like effects were assessed by using NSF (Novelty Suppressed Feeding Test) and other behavioral tests following a single administration. The identified formula was further tested in a lipopolysaccharide (LPS)-induced depressive model, and the molecular signaling mechanisms were investigated using Western blot analysis, immunofluorescence, and pharmacological inhibition of mTOR signaling. Scopolamine (Scop) was used as a positive control for induction of rapid antidepressant effects. ResultsA combination of GF, MC and ASR (GMA) at their dosages proportional to JWX induced behavioral signs of rapid antidepressant-like responses in both normal and LPS-treated mice, with the antidepressant-like effects sustained for 5 d. Similar to JWX or Scop, GMA rapidly reduced the neuroinflammation signaling of Iba-1-NF-кB, enhanced neuroplasticity signaling of CaMKII-mTOR-BDNF, and attenuated the upregulated expressions of the NMDAR sub-units GluN1 and GluN2B in the hippocampus of LPS-treated mice. GMA, JWX and Scop rapidly restored the number of BDNF-positive cells reduced by LPS treatment in the CA3 region of the hippocampus. Furthermore, rapamycin, a selective inhibitor of mTOR, blunted the rapid antidepressant-like effects and hippocampal BDNF signaling upregulation by GMA. ConclusionGMA may serve as a refined formula from JWX, capable of inducing rapid antidepressant-like effects. In the LPS-induced depression model, the effects of GMA were mediated via rapidly alleviating neuroinflammation and enhancing neuroplasticity.

Effects of ketamine on GABAergic and glutamatergic activity in the mPFC: biphasic recruitment of GABA function in antidepressant-like responses.

Major depressive disorder (MDD) is associated with disruptions in glutamatergic and GABAergic activity in the medial prefrontal cortex (mPFC), leading to altered synaptic formation and function. Low doses of ketamine rapidly rescue these deficits, inducing fast and sustained antidepressant effects. While it is suggested that ketamine produces a rapid glutamatergic enhancement in the mPFC, the temporal dynamics and the involvement of GABA interneurons in its sustained effects remain unclear. Using simultaneous photometry recordings of calcium activity in mPFC pyramidal and GABA neurons, as well as chemogenetic approaches in Gad1-Cre mice, we explored the hypothesis that initial effects of ketamine on glutamate signaling trigger subsequent enhancement of GABAergic responses, contributing to its sustained antidepressant responses. Calcium recordings revealed a biphasic effect of ketamine on activity of mPFC GABA neurons, characterized by an initial transient decrease (phase 1, <30 min) followed by an increase (phase 2, >60 min), in parallel with a transient increase in excitation/inhibition levels (10 min) and lasting enhancement of glutamatergic activity (30-120 min). Previous administration of ketamine enhanced GABA neuron activity during the sucrose splash test (SUST) and novelty suppressed feeding test (NSFT), 24 h and 72 h post-treatment, respectively. Chemogenetic inhibition of GABA interneurons during the surge of GABAergic activity (phase 2), or immediately before the SUST or NSFT, occluded ketamine's behavioral actions. These results indicate that time-dependent modulation of GABAergic activity is required for the sustained antidepressant-like responses induced by ketamine, suggesting that approaches to enhance GABAergic plasticity and function are promising therapeutic targets for antidepressant development.

Hippocampal PACAP signaling activation triggers a rapid antidepressant response

BackgroundThe development of ketamine-like rapid antidepressants holds promise for enhancing the therapeutic efficacy of depression, but the underlying cellular and molecular mechanisms remain unclear. Implicated in depression regulation, the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is investigated here to examine its role in mediating the rapid antidepressant response.MethodsThe onset of antidepressant response was assessed through depression-related behavioral paradigms. The signaling mechanism of PACAP in the hippocampal dentate gyrus (DG) was evaluated by utilizing site-directed gene knockdown, pharmacological interventions, or optogenetic manipulations. Overall, 446 mice were used for behavioral and molecular signaling testing. Mice were divided into control or experimental groups randomly in each experiment, and the experimental manipulations included: chronic paroxetine treatments (4, 9, 14 d) or a single treatment of ketamine; social defeat or lipopolysaccharides-injection induced depression models; different doses of PACAP (0.4, 2, 4 ng/site; microinjected into the hippocampal DG); pharmacological intra-DG interventions (CALM and PACAP6-38); intra-DG viral-mediated PACAP RNAi; and opotogenetics using channelrhodopsins 2 (ChR2) or endoplasmic natronomonas halorhodopsine 3.0 (eNpHR3.0). Behavioral paradigms included novelty suppressed feeding test, tail suspension test, forced swimming test, and sucrose preference test. Western blotting, ELISA, or quantitative real-time PCR (RT-PCR) analysis were used to detect the expressions of proteins/peptides or genes in the hippocampus.ResultsChronic administration of the slow-onset antidepressant paroxetine resulted in an increase in hippocampal PACAP expression, and intra-DG blockade of PACAP attenuated the onset of the antidepressant response. The levels of hippocampal PACAP expression were reduced in both two distinct depression animal models and intra-DG knockdown of PACAP induced depression-like behaviors. Conversely, a single infusion of PACAP into the DG region produced a rapid and sustained antidepressant response in both normal and chronically stressed mice. Optogenetic intra-DG excitation of PACAP-expressing neurons instantly elicited antidepressant responses, while optogenetic inhibition induced depression-like behaviors. The longer optogenetic excitation/inhibition elicited the more sustained antidepressant/depression-like responses. Intra-DG PACAP infusion immediately facilitated the signaling for rapid antidepressant response by inhibiting calcium/calmodulin-dependent protein kinase II (CaMKII)-eukaryotic elongation factor 2 (eEF2) and activating the mammalian target of rapamycin (mTOR). Pre-activation of CaMKII signaling within the DG blunted PACAP-induced rapid antidepressant response as well as eEF2-mTOR-brain-derived neurotrophic factor (BDNF) signaling. Finally, acute ketamine treatment upregulated hippocampal PACAP expression, whereas intra-DG blockade of PACAP signaling attenuated ketamine’s rapid antidepressant response.ConclusionsActivation of hippocampal PACAP signaling induces a rapid antidepressant response through the regulation of CaMKII inhibition-governed eEF2-mTOR-BDNF signaling.