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Rationale: Pharmacological treatments for depression are not always effective and produce unwanted side effects. Male and female sexual dysfunction is one of these side effects, which can lead to treatment withdrawal. Combination of two antidepressants with different mechanisms of action, like mirtazapine (MTZ) and venlafaxine (VLF) have been shown to be effective for treatment-resistant depression in humans. Combination of low doses of these drugs may still exert antidepressant-like effects without altering sexual behavior. Objectives: To investigate the potential antidepressant-like effect of the chronic administration of low doses of MTZ plus VLF combined, as well as its impact on male and female sexual behavior in rats. Methods: The antidepressant-like effect of a 14-day treatment with combinations of MTZ plus VLF (0/0, 2.5/3.75 or 5/7.5 mg/kg) was assessed in young adult male and female rats in the forced swim test (FST). The 5/7.5 mg/kg MTZ/VLF combination was also tested in the chronic mild stress (CMS) test, in both males and females treated for 21 days. The sexual effects of this last treatment were assessed in sexually experienced males and in gonadally-intact females during proestrus. Results: The 5/7.5 mg/kg MTZ/VLF combination produced an antidepressant-like effect in the FST and reversed the CMS-induced anhedonia in both male and female rats. This combination did not alter male sexual behavior, female proceptive and receptive behaviors or the regularity of the estrous cycle. Conclusion: The combination of low doses of MTZ and VLF might be a promising therapeutic alternative to treat depression without affecting the sexual response. [ABSTRACT FROM AUTHOR]

Acetylcholinesterase inhibitors (AChEIs) are drugs that enhance cholinergic neuro-transmission and are used for the treatment of Alzheimer's disease and myasthenia gravis. Common AChEIs include rivastigmine, donepezil and galantamine (GAL), but they can cause side effects like nausea, vomiting, depression and bradycardia. A potential link exists between AChEIs and increased depression risk. Recently, we have discovered a hybrid compound (4b) combining GAL and curcumin (CCN), which shows improved anticholinesterase activity and neuroprotective effects. It could be developed as a potential multitarget agent for neurodegenerative disorders. Here, we examine the compound's depressant side effect on mice, comparing it to GAL and CCN. Tests were conducted twice using the tail suspension test (TST) and the forced swim test over an 8-day treatment period. The results showed that 4b lacked the depressant effect of GAL and even displayed a mild antidepressant effect similar to CCN in TST. This suggests that incorporating antidepressant fragments, like CCN, into AChEIs can potentially neutralize their depressive side effects. [ABSTRACT FROM AUTHOR]

Depression, a prevalent neuropsychiatric disorder, involves the dysregulation of neurotransmitters such as dopamine (DA). The restoration of DA balance is a pivotal therapeutic target for this condition. Recent studies have indicated that both antidepressant medications and non-pharmacological treatments, such as transcutaneous auricular vagus nerve stimulation (taVNS), can promote recovery from depressive symptoms. Despite the promise of taVNS as a non-invasive depression therapy, its precise mechanism remains unclear. We hypothesized that taVNS exerts antidepressant effects by modulating the DAergic system. To investigate this, we conducted experiments demonstrating that taVNS in anesthetized mice reduced depressive-like behaviors. However, this effect was abolished when DA neurons in the ventral tegmental area (VTADA) were inhibited. Additionally, taVNS in anesthetized mice enhanced VTADA activity, providing further evidence to support its antidepressant effects. Overall, our findings suggest that taVNS alleviates depression by augmenting VTADA activity, thereby contributing to a more comprehensive understanding of its therapeutic mechanisms. [ABSTRACT FROM AUTHOR]

The aim of the study was to determine the optimal duration of chronic unpredictable mild stress (CUMS) exposure for the formation of depressive-like state (DLS) in rats of different ages. Male Wistar rats aged 6 weeks (named young), 10 months (adult), and 20 months (old) were divided into control and experimental groups. DLS was induced using the CUMS procedure, for which the animals were subjected to alternating short and long-term stress stimuli for 4 or 7 weeks. The hedonic state of the rats was assessed by their preferences for sucrose, while the development of DLS was evaluated using open field and forced swim tests, as well as by corticosterone levels in blood plasma. In rats from all age groups, the reduction in sucrose intake was observed starting from 4th week after the exposure to chronic stress. However, all individuals in the CUMS groups were classified as having anhedonia-like symptoms after 7 weeks of stress exposure only. Longer exposure to chronic stress resulted in decreased exploratory activity and an increased anxiety in animals of all ages in the open field test. In the forced swimming test, the signs of behavioral despair including the decline in latency to the first episode of immobility and an increase in the total duration of immobility were also more pronounced in rats exposed to stress for 7 weeks. Additionally, young rats that underwent CUMS protocol demonstrated more prominent behavioral abnormalities compared to adult and older individuals. 7-weeks of CUMS exposure led to significant increase in corticosterone levels, indicative of DLS, in all rats. Therefore, the findings from all tests suggest that a longer CUMS protocol is required for the development of depression-like behavior in male Wistar rats, and younger individuals are more vulnerable to the effects of chronic stress. [ABSTRACT FROM AUTHOR]

Introduction: Athletes typically try to enhance performance and reduce fatigue, and certain plants may offer performance-enhancing and recovery-accelerating benefits, as well as other health benefits. Fridericia chica (Bonpl.) L. G. Lohmann is a species that is commonly used as a herbal medicine, mainly because of its healing and anti-inflammatory properties. The effect of F. chica on physical performance parameters has not yet been investigated, though there is evidence that this species can act in this sense. Purpose: This study investigated the effect of an aqueous extract of F. chica leaves on physical performance parameters in Wistar rats. Materials & Methods: The animals were treated during 28-days with and without continuous swimming exercise, with an aqueous dried extract from F chica leaves administered via gavage. Doses of 15 or 30 mg/kg of F. chica extract were compared with the negative control (no treatment) or 5 mg/kg of caffeine (positive control). Biochemical and hematological blood markers were evaluated at the end of the experiment. Results: In the forced swim test, there was an increase in swimming time in the groups that consumed the F. chica extract at doses of 15 or 30 mg/kg of weight. Lactate and creatine kinase values were reduced in the group that consumed F. chica at 30 mg/kg (p=0.05) and 15 mg/kg for the exercise group (p=0.05), when compared to the other groups investigated. Conclusions: The aqueous extract of F. chica leaves influences the aerobic performance parameters and markers of fatigue in rats. This is the first study to report the ergogenic effect of F. chica extract, which can be explored in the development of products to increase the physical performance of athletes. [ABSTRACT FROM AUTHOR]

AbstractEmpagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, has recently reported to prevent the depression in chronic animal model. The present study aimed to explore the antidepressant potential of empagliflozin using a neuroinflammation-mediated depression involving the olfactory bulbectomy (OBX) model in diabetic rats. A low dose of streptozotocin was injected to induce diabetes in all group of animals. Following the confirmation of hyperglycemia, OBX surgery was performed. Post-surgery, the drug treatments were administered orally for 14 consecutive days. The study evaluated the effects of daily oral administration of empagliflozin at doses of 5 and 10 mg/kg, alongside metformin (200 mg/kg) and clomipramine (50 mg/kg), on OBX-induced behavioral depression in rats. Separate sham and vehicle control groups were also maintained. Behavioral parameters in open field, forced swim test, elevated plus maze and splash test were recorded on 28th day. Results showed that empagliflozin, at the higher dose, significantly enhanced behavioral outcomes, evidenced by increased distance travelled, greater open arm entries, and reduced immobility, alongside a notable reduction in grooming time. Moreover, empagliflozin significantly restored the antioxidants level specifically Glutathione (GSH) and Catalase (CAT) in OBX insulted rat brain and decreased Lipid peroxidase (LPO). Notably, molecular docking study demonstrated a good binding affinity of empagliflozin for Brain-Derived Neurotrophic Factor (BDNF), suggesting that its antidepressant effects may be mediated through the modulation of the BDNF pathway. These findings support the potential therapeutic application of empagliflozin for depression, particularly in cases associated with neuroinflammation and oxidative stress. [ABSTRACT FROM AUTHOR]

Background and Purpose: Demand for new antidepressants has resulted in a re‐evaluation of the therapeutic potential of psychedelic drugs. Several tryptamines found in psilocybin‐containing "magic" mushrooms share chemical similarities with psilocybin. Early work suggests they may share biological targets. However, few studies have explored their pharmacological and behavioural effects. Experimental Approach: We compared baeocystin, norbaeocystin and aeruginascin with psilocybin to determine if they are metabolized by the same enzymes, similarly penetrate the blood–brain barrier, serve as ligands for similar receptors and modulate behaviour in rodents similarly. We also assessed the stability and optimal storage and handling conditions for each compound. Key Results: In vitro enzyme kinetics assays found that all compounds had nearly identical rates of dephosphorylation via alkaline phosphatase and metabolism by monoamine oxidase. Further, we found that only the dephosphorylated products of baeocystin and norbaeocystin crossed a blood–brain barrier mimetic to a similar degree as the dephosphorylated form of psilocybin, psilocin. The dephosphorylated form of norbaeocystin was found to activate the 5‐HT2A receptor with similar efficacy to psilocin and norpsilocin in in vitro cell imaging assays. Behaviourally, only psilocybin induced head twitch responses in rats, a marker of 5‐HT2A‐mediated psychedelic effects and hallucinogenic potential. However, like psilocybin, norbaeocystin improved outcomes in the forced swim test. All compounds caused minimal changes to metrics of renal and hepatic health, suggesting innocuous safety profiles. Conclusions and Implications: Collectively, this work suggests that other naturally occurring tryptamines, especially norbaeocystin, may share overlapping therapeutic potential with psilocybin, but without causing hallucinations. [ABSTRACT FROM AUTHOR]

The study examines the therapeutic benefits of Centella asiatica ethanolic stem extract. This study aims to promote Centella asiatica stem as an effective herbal remedy by examining its in vitro anti-inflammatory and in vivo depressive properties. The goal of the research is to give a natural medicine to ease symptoms and lessen reliance on allopathic medications and their associated adverse effects. The assessment of efficacy of the ethanolic stem extract is done using both in vivo and in vitro models to address these two interconnected health concerns. The in vivo model involves measuring of behavioural changes in animals treated with the extract. Careful examination and comprehension of the findings add more proof suggesting that the Centella asiatica stem maybe beneficial for many health problems. According to the results, this implies that the use of herbs like Centella asiatica may be a new treatment option rather than relying on prescription drugs. As a result, individuals may need to take fewer medications at lower doses. To understand more about the potential benefits of herbal therapy, collaborative research and through experimentation are required. This study demonstrates on how plants can be used to improve human wellbeing. [ABSTRACT FROM AUTHOR]

Due to the prevalence of depression as a mental health problem, there is a need for innovative and effective treatment regimen. The aim of this study is to evaluate the ethanolic leaves extract of pomelo plant viz Citrus maxima, having antidepressant potential by employing behavioral tests on Wistar albino rats. The phytochemical investigation of ethanolic leaves extract of Citrus maxima show the presence of secondary metabolites such as flavonoid, tannin, saponin, amino acid, alkaloids, coumarins, protein and steroid respectively. The antidepressant potential of ethanolic leaves extract of Citrus maxima was investigated by employing behavioral parameters viz Force swim test (FST), Tail suspension test (TST), Locomotor activity (LA), and effect of depression was assessed by estimated serum corticosterone (CORT) level of respective animals group. Animals were divided into five major groups, Gp I treated as normal control rats and received carboxy methyl cellulose only (10ml/kg, p.o) daily for 14 days; Gp II (stress control) rats received carboxy methyl cellulose (10ml/kg, p.o) daily for 14 days and subjected to acute restraint on 13th day respectively Gp III (standard drug treatment) rats received imipramine (15mg/kg, p.o) daily for 14 days and subjected to acute restraint on 13th day respectively; similarly the rats of Gp IV and Gp V received 200 mg/kg, p.o and 400 mg/kg, p.o of EECM daily for 14 days and subjected to restraint stress on 13th day respectively. Results revealed that the administration with leaves extract from Citrus maxima lowered immobility time by a substantial amount, dose-dependently, in both the FST and TST. More research is required to determine the underlying mechanisms of action, as well as to assess the safety and efficacy of the extract in treating human depression. [ABSTRACT FROM AUTHOR]

Introduction: Doxazosin is an alpha-1 antagonist used for the treatment of benign prostatic hypertrophy (BPH) symptoms and hypertension. An α (1)-adrenergic receptor antagonist called Doxazosin is used to treat benign prostatic hyperplasia and excessive blood pressure. There is evidence linking peripheral α-adrenergic receptors to inflammation. Aim and Objective: To study the antidepressant effect of Doxazosin by an experimental model in swiss albino mice. Material and Methods: The study was conducted in the Department of Pharmacology & Therapeutics at King George’s Medical University, Lucknow. The present study was designed to evaluate antidepressant in an experimental model in Swiss albino mice. A total number of 18 female Swiss albino mice were included in the study. They were kept in the institutional animal house under standard conditions. They received normal pellet diet and water ad libitum. They were allowed to get acclimatized to the new environment for a period of 2 weeks. Mice were randomly divided into 3 groups, each group containing 6 mice. Results: In the present study antidepressant activity was observed by the period of immobility in Forced swim test. Each activity was conducted on 18 mice, 6 mice in each group (Group A: Vehicle, Group B: Doxazosin, Group C: Imipramine). Therefore on Day 1, period of immobility of mice in the above 3 groups was found to be comparable. On Day 11, period of immobility of mice in the above 3 groups was found to be comparable again. It was observed that there was a slight decrease in period of immobility indicating that Doxazosin (4 mg/kg) may have some weak antidepressant activity at Day 21. Decreasing period of immobility significantly more than control indicating that Doxazosin (4 mg/kg) may have moderate antidepressant activity at Day 31. Conclusion: Doxazosin (4 mg/kg) appeared to be a promising therapy option for patients presenting with depression. [ABSTRACT FROM AUTHOR]

Background: Xylopic acid (XA), a kaurene diterpene from the dried fruits of Xylopia aethiopica, has anxiolytic- and antidepressant-like activity in mice and zebrafish. We aimed to assess the potential synergistic antidepressant-like effects of XA when combined with selected antidepressants in the mouse forced-swim test. Materials and methods: The antidepressant-like effect of xylopic acid (XA) (10, 30, 100 mgkg−1), fluoxetine (Flx) (3, 10, 30 mgkg−1), sertraline (Sert) (3, 10, 30 mgkg−1), imipramine (Imi) (10, 30, 100 mgkg-1) and ketamine (Ket) (0.1, 0.3, 1.0 mgkg−1), was evaluated in forced swim test. The dose (ED50) that achieved a 50% reduction in immobility time was determined from the respective log-dose response curves. XA and the selected antidepressants were co-administered in fixed-dose ratio combinations (1/2:1/2, 1/4:1/4, 1/8:1/8) of the ED50 to identify the experimental ED50 (ED50mix). The theoretical ED50(ED50add), of all combinations was determined using isobolograms and compared with the ED50mix to identify the nature of the interaction. The effect of dose combinations on general locomotor activity was assessed in the open-field test. Results: The interaction index (γ) for the following XA combinations, XA/Flx, XA/Sert, XA/Imi and XA/Ket were 0.42, 0.41, 0.31 and 0.34. An independent sample t-test revealed that the experimental ED50 (ED50mix) was significantly lower than the theoretical ED50 (ED50add) in all combinations of XA, indicative of a synergistic antidepressant-like effect. However, combinations of XA with ketamine significantly reduced general locomotor activity at all dose combinations. Conclusion: The co-administration of xylopic acid and fluoxetine, imipramine, sertraline and ketamine produces a synergistic antidepressant-like effect in mice.

Housing conditions and prior life experiences are known to affect animal behavior and brain regions that regulate important neural and physiological functions, such as memory and stress responses. Stressors of low to moderate intensity can provide an enriched environment and promote cognitive functions. In contrast, exposures of excessive severity and/or duration can lead to maladaptation and distress, altering cognitive functions. Such excessive stressors can thus be used to model pathological conditions and test diverse therapeutic approaches. In this study, we addressed whether inescapable exposure of rats to aversive water environment of the "forced swim test" would interfere with their cognitive performance on the subsequent "water escape" test. The data show that a single exposure to a 15-min forced swim session interferes significantly with the ability to escape the water environment. This is manifested by a significant increase in the latency of diving under the cylinder and a reduction in the proportion of rats capable of completing the test task during the initial session. Additionally, there is a lack of development in diving skills during repeated sessions at 15-minute intervals. These negative effects can persist for at least 2 weeks. The use of the "forced swim" procedure prior to the "water escape" test may, therefore, provide a novel experimental approach to modeling stress-induced cognitive dysfunctions and evaluating the effects of pharmacological agents with potential antidepressant and procognitive properties. [ABSTRACT FROM AUTHOR]

Depression often known as depressive disorder is described by a persistent lack of enjoyment, enthusiasm in pursuits, or melancholy feelings. Depression is not the same as normal mood swings and feelings about day-to-day living. It could affect every aspect of life, including relationships with friends, family, and the community. It could be brought on by or exacerbated by problems at work or in the classroom. This study aims to evaluate antidepressant like activity of ethanolic extract of roots of Boerhavia diffusa (Nyctaginaceae). control and cure of this diseases, a vast variety of medications are used daily. The herbal drugs are biodegradable and are natural medications hence are becoming more and more popular. Using a Soxhlet equipment and a normal extraction procedure, the ethanolic extract was produced. The mice were administered several dosages of the extract (100, 200, and 400 mg/kg) in addition to the vehicle (normal saline) for the control group & ARS (Acute Restraint Stress) Group and fluoxetine as the conventional medication. The mice were subjected to ARS and were treated with ethanolic extract of Boerhavia diffusa at a dose of 100mg/kg, 200mg/kg and 400mg/kg respectively. After that they were subjected to animal models, the tail suspension test (TST), force suspension test (FST) to assess the antidepressant potential and open field test (OFT), to assess locomotor & antidepressant potential of administered drug The TST revealed prolonged immobility in the BDEE (Boerhavia diffusa ethanolic extract) treated animals. The crossing over of squares activity in the OFT rose, indicating a decline in depression levels. The mice's FST revealed a decrease in their ability to reach the plateau stage following immobility. According to the study, BDEE demonstrates strong antidepressant effect and offer a natural alternative to pharmaceutical treatment for depression disorders. In futuristic study, further investigation is required to identify certain active molecules and have a deeper comprehension of the underlying processes of action. [ABSTRACT FROM AUTHOR]

The small‐molecule drug, FTY720 (fingolimod), is a synthetic sphingosine 1‐phosphate (S1P) analogue currently used to treat relapsing–remitting multiple sclerosis in both adults and children. FTY720 can cross the blood–brain barrier (BBB) and, over time, accumulate in lipid‐rich areas of the central nervous system (CNS) by incorporating into phospholipid membranes. FTY720 has been shown to enhance cell membrane fluidity, which can modulate the functions of glial cells and neuronal populations involved in regulating behaviour. Moreover, direct modulation of S1P receptor‐mediated lipid signalling by FTY720 can impact homeostatic CNS physiology, including neurotransmitter release probability, the biophysical properties of synaptic membranes, ion channel and transmembrane receptor kinetics, and synaptic plasticity mechanisms. The aim of this study was to investigate how chronic FTY720 treatment alters the lipid composition of CNS tissue in adolescent mice at a key stage of brain maturation. We focused on the hippocampus, a brain region known to be important for learning, memory, and the processing of sensory and emotional stimuli. Using mass spectrometry‐based lipidomics, we discovered that FTY720 increases the fatty acid chain length of hydroxy‐phosphatidylcholine (PCOH) lipids in the mouse hippocampus. It also decreases PCOH monounsaturated fatty acids (MUFAs) and increases PCOH polyunsaturated fatty acids (PUFAs). A total of 99 lipid species were up‐regulated in the mouse hippocampus following 3 weeks of oral FTY720 exposure, whereas only 3 lipid species were down‐regulated. FTY720 also modulated anxiety‐like behaviours in young mice but did not affect spatial learning or memory formation. Our study presents a comprehensive overview of the lipid classes and lipid species that are altered in the hippocampus following chronic FTY720 exposure and provides novel insight into cellular and molecular mechanisms that may underlie the therapeutic or adverse effects of FTY720 in the central nervous system. [ABSTRACT FROM AUTHOR]

Depression is a major world health issue. Though conventional antidepressants are employed for its management, they are fraught with inconsistent efficacy and untoward side effects. Therefore, finding alternative medicines for depression treatment is critical. The present study evaluated the possible antidepressant-like properties of hydroethanolic leaf extract of Morinda longiflora (MLE) in animal models. Acute animal models—Forced swim (FST) and tail suspension tests (TST)—as well as a chronic model, open space swim test, were used to establish antidepressant-like activity. The open field test was performed to exclude confounding psychostimulatory effects. Attempts were also made to investigate the possible underlying mechanism(s) of the antidepressant-like action of MLE. Oral treatment with MLE (30–300 mg/kg) significantly decreased the duration of immobility in the TST and FST. Also, treatment of mice with para-chlorophenylalanine (PCPA, 300 mg/kg, i.p.) failed to reverse the reduction in immobility duration induced by MLE. Furthermore, after treating mice with reserpine (1 mg/kg), α-methyl-p-tyrosine (AMPT, 100 mg/kg, i.p.), or both drugs combined, the reduction in immobility duration caused by MLE was reversed. Again, the anti-immobility actions produced by the extract were significantly reversed by l-arginine, sildenafil, haloperidol and prazosin but not propranolol, yohimbine or cyproheptadine. Pre-treatment of mice with l-NAME and methylene blue potentiated the anti-immobility action produced by the extract. The extract markedly reduced the duration of immobility in the OSST model. However, the extract (30–300 mg/kg) had no significant effect on the total distance travelled in the open field test. In conclusion, the current findings suggest that hydroethanolic leaf extract of Morinda longiflora has significant antidepressant-like activity and may involve catecholaminergic and nitric oxide-cyclic guanosine monophosphate pathways.

Background: Chronic physical stress has many effects on the nervous system and can cause structural changes in different parts of the brain and hemomodulatory, including hormonal. Current pharmacotherapeutic treatments have limited efficacy and are associated with many deleterious side effects Aim: The aim of this research is to determine how apis dorsata forest honey administration affects FSH and LH levels in rats who are subjected to forced swim tests as a model of chronic physical stress placed in a container filled with water from which it cannot escape. Methods: This was an experimental laboratory study with 32 rats divided into four treatment groups: control (C), Treatment 1 (T1) with a forced swim test + honey (2 g/rat/day), Treatment 2 (T2) with a forced swim test + honey (4 g/rat/day), and Treatment 3 (T3) with a forced swim test + honey (6 g/rat/day). All treatments were administered for 14 days. Then blood was taken for FSH and LH serum tests, and a one-way ANOVA and Duncan test were used to statistically test the data analysis. Results: The results of this study indicate that the administration of forest honey had no significant effect (p > 0.05) on the FSH parameter, but there was a significant decrease in LH levels in the T2 and T3 groups (p [Open Vet J 2024; 14(2.000): 738-742]

In order to assess the depression decreasing effect of the molecules, a forced swim protocol in rats was used to manufacture azetidinone compounds with a tricyclic nucleus. Three different procedures were used in order to synthesize the necessary compounds. Step one involved reacting anthracene-9,10-dione with hydrazine hydrate in the presence of methanol under refluxing conditions to produce 2. Next, several substituted aromatic aldehydes were refluxed with 2 under the influence glacial acetic acid as catalyst to create Schiff bases. Chloracetyl chloride was used under alkaline circumstances to accomplish cyclization in the last stage. The produced compounds 4a-e had a yield range from 61-70% and shown solubility or mild solubility in DMSO, methanol, and chloroform. Using methanol:ethyl acetate (4:6) as the solvent solution, TLC was used to evaluate the purity of the produced compounds. The compounds' Rf values ranged from 0.59 to 0.73. The compounds have a melting temperature range of 172-214°C and were produced as a white to yellow solid. The compounds demonstrated antidepressant activity that was dosage dependent. Compounds 4a, 4b, and 4d had significantly shorter immobility times (p<0.01) than the control group. It became clear that each test chemical may exhibit antidepressant activity when the dosage was increased. [ABSTRACT FROM AUTHOR]

Experimental animal models are considered an important scientific tool used to understand the pathogenesis of depression and the mechanism of anti-depressant agents. Human depression is a unique and complex process of multifactorial etiologies. The research-based evidence suggested that a functional deficiency of norepinephrine (NE), 5-hydroxy tryptamine (5-HT), and other neurotransmitters result in depression. A mood alteration disease associated with neurotransmitter dysfunction or psychological stress. There are numerous experimental animal models available to screen antidepressant drugs, but their precise pathophysiology is not entirely wellknown. The present review focused on depression assay studies that used a variety of experimental models, including acute stress models such as the forced swim test, models of prolonged physical or social stress such as social defeat, genetic models of secondary depression, and other experiments meant to clarify the mechanisms of antidepressant medications. [ABSTRACT FROM AUTHOR]

Depression is a common non-motor symptom in Parkinson's disease (PD) that includes anhedonia and impacts quality of life but is not effectively treated with conventional antidepressants clinically. Vagus nerve stimulation improves treatment-resistant depression in the general population, but research about its antidepressant efficacy in PD is limited. Here, we administered peripheral non-invasive focused ultrasound to hemiparkinsonian ('PD') and non-parkinsonian (sham) rats to mimic vagus nerve stimulation and assessed its antidepressant-like efficacy. Following 6-hydroxydopamine (6-OHDA) lesion, akinesia-like immobility was assessed in the limb-use asymmetry test, and despair- and anhedonic-like behaviors were evaluated in the forced swim test and sucrose preference test, respectively. After, tyrosine hydroxylase immuno-staining was employed to visualize and quantify dopaminergic degeneration in the substantia nigra pars compacta, ventral tegmental area, and striatum. We found that PD rats exhibited akinesia-like immobility and > 90% reduction in tyrosine hydroxylase immuno-staining ipsilateral to the lesioned side. PD rats also demonstrated anhedonic-like behavior in the sucrose preference test compared to sham rats. No 6-OHDA lesion effect on immobility in the forced swim test limited conclusions about the efficacy of ultrasound on despair-like behavior. However, ultrasound improved anhedonic-like behavior in PD rats and this efficacy was sustained through the end of the 1-week recovery period. The greatest number of animals demonstrating increased sucrose preference was in the PD group receiving ultrasound. Our findings here are the first to posit that peripheral non-invasive focused ultrasound to the celiac plexus may improve anhedonia in PD with further investigation needed to reveal its potential for clinical applicability. [ABSTRACT FROM AUTHOR]

Background: Chronic physical stress has many effects on the nervous system and can cause structural changes in different parts of the brain and hemomodulatory, including hormonal. Current pharmacotherapeutic treatments have limited efficacy and are associated with many deleterious side effects Aim: The aim of this research is to determine how Apis dorsata forest honey administration affects follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels in rats who are subjected to forced swim tests as a model of chronic physical stress placed in a container filled with water from which it cannot escape. Methods: This was an experimental laboratory study with 32 rats divided into four treatment groups: control (C), Treatment 1 (T1) with a forced swim test + honey (2 g/rat/day), Treatment 2 (T2) with a forced swim test + honey (4 g/rat/day), and Treatment 3 (T3) with a forced swim test + honey (6 g/rat/day). All treatments were administered for 14 days. Then, blood was taken for FSH and LH serum tests, and a one-way ANOVA and Duncan test were used to statistically test the data analysis. Results: The results of this study indicate that the administration of forest honey had no significant effect (p > 0.05) on the FSH parameter, but there was a significant decrease in LH levels in the T2 and T3 groups (p < 0.05). Conclusion: It can be concluded that giving forest honey to rats who were subjected to a 14-day forced swim test had no effect on FSH and LH levels. In rats given a forced swim test as a model of chronic stress, administration at doses of 4 and 6 g/rat/day reduced LH serum levels. Thus, giving forest honey could maintain reproductive health in rat that experience chronic stress. [ABSTRACT FROM AUTHOR]

Depression remains the major cause of global disease burden and affects individuals in all communities around the world. More than 300 million individuals worldwide suffer from depression. The objective of the present study was to evaluate the antidepressant activity of ethanol leaf extract of Entada africana (ELEEA) in mice. Preliminary phytochemical screening and acute toxicity studies of the extract were carried out using standard methods. Antidepressant activity screening of the extract was conducted using Tail Suspension Test (TST), Forced Swim Test (FST), and Open Field Test (OFT) in mice. Phytochemical screening shows the presence of terpenoids, steroids, cardiac glycosides, tannins, saponins, flavonoids and carbohydrates in the extract. The result of the acute toxicity studies revealed an LD50 value of 28.3 mg/kg body weight in mice. ELEEA at all the tested doses significantly (p < 0.05) reduced the duration of immobility of mice in TST compared to the normal saline (control) group. In the FST, the extract at doses of 2, 4 and 8 mg/kg body weight exhibited significant (p < 0.01) reduction in the immobility time when compared to the control group. However, in the OFT, ELEEA at doses of 2, 4 and 8 mg/kg body weight and diazepam (0.5 mg/kg) had no significant effect (p > 0.05) on the number of lines crossed by the mice compared to the control group. The results of our study suggest that the ethanol leaf extract of Entada africana has potential for use as an antidepressant agent. [ABSTRACT FROM AUTHOR]

Context: The forced swim test (FST) is employed to examine depression and depressive-like behaviors in rodents, such as mice and rats. In this test, increased periods of immobility and decreased swimming by the animal indicate heightened despair and depression-like behaviors. Evidence Acquisition: This review discusses the impacts of the animals' race, gender, age, and weight and environmental factors like light, noise, and smell on the FST. Results: Our review reveals that racial differences in rats and mice can influence their behavior. Differences in the nervous system structure and sex hormones related to gender are also significant. Additionally, animals that are very young or old, and those that are either very overweight or underweight, are unsuitable for the FST. Environmental factors such as light, noise, and smell were identified as confounding factors that could influence the outcomes and compromise the study's reliability. Conclusions: It is essential to consider these factors and enhance the conditions and environment to carry out a standardized test. Furthermore, by acquiring more detailed information about these factors and minimizing or eliminating their effects, studies can yield more reliable results. [ABSTRACT FROM AUTHOR]

Rationale: There is an urgent need to identify behaviours in animals that can provide insight into the aetiology and potential treatment of depression in humans. Objectives: This study aimed to validate a repeated measures cognitive affective bias (CAB) test in a rat model of chronic stress and compare CAB with forced swim test (FST) measures. Methods: Male and female Sprague Dawley rats were trained to associate large and small rewards with scent, spatial, and tactile cues, and their response to an ambiguous tactile stimulus tested. Rats underwent weekly CAB testing for 4 weeks with no intervention, or for 2 weeks of chronic restraint stress (CRS), followed by 2 weeks of fluoxetine, vehicle, or no treatment. CRS rats also underwent the FST at selected timepoints. Results: In control rats, CAB was positive and remained stable over the 4-week period. In CRS-fluoxetine and CRS-vehicle groups, CAB was initially positive, became negative during chronic restraint stress, and returned to positive by 2 weeks after treatment. However, in the CRS-no treatment group, CAB was variable at the outset and unstable over time. Behaviour in the FST was not affected by treatment, and there was no correlation between CAB and FST outcomes. Conclusions: Instability in the CRS-no treatment group precluded interpretation of the impact of fluoxetine on CAB post-CRS. Our results suggest that behaviour in the FST does not reflect or alter affective state and support the use of CAB tests as part of the behavioural testing repertoire for preclinical animal models of affective disorders. [ABSTRACT FROM AUTHOR]

Rationale: Unconditioned tasks in rodents have been the mainstay of behavioural assessment for decades, but their validity and sensitivity to detect the behavioural consequences of early life stress (ELS) remains contentious and highly variable. Objectives: In the present study, we carried out a meta-analysis to investigate whether persistent behavioural effects, as assessed using unconditioned procedures in rats, are a reliable consequence of early repeated maternal separation, a commonly used procedure in rodents to study ELS. Methods: A literature search identified 100 studies involving maternally separated rats and the following unconditioned procedures: the elevated plus maze (EPM); open field test (OFT); sucrose preference test (SPT) and forced swim task (FST). Studies were included for analysis if the separation of offspring from the dam was at least 60 min every day during the pre-weaning period prior to the start of adolescence. Results: Our findings show that unconditioned tasks are generally poor at consistently demonstrating differences between control and separated groups with pooled effect sizes that were either small or non-existent (EPM: Hedge's g = − 0.35, p = 0.01, OFT: Hedge's g = − 0.32, p = 0.05, SPT: Hedge's g = − 0.33, p = 0.21, FST: Hedge's g = 0.99, p = 0.0001). Despite considerable procedural variability between studies, heterogeneity statistics were low; indicating the lack of standardization in the maternal separation protocol was the not the cause of these inconsistent effects. Conclusions: Our findings indicate that in general, unconditioned tests of depression and anxiety are not sufficient to reveal the full behavioural repertoire of maternal separation stress should not be relied upon in isolation. We argue that more objective tasks that sensitively detect specific cognitive processes are better suited for translational research on stress-related disorders such as depression. [ABSTRACT FROM AUTHOR]

A limitation of simulated space radiation studies is that radiation exposure is not the only environmental challenge astronauts face during missions. Therefore, we characterized behavioral and cognitive performance of male WAG/Rij rats 3 months after sham-irradiation or total body irradiation with a simplified 5-ion mixed beam exposure in the absence or presence of simulated weightlessness using hindlimb unloading (HU) alone. Six months following behavioral and cognitive testing or 9 months following sham-irradiation or total body irradiation, plasma and brain tissues (hippocampus and cortex) were processed to determine whether the behavioral and cognitive effects were associated with long-term alterations in metabolic pathways in plasma and brain. Sham HU, but not irradiated HU, rats were impaired in spatial habituation learning. Rats irradiated with 1.5 Gy showed increased depressive-like behaviors. This was seen in the absence but not presence of HU. Thus, HU has differential effects in sham-irradiated and irradiated animals and specific behavioral measures are associated with plasma levels of distinct metabolites 6 months later. The combined effects of HU and radiation on metabolic pathways in plasma and brain illustrate the complex interaction of environmental stressors and highlights the importance of assessing these interactions.

Social interaction and empathy play critical roles in determining the emotional well-being of humans. Stress-related depression and anxiety can be exacerbated or mitigated depending on specific social conditions. Although rodents are well known to exhibit emotional contagion and consolation behavior, the effects of group housing on stress-induced phenotypes in both males and females are not well established. Here, we investigated how the presence of stressed or unstressed conspecifics within a cage impact depression-related phenotypes. We housed male and female C57BL/6J mice in same-sex groups and subjected them to either gentle handling (GH) or the daily administration of corticosterone (CORT) for 10 days. The GH and CORT treatment groups were divided into cages of unmixed (GH or CORT) and mixed (GH and CORT) treatments. Depression-related phenotypes were measured using the forced swim test (FST) and sucrose preference test (SPT). We found that mixed housing alters FST behavior in a sex-specific manner. Male mice given chronic corticosterone (CORT) that were housed in the same cage as gently handled animals (GH) exhibited increased immobility, whereas GH females housed with CORT females demonstrated the opposite effect. This study underscores the importance of social housing conditions when evaluating stress-induced behavioral phenotypes and suggests that mixed cages of GH and CORT animals yield the greatest difference between treatment groups. The latter finding has important implications for identifying therapeutics capable of rescuing stress-induced behavioral deficits in the FST.

Depression is a serious mental disorder and the most prevalent cause of disability and suicide worldwide. Quercetin (QER) demonstrated antidepressant effects in rats exhibiting anxiety and depressive-like behaviors. In an attempt to improve QER's antidepressant activity, a QER-loaded transferosome (QER-TFS) thermosensitive gel for intranasal administration was formulated and optimized. The therapeutic effectiveness of the optimized formulation was assessed in a depressed rat model by conducting a behavioral analysis. Behavioral study criteria such as immobility, swimming, climbing, sucrose intake, number of crossed lines, rearing, active interaction, and latency to feed were all considerably enhanced by intranasal treatment with the QER-TFS in situ gel in contrast to other formulations. A nasal histopathological study indicated that the QER-TFS thermosensitive gel was safe for the nasal mucosa. An immunohistochemical analysis showed that the animals treated with the QER-TFS thermosensitive gel had the lowest levels of c-fos protein expression, and brain histopathological changes in the depressed rats were alleviated. According to pharmacodynamic, immunohistochemical, and histopathological experiments, the intranasal administration of the QER-TFS thermosensitive gel substantially alleviated depressive symptoms in rats. However, extensive preclinical investigations in higher animal models are needed to anticipate its effectiveness in humans. [ABSTRACT FROM AUTHOR]

Context Michelia champaca L. (Magnoliaceae) has been known since ancient times for its rich medicinal properties.Objective The ethanol extract of Michelia champaca leaves (EEMC) was evaluated on depression and anxiety using in vivo and in silico studiesMaterials and methods Swiss albino mice were divided into control, standard, 100 and 200 mg/kg b.w. EEMC groups and for drug administration using oral gavage. The antidepressant activity was evaluated using forced swim test (FST) and tail suspension test (TST) whereas the anxiolytic activity through elevated plus maze and light and dark tests. The in silico studies included molecular docking against human potassium channel KCSA-FAB and human serotonin transporter, and ADME/T analysis.Results Open arm duration and entries were comparable between 200 mg/kg b.w. group (184.45 ± 1.00 s and 6.25 ± 1.11, respectively) and that of diazepam treated group (180.02 s ± 0.40 and 6.10 ± 0.05, respectively). Time spent in the light cubicle was higher (46.86 ± 0.03%), similar to that of diazepam (44.33 ± 0.64%), suggesting its potent anxiolytic activity. A delayed onset of immobility and lowered immobility time was seen at both the treatment doses (FST: 93.7 ± 1.70 and 89.1 ± 0.40 s; TST: 35.05 ± 2.75 and 38.50 ± 4.10 s) and the standard drug imipramine (FST: 72.7 ± 3.72 and TST: 30.01 ± 2.99 s), indicative of its antidepressant ability. In silico studies predicted doripenem to induce anxiolytic and antidepressant activity by inhibiting human potassium channel KCSA-FAB and human serotonin transporter proteins, respectively.Conclusions EEMC is a rich source of bioactive compounds with strong antidepressant and anxiolytic properties.

Purpose: The aim of this study was to design fast dissolving tablets (FDT) of the anti –psychiatric drug haloperidol in solid dispersion forms as a way to enhance its dissolution profile and anti-psychiatric effect. Methods: Solubility studies of haloperidol in various polymers solutions were investigated. The selected polymer with high drug solubility (Poly ethylene glycol 4000) was used for preparation of solid dispersion through two methods solvent evaporation method and melting method. Haloperidol solid dispersion mixed with other solid powder excipients and compressed into tablets. The resulted tablets were evaluated according to British Pharmacopoeia (B.P.) specifications. Pre- and post -compression studies were performed to determine the flow properties and evaluate the solid dispersion systems, followed by in vivo studies through forced swimming test (FST) Results: Pre-compression studies showed adequate flowability and compatibility of polymer and solid excipients with haloperidol. The selected solid dispersion tablet (SD2) demonstrated the best disintegration and water absorption ratio in addition to satisfactory friability and hardness. Attempts of in vitro dissolution results and thermodynamic stability studies showed acceptable results for (SD2) formulation containing PEG 4000 polymer prepared by melting method.The in vivo study of (SD2) formulation revealed the highest immobility time to rats compared to control rats and others treated with commercial haloperidol product. Conclusion: Fast dissolving tablets prepared from solid dispersion of haloperidol with PEG4000 expressed rapid onset of action with enhanced anti-psychiatric effect of haloperidol.

As depression is projected to become the leading mental disease burden globally by 2030, understanding the underlying pathology, as well as screening potential anti-depressants with a higher efficacy, faster onset of action, and/or fewer side-effects is essential. A commonly used test for screening novel antidepressants and studying depression-linked aspects in rodents is the Porsolt Forced Swim Test. The present systematic mappping review gives a comprehensive overview of the evolution and of the most prevalently used set-ups of this test in rats, including the choice of animals (strain, sex, and age), technical aspects of protocol and environment, as well as reported outcome measures. Additionally, we provide an accessible list of all existing publications, to support informed decision-making for procedural and technical aspects of the test, to thereby enhance reproducibility and comparability. This should further contribute to reducing the number of unnecessarily replicated experiments, and consequently, reduce the number of animals used in future.

The liver's susceptibility to oxidative stress after a combination of forced swim test (FST) and low-dose-rate γ-irradiation has been observed. Therefore, this study aims to clarify the effects of low-dose (0.1 and 0.5 Gy)/high-dose-rate (1.2 Gy/min) irradiation on combined oxidative stressors—liver damage associated with FST and alcohol administration. In addition, the effects of similar irradiation on FST-induced immobility, which induces psychomotor retardation, and antioxidative effects on the brain, lungs, liver and kidneys were investigated, and the results were compared with those of a similar previous study that utilized low-dose-rate irradiation. Low-dose/high-dose-rate (especially 0.5 Gy) irradiation temporarily worsened liver antioxidant function and hepatic function with FST- and alcohol administration-related oxidative damage; however, the damages improved soon after. In addition, the increase in total glutathione content in the liver contributed to the early improvement of hepatic functions. However, pre-irradiation did not suppress immobility during the FST. The results also suggested that the effects of low-dose/high-dose-rate irradiation on the antioxidant functions of each organ after the FST were different from those of low-dose/low-dose-rate irradiation. Overall, this study provides further insights into the effects of low-dose irradiation on exposure to a combination of different oxidative stressors. It will also contribute to the elucidation of dose rate effects on oxidative stress in the low-dose irradiation range. [ABSTRACT FROM AUTHOR]

Annona muricata L. (Annonaceae) is widely used in the Amazon and Carribean in natural medicine as an antiparasitic, insecticidal, sedative and as an astringent for diarrhea among others. In Nigeria however, Annona muricata is among the under-utilized species of plants. This study investigated the antidepressant and ambulatory effect of A. muricata, using the open field test and forced swim tests on Sprague-Dawley rats administered ethanol stem-bark extracts of the Nigerian grown species. Rats were administered A. muricata stem-bark extract (50, 150 and 300mg/kg) alone and in combination with the drugs imipramine and sertraline (10mg/kg), respectively for 14 days. The administration of the extract was observed to cause a significant reduction in the swimming time and immobility time of the rats in the forced swim test. The ambulatory behavior of the rats was observed to decrease when the extract (150 and 300mg/kg) was administered alone to the rats while a much further decrease was observed in the explorative tendencies of the rats when the extract was combined with the imipramine and sertraline. The results suggested that the ethanol stem-bark extract of A.muricata, possess sedative and antidepressant effects. [ABSTRACT FROM AUTHOR]

Major depression is one of the most common psychiatric disorders worldwide, usually associated with anxiety. The multi-etiological nature of depression has increased the search for new antidepressant molecules, including irisin, for which, in a previous study, we tested its effect in young mice when administered intraperitoneally in a long-term intermittent manner. Here, we evaluated the effect of subcutaneous short-term irisin administration (100 µg/Kg/day/5 days) in male and female mice subjected to behavioral paradigms: Tail Suspension Test (TST), Forced Swim Test (FST), Elevated Plus Maze (EPM), and Y Maze (YM). Moreover, a qRT-PCR assay was performed to analyze the impact of irisin treatment on Pgc-1α/FNDC5 expression in the brain. A significant reduction in immobility time in TST and FST was observed in irisin-treated mice. Furthermore, irisin treatment significantly increased the number of entries and time spent in open arms, demonstrating its anxiolytic effect. Memory-enhancing effects were not reported in YM. Interestingly, no gender differences were observed in all behavioral tests. Overall, these results suggest that short-term subcutaneous irisin administration can exert an antidepressant and anxiolytic role, probably due to the activation of the Pgc-1α/FNDC5 system in the brain. Further investigation could lead to the identification of irisin as a new agent for the treatment of psychiatric disorders. [ABSTRACT FROM AUTHOR]

Depression is a serious psychological disorder which negatively affects human feelings and actions. The use of antidepressants is the therapy of choice while treating depression. However, such drugs are associated with severe side effects. There is a need for efficient and harmless drugs. In this connection, the present study was designed to synthesize several substituted benzodiazepine derivatives and explore their antidepressant potentials in an animal model. The chalcone backbone was initially synthesized, which was then converted into several substituted benzodiazepine derivatives designated as 1–6. The synthesized compounds were identified using spectroscopic techniques. The experimental animals (mice) after acclimatation were subjected to forced swim test (FST) and tail suspension test (TST) after oral administration of the synthesized compounds to evaluate their antidepressant potentials. At the completion of the mentioned test, the animals were sacrificed to determine GABA level in their brain hippocampus. The chloro-substituent compound (2) significantly reduced the immobility time (80.81 ± 1.14 s; p < 0.001 at 1.25 mg/kg body weight and 75.68 ± 3.73 s with p < 0.001 at 2.5 mg/kg body weight dose), whereas nitro-substituent compound (5) reduced the immobility time to 118.95 ± 1.31 and 106.69 ± 3.62 s (p < 0.001), respectively, at the tested doses (FST). For control groups, the recorded immobility time recorded was 177.24 ± 1.82 s. The standard drug diazepam significantly reduced immobility time to 70.13 ± 4.12 s while imipramine reduced it to 65.45 ± 2.81 s (p < 0.001). Similarly, in the TST, the compound 2 reduced immobility time to 74.93 ± 1.14 s (p < 0.001) and 70.38 ± 1.43 s (p < 0.001), while compound 5 reduced it to 88.23 ± 1.89 s (p < 0.001) and 91.31 ± 1.73 s (p < 0.001) at the tested doses, respectively, as compared to the control group immobility time (166.13 ± 2.18 s). The compounds 1, 3, 4, and 6 showed weak antidepressant responses as compared to compounds 2 and 5. The compounds 2 and 5 also significantly enhanced the GABA level in the brain's hippocampus of experimental animals, indicating the possible involvement of GABAergic mechanism in alleviating the depression which is evident from the significant increase in mRNA levels for the α subunit of the GABAA receptors in the prefrontal cortex of mice as well. From the results, it can be concluded that compound 2 and 5 could be used as alternative drugs of depression. However, further exploration in this connection is needed in other animal models in order to confirm the observed results in this study. [ABSTRACT FROM AUTHOR]

Epilepsy and major depressive disorder are the two of the most common central nervous system (CNS) diseases. Clinicians and patients call for new antidepressants, antiseizure medicines, and in particular drugs for depression and epilepsy comorbidities. In this work, a dozen new triazole-quinolinones were designed, synthesized, and investigated as CNS active agents. All compounds reduced the immobility time significantly during the forced swim test (FST) in mice at the dosage of 50 mg/kg. Compounds 3f–3j gave superior performance over fluoxetine in the FST with more reductions of the immobility time. Compound 3g also reduced immobility time significantly in a tail suspension test (TST) at the dosage of 50 mg/kg, though its anti-immobility activity was inferior to that of fluoxetine. An open field test was carried out and it eliminated the false-positive possibility of 3g in the FST and TST, which complementarily supported the antidepressant activity of 3g. We also found that almost all compounds except 3k exhibited antiseizure activity in the maximal electroshock seizure (MES) model at 100 or 300 mg/kg. Compounds 3c, 3f, and 3g displayed the ED50 of 63.4, 78.9, and 84.9 mg/kg, and TD50 of 264.1, 253.5, and 439.9 mg/kg, respectively. ELISA assays proved that the mechanism for the antiseizure and antidepressant activities of compound 3g was via affecting the concentration of GABA in mice brain. The molecular docking study showed a good interaction between 3g and the amino acid residue of the GABAA receptor. Excellent drug-like properties and pharmacokinetic properties of compound 3a–l were also predicted by Discovery Studio. These findings provided a new skeleton to develop agents for the treatment of epilepsy and depression comorbidities. [ABSTRACT FROM AUTHOR]

The Wistar Hannover rat (WHR) is a strain commonly used for toxicity studies but rarely used in studies investigating depression neurobiology. In this study, we aimed to characterise the behavioural responses of WHR to acute and repeated antidepressant treatments upon exposure to the forced swim test (FST) or learned helplessness (LH) test. WHR were subjected to forced swimming pre-test and test with antidepressant administration (imipramine, fluoxetine, or escitalopram) at 0, 5 h and 23 h after pre-test. WHR displayed high immobility in the test compared to unstressed controls (no pre-swim) and failed to respond to the antidepressants tested. The effect of acute and repeated treatment (imipramine, fluoxetine, escitalopram or s-ketamine) was then tested in animals not previously exposed to pre-test. Only imipramine (20 mg/kg, 7 days) and s-ketamine (acute) reduced the immobility time in the test. To further investigate the possibility that the WHR were less responsive to selective serotonin reuptake inhibitors, the effect of repeated treatment with fluoxetine (20 mg/kg, 7 days) was investigated in the LH model. The results demonstrated that fluoxetine failed to reduce the number of escape failures in two different protocols. These data suggest that the WHR do not respond to the conventional antidepressant treatment in the FST or the LH. Only s-ketamine and repeated imipramine were effective in WHR in a modified FST protocol. Altogether, these results indicate that WHR may be an interesting tool to investigate the mechanisms associated with the resistance to antidepressant drugs and identify more effective treatments. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is a complex illness caused by both genetic and environmental factors. Antidepressant resistance also has a genetic component. To date, however, very few genes have been identified for major depression or antidepressant resistance. In this study, we investigated whether outbred heterogeneous stock (HS) rats would be a suitable model to uncover the genetics of depression and its connection to antidepressant resistance. The Wistar Kyoto (WKY) rat, one of the eight founders of the HS, is a recognized animal model of juvenile depression and is resistant to fluoxetine antidepressant treatment. We therefore hypothesized that adolescent HS rats would exhibit variation in both despair-like behavior and response to fluoxetine treatment. We assessed heritability of despair-like behavior and response to sub-acute fluoxetine using a modified forced swim test (FST) in 4-week-old HS rats. We also tested whether blood transcript levels previously identified as depression biomarkers in adolescent human subjects are differentially expressed in HS rats with high vs. low FST immobility. We demonstrate heritability of despair-like behavior in 4-week-old HS rats and show that many HS rats are resistant to fluoxetine treatment. In addition, blood transcript levels of Amfr, Cdr2 and Kiaa1539, genes previously identified in human adolescents with MDD, are differentially expressed between HS rats with high vs. low immobility. These data demonstrate that FST despair-like behavior will be amenable to genetic fine-mapping in adolescent HS rats. The overlap between human and HS blood biomarkers suggest that these studies may translate to depression in humans.