Increased Sucrose Consumption Research Articles

Neurobehavioral and molecular changes in a rodent model of ACTH-induced HPA axis dysfunction

Hypothalamic-pituitary-adrenal (HPA) axis dysregulation is linked to the pathophysiology of depression. Although exogenous adrenocorticotropic hormone (ACTH) is associated with a depressive-like phenotype in rodents, comprehensive neurobehavioral and mechanistic evidence to support these findings are limited. Sprague-Dawley rats (male, n = 30; female, n = 10) were randomly assigned to the control (male, n = 10) or ACTH (male, n = 20; female n = 10) groups that received saline (0.1 ml, sc.) or ACTH (100 μg/day, sc.), respectively, for two weeks. Thereafter, rats in the ACTH group were subdivided to receive ACTH plus saline (ACTH_S; male, n = 10; female, n = 5; 0.2 ml, ip.) or ACTH plus imipramine (ACTH_I; male, n = 10; female, n = 5;10 mg/kg, ip.) for a further four weeks. Neurobehavioral changes were assessed using the forced swim test (FST), the sucrose preference test (SPT), and the open field test (OFT). Following termination, the brain regional mRNA expression of BDNF and CREB was determined using RT-PCR. After two-weeks, ACTH administration significantly increased immobility in the FST (p = 0.03), decreased interaction with the center of the OFT (p < 0.01), and increased sucrose consumption (p = 0.03) in male, but not female rats. ACTH administration significantly increased the expression of BDNF in the hippocampus and CREB in all brain regions in males (p < 0.05), but not in female rats. Imipramine treatment did not ameliorate these ACTH-induced neurobehavioral or molecular changes. In conclusion, ACTH administration resulted in a sex-specific onset of depressive-like symptoms and changes in brain regional expression of neurotrophic factors. These results suggest sex-specific mechanisms underlying the development of depressive-like behavior in a model of ACTH-induced HPA axis dysregulation.

Methanol leaf extract of Leptadenia hastata ameliorates chronic, unpredictable, mild stress-induced depression

Leptadenia hastata (Pers) Decne is a tropical herb widely used in the phytotherapy of neuropsychiatric disorders, including depression. Despite the availability of synthetic antidepressant drugs, depression remains a major medical problem. The study aimed to evaluate the effect of methanol leaf extract of Leptadenia hastata (LHME) on chronic unpredictable mild stress-induced depression. Acute toxicity of Leptadenia hastata was determined using Organization for Economic Co-operation and Development (OECD) guidelines. The chronic unpredictable mild stress (CUMS) model-induced depression involves the evaluation of baseline behavioural changes in the sucrose preference test, open field test, and tail suspension test. The brain-derived neurotrophic factor (BDNF) concentrations and serum cortisol were assessed using an enzyme-linked immunosorbent assay (ELISA). The levels of superoxide dismutase (SOD) and malondialdehyde (MDA) were also assessed using standard procedure. The median lethal dose (LD50) value was &gt; 5000 mg/kg. LHME at doses of 250 – 1000 mg significantly (p&lt;0.01) decreased CUMS-induced depression in a dose-dependent manner. LHME significantly (p&lt;0.01) reversed depression associated weight loss from 14.00±0.62 g in week two to 22.57±1.13 g in week five of the experiment. It also increased sucrose consumption in the sucrose preference test (SPT) from 4.29±0.52 ml in week two to 9.71±0.68 ml in week five. The LHME also significantly (p&lt;0.01) decreased the duration of immobility from 190.00±4.55 sec in week two to 158.00±3.83 sec in week five in the tail suspension test (TST). Furthermore, LHME at the tested dose significantly (p&lt;0.01) increased the locomotor activity from 36.29±1.25 sec in week two to 62.43±1.73 sec in week five in the open field test (OFT). LHME significantly (p&lt;0.01) and dose-dependently increased the levels of BDNF (204.74±22.97 pg/ml) and decreased the levels of plasma cortisol (0.98±0.06 ng/ml). However, treatment with LHME and the standard drug imipramine did not significantly change SOD activity and the MDA level in CUMS-induced mice. The findings demonstrated that LHME ameliorates CUMS-induced depressive-like behaviours, and its effect is possibly mediated via the neuroendocrine (cortisol) and neurotrophic (BDNF).

Tactile stimulation of young WAG/Rij rats prevents development of depression but not absence epilepsy.

Investigations in Wistar Albino Glaxo from Rijswijk (WAG/Rij) rats that are susceptible to genetic absence epilepsy have demonstrated that environmental modifications affect absence seizures. Previously, we showed that neonatal tactile stimulations produce disease-modifying effect on genetically determined absence epilepsy and associated depression in Wag/Rij rats. The study presented here examined the effect of TS during late ontogenesis (adolescence and young adulthood) on epilepsy and depression outcomes in this genetically epileptic rat strain. On postnatal day (PND) 38, male WAG/Rij rats randomly were assigned to either the tactile stimulation (TS), handled or control group (unhandled) with 8 animals in each group. Following a 7-day adaptation period to their new surroundings, the animals were submitted to tactile stimulation from PND 45 to PND 90, five days per week, for 5 min daily. The tactile-stimulated rat was removed from its cage, placed on the experimenter's lap, and had its neck and back gently stroked by the researcher. The handled rats were taken to another cage and left alone for 5 min daily from PND 45 to PND 90. The control rats were left undisturbed in their home cage, except for regular cage cleaning. After PND 90, all rats were left undisturbed until behavioral testing and EEG recording. When the animals were 7 months old, they were subjected to the sucrose consumption test (SCT) and the forced swimming test (FST). Electroencephalogram (EEG) recordings were made at 8 months of age in order to measure electroencephalographic seizure activity, thus, the spike-wave discharges (SWDs). Tactile-stimulated rats showed increased sucrose consumption and number of approaches to the sucrose solution in the SCT when compared with the handled and control rats. In the FST, rats in TS group showed lower immobility time and greater immobility latency, active swimming time and diving frequency than the handled and control rats. The duration and the number of seizures were not different amongst the groups. The data obtained suggest that TS in young rats is able to prevent depression in WAG/Rij rats.

Antidepressant-like effects of the aqueous lyophilizate of the roots bark of Capparis sepiaria (Capparaceae) on an animal’s model of depression

Background: Major Depressive Disorder is a common mental illness characterized by persistent low mood, cognitive impairment, anhedonia, weight gain, or loss and several other symptoms, ranging from psychomotor to cognitive impairments. Commonly available antidepressants show side effects and limited efficacy; therefore, an alternative is to be considered. Capparis sepiaria (Capparaceae) is a plant used in traditional medicine to treat mental disorders. The aim of this study was to investigate possible antidepressant-like effects of the aqueous lyophilizate of Capparis sepiaria in Wistar rats. Methods: Depressive-like behavior was induced using restraint stress for 14 days. The forced swimming test, the open field test, the sucrose preference test, body weight, and the food consumption were done to assess depressive-like behavior. On day 15 animals were sacrificed and the adrenal glands mass and the hippocampi were collected for Hypothalamo-pituitary-axis activity and oxidative stress markers assessment. Results: The aqueous lyophilizate of the root bark of Capparis sepiaria increased swimming time and decreased immobility time (p&lt;0.001) in the forced swimming test and, increased sucrose consumption in the sucrose preference test (p&lt;0.001). In the open field test, there was no difference in the number of lines crossed between groups. Chronic stress significantly increased adrenal weight (p&lt;0.05) which was prevented by the aqueous lyophilizate of Capparis sepiaria at the dose 10 mg/kg. Chronic stress decreased food consumption and weight which was prevented by the aqueous lyophilizate of Capparis sepiaria. The lyophilizate increased the reduced glutathione (GSH) level (p&lt;0.001), and Catalase activity (p&lt;0.001), and decreased the malondialdehyde level (p&lt;0.001) in the determination of some oxidative stress markers. Conclusion: These results suggest that the aqueous lyophilizate of the roots bark of C. sepiaria possesses antidepressant-like effects. Keywords: Depression; Capparis sepiaria; restraint stress; oxidative stress.

Increased sucrose consumption in mice gene-targeted for Vmat2 selectively in NeuroD6-positive neurons of the ventral tegmental area.

Ventral tegmental area (VTA) dopamine (DA) neurons are implicated in reward processing, motivation, reward prediction error, and in substance use disorder. Recent studies have identified distinct neuronal subpopulations within the VTA that can be clustered based on their molecular identity, neurotransmitter profile, physiology, projections and behavioral role. One such subpopulation is characterized by expression of the NeuroD6 gene, and projects primarily to the nucleus accumbens medial shell. We recently showed that optogenetic stimulation of these neurons induces real-time place preference while their targeted deletion of the Vmat2 gene caused altered response to rewarding substances, including ethanol and psychostimulants. Based on these recent findings, we wanted to further investigate the involvement of the NeuroD6-positive VTA subpopulation in reward processing. Using the same NeuroD6Cre+/wt ;Vmat2flox/flox mice as in our prior study, we now addressed the ability of the mice to process sucrose reward. In order to assess appetitive behavior and motivation to obtain sucrose reward, we tested conditional knockout (cKO) and control littermate mice in an operant sucrose self-administration paradigm. We observed that cKO mice demonstrate higher response rates to the operant task and consume more sucrose rewards than control mice. However, their motivation to obtain sucrose is identical to that of control mice. Our results highlight previous observations that appetitive behavior and motivation to obtain rewards can be served by distinct neuronal circuits, and demonstrate that the NeuroD6 VTA subpopulation is involved in mediating the former, but not the latter. Together with previous studies on the NeuroD6 subpopulation, our findings pinpoint the importance of unraveling the molecular and functional role of VTA subpopulations in order to better understand normal behavior and psychiatric disease.

Estradiol withdrawal following a hormone simulated pregnancy induces deficits in affective behaviors and increases ∆FosB in D1 and D2 neurons in the nucleus accumbens core in mice

In placental mammals, estradiol levels are chronically elevated during pregnancy, but quickly drop to prepartum levels following birth. This may produce an “estrogen withdrawal” state that has been linked to changes in affective states in humans and rodents during the postpartum period. The neural mechanisms underlying these affective changes, however, are understudied. We used a hormone-simulated pseudopregnancy (HSP), a model of postpartum estrogen withdrawal, in adult female C57BL/6 mice to test the impact of postpartum estradiol withdrawal on several behavioral measures of anxiety and motivation. We found that estradiol withdrawal following HSP increased anxiety-like behavior in the elevated plus maze, but not in the open field or marble burying tests. Although hormone treatment during HSP consistently increased sucrose consumption, sucrose preference was generally not impacted by hormone treatment or subsequent estradiol withdrawal. In the social motivation test, estradiol withdrawal decreased the amount of time spent in proximity to a social stimulus animal. These behavioral changes were accompanied by changes in the expression of ∆FosB, a transcription factor correlated with stable long-term plasticity, in the nucleus accumbens (NAc). Specifically, estrogen-withdrawn females had higher ∆FosB expression in the nucleus accumbens core, but ∆FosB expression did not vary across hormone conditions in the nucleus accumbens shell. Using transgenic reporter mice, we found that this increase in ∆FosB occurred in both D1- and D2-expressing cells in the NAc core. Together, these results suggest that postpartum estrogen withdrawal impacts anxiety and motivation and increases ∆FosB in the NAc core.

Voluntary wheel running promotes resilience to the behavioral effects of unpredictable chronic mild stress in male and female mice

Besides significant benefits to physical health, exercise promotes mental health, reduces symptoms of mental illness, and enhances psychological development. Exercise can offset the impact of chronic stress, which is a major precursor to the development of mental disorders. The effects of exercise on chronic stress-induced behaviors are contradictory in preclinical studies, primarily due to the lack of data and sex-specific investigations. We sought to evaluate the effects of exercise on chronic stress-induced behavioral changes in both male and female mice. Mice were subjected to an Unpredictable Chronic Mild Stress (UCMS) paradigm with accessibility to running wheels for 2 h daily. Physiological and behavioral evaluations were conducted throughout the stress paradigm to determine if exercise blunts the effects of UCMS. Chronic stress induced voluntary wheel running (VWR) and weight loss in male and female mice. Compared to males, increased VWR was reported in females who also regained their weight lost by the end of the UCMS protocol. Exercise promoted resilience to stress-induced hyponeophagia in the novelty-suppressed feeding test and increased sucrose consumption. Exercise induced a sex-specific reduction in immobility and avoidance behavior in the tail suspension and open field tests and increased exploratory behavior in the light-dark test. These results indicate that exercise can promote resilience to the behavioral effects of chronic stress in males and females, and can affect behavior independent of chronic stress.

Chaihu-Shugan-San ameliorates tumor growth in prostate cancer promoted by depression via modulating sphingolipid and glycerinphospholipid metabolism.

Background: Psychologic depression is a pivotal pathological characteristic and has been shown to promote prostate cancer (PCa) progression. Chaihu-Shugan-San (CSS), a well-known Chinese herbal decoction, exhibits efficacy in the treatment of stress-accelerated PCa. However, the underlying mechanism of CSS in resisting PCa growth is still unknown, and further study is needed. Objective: To evaluate the effects of CSS on stress-accelerated PCa in a BALB/C nude mice model and to investigate the underlying mechanisms. Methods: PC-3 cells were implanted into BALB/C nude mice, and the stressed mice were exposed to chronic unpredictable mild stress (CUMS) to study the effects of CSS. The PCa growth were evaluated by tumor volume and tumor weight. Analyses of depression-like behaviors were evaluated by sucrose consumption test, tail suspension test and open field test. Network pharmacology was used to analyze the potential targets and signaling pathways of CSS against PCa. Untargeted lipidomics were used to analyze the serum lipid profiles and further elucidate the possible mechanism. Results: In the CUMS stressed PCa mice, CSS can restrain tumor growth with reduced tumor volume and tumor weight, and depression-like behaviors with increased sucrose consumption, reduced immobility duration, and increased total distance and center distance. Network pharmacology suggested that the lipid metabolism-related pathways are the most likely potential targets of CSS against PCa. Using untargeted lipidomics analysis, 62 lipids were found to have significant changes in PCa mice under CUMS treatment. The levels of glycerophospholipids containing phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI) and phosphatidylglycerol (PG), except PC (18:0_22:6) and PC (18:0_20:4), were significantly increased. Likewise, the levels of all sphingolipids (including sphingomyelin (SM), ceramides (Cer) and hexosyl-1-ceramide (Hex1Cer)) and diglyceride (DG) (32:1e) were significantly increased. CSS water extract was found to contribute to restore 32 lipids including 6 sphingolipids, 25 glycerophospholipids and 1 glyceride. Conclusion: This study is the first to delineate the lipid profile of stressed PCa BALB/C nude mice using untargeted lipidomics analysis. CSS restrained tumor growth and ameliorated depression-like behaviors by reprogramming lipid metabolism. Intervention of lipid metabolism could be a preventive and therapeutic approach for PCa patients with depression.

Montelukast induces beneficial behavioral outcomes and reduces inflammation in male and female rats.

BackgroundAccumulative data links inflammation and immune dysregulation to the pathophysiology of mental disorders; little is known regarding leukotrienes’ (LTs) involvement in this process. Circumstantial evidence suggests that treatment with leukotriene modifying agents (LTMAs) such as montelukast (MTK) may induce adverse neuropsychiatric events. Further methodic evaluation is warranted.ObjectiveThis study aims to examine behavioral effects, as well as inflammatory mediator levels of chronic MTK treatment in male and female rats.MethodsDepression-like phenotypes were induced by exposing male and female rats to a chronic unpredictable mild stress (CUMS) protocol for four weeks. Thereafter, rats were treated (intraperitoneally) once daily, for two weeks, with either vehicle (dimethyl sulfoxide 0.2 ml/rat) or 20 mg/kg MTK. Following treatment protocols, behavioral tests were conducted and brain regions were evaluated for inflammatory mediators including tumor necrosis factor (TNF)-α, interleukin (IL)-6 and prostaglandin (PG) E2.ResultsOverall, MTK did not invoke negative behavioral phenotypes (except for an aggression-inducing effect in males). Numerous positive behavioral outcomes were observed, including reduction in aggressive behavior in females and reduced manic/hyperactive-like behavior and increased sucrose consumption (suggestive of antidepressant-like effect) in males. Furthermore, in control males, MTK increased IL-6 levels in the hypothalamus and TNF-α in the frontal cortex, while in control females it generated a robust anti-inflammatory effect. In females that were subjected to CUMS, MTK caused a prominent reduction in TNF-α and IL-6 in brain regions, whereas in CUMS-subjected males its effects were inconsistent.ConclusionContrary to prior postulations, MTK may be associated with select beneficial behavioral outcomes. Additionally, MTK differentially affects male vs. female rats in respect to brain inflammatory mediators, plausibly explaining the dissimilar behavioral phenotypes of sexes under MTK treatment.

Prophylactic administration of rosmarinic acid ameliorates depression-associated cardiac abnormalities in Wistar rats: Evidence of serotonergic, oxidative, and inflammatory pathways.

Psychiatric disorders and associated cardiac comorbidities have increased the risk of mortality worldwide. Researchers reported that depression increases the possibility of future cardiac abnormalities by approximately 30%. Therefore, there is an unmet need to develop therapeutic interventions to treat depression and associated cardiac abnormalities. The present study was conducted to evaluate the prophylactic effect of rosmarinic acid (RA) against chronic unpredictable stress (CUS)-induced depression associated cardiac abnormalities in Wistar rats. The CUS paradigm, which comprised several stressors, was employed for 40 days to induce depressive-like behavior and associated cardiac abnormalities in rats. Along with CUS, RA at a dose of 25 and 50 mg/kg was administered orally to two groups of animals for 40 days. Behavioral tests (forced swim test and sucrose consumption test) and molecular biomarkers (corticosterone and serotonin) were performed. Electrocardiography was performed before CUS (Day 0), Day 20, and Day 40 to study electrocardiogram parameters. Furthermore, changes in body weight, organ weight, tissue lipid peroxidation, glutathione, catalase, cTn-I, MMP-2, and proinflammatory cytokines (TNF-α and IL-6) were estimated. Our results showed that RA treatment caused a reduction in immobility period, adrenal hyperplasia, corticosterone level, tissue lipid peroxidation, cTn-I, MMP-2, proinflammatory cytokines, and QRS complex duration, while an increase in sucrose consumption, brain serotonin level, T-wave width, glutathione, and catalase activity as compared with the CUS-control group. The results of our study proved that RA administration ameliorates CUS-induced depression-associated cardiac abnormalities in rats via serotonergic, oxidative, and inflammatory pathways.

Crocin ameliorates depressive-like behaviors induced by chronic restraint stress via the NAMPT-NAD+-SIRT1 pathway in mice

AimTo investigate the effects of crocin on depression induced by chronic restraint stress (CRS) in mice. MethodsDepression model was established induced by CRS. All mice were divided into 4 groups randomly: normal group, model group, sertraline group and crocin group. From the 28th day after treatment, serials behaviors were conducted to evaluate the effects of crocin, including sucrose preference test (SPT), tail suspension test (TST), forced swimming test (FST), open field test (OFT), novel objective recognition test (NORT), social interaction test (SIT), and dominance tube test (DTT). Contents of Nicotinamide phosphoribosyltransferase (NAMPT), BDNF, CREB, pCREB and SIRT1 in prefrontal cortex (PFC) were detected by WB. The levels of CORT, DA, 5-HT, NE and NAD+ in PFC were also detected by ELISA. ResultsThe results showed that crocin ameliorated the depressive-like behaviors, which manifested by increased sucrose consumption ratio and decreased immobility time in FST and TST. Crocin also increased the exploration time and exploration number in T2 phase in NORT, social preference index and social novelty index in SIT, reduced the defensive behavior in DTT. The results of WB showed crocin reversed the decreased contents of NAMPT, SIRT1, BDNF and pCREB/CREB in PFC induced by CRS. Additionally, crocin decreased the expression of cortisol (CORT) and increased the contents of DA, 5-HT, NAD+, but had no effects on NE between groups in PFC. ConclusionIn view of the findings, crocin ameliorates depression in mice, which may be associated with regulating NAMPT-NAD+-SIRT1 pathway.

Liquiritin Alleviates Depression-Like Behavior in CUMS Mice by Inhibiting Oxidative Stress and NLRP3 Inflammasome in Hippocampus.

Objective Central inflammation is generally accepted to be involved in the pathology of depression. We investigated whether liquiritin exerts antidepressant effects by inhibiting central NLRP3 inflammasomes. Results The behavioral despair model and chronic unpredictable mild stress (CUMS) model in mice were established to evaluate the antidepressant action of liquiritin. In the despair model study, liquiritin (40 mg/kg) administration reduced immobility time in tail suspension test (TST) and forced swimming test (FST) without affecting locomotion activity. In CUMS model study, liquiritin (40 mg/kg, once daily for 4 weeks) significantly increased sucrose consumption and body weight of CUMS mice. The behavioral experiment results showed that liquiritin reduced the immobile time of CUMS mice in TST and FST, respectively, and increased the time spent and open arm entries in the elevated plus-maze (EPM) test. Further, the hippocampal superoxide dismutase (SOD) activity was increased in liquiritin-treated group, while malonaldehyde (MDA) decreased. Additionally, the hippocampal cytokines interleukin-18 (IL-18) and interleukin-1 beta (IL-1β) contents were reduced in the liquiritin-treated group. Further, liquiritin downregulated the expression of NLRP3 in the hippocampus of CUMS mice rather than TLR4. Besides, NLRP3 inflammasome-associated proteins caspase-1 and ASC were also downregulated. However, liquiritin did not alter the thermal stability of NLRP3 in the cellular thermal shift assay (CETSA), suggesting that its inhibition of NLPR3 was not by direct targeting of NLRP3 protein. Conclusions Liquiritin attenuates depression-like behavior of CUMS mice and inhibited cytokines levels triggered by NLRP3 inflammasome, suggesting the antidepressant action is, at least partially, associated with antioxidant stress and inhibition of NLRP3 inflammasome activation.

Ad libitum consumption of milk supplemented with omega 3, 6, and 9 oils from infancy to middle age alters behavioral and oxidative outcomes in male mice

We tested the hypothesis that administration of omega (ω)-9, ω-3, and ω-6 to mice can prevent oxidative alterations responsible for behavioral and cognitive alterations related with aging. Twenty-eight-day-old mice received skim milk (SM group), SM enriched with omega oil mixture (EM group), or water (control group) for 10 and 14 months, equivalent to middle age. Mice were evaluated for behavioral alterations related to depression and memory and oxidative status [brain levels of thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH), and myeloperoxidase (MPO)]. The 10-month EM group increased immobility time during the forced swimming test compared with control, indicating increased stress response. The 14-month SM- and EM-treated groups increased sucrose consumption compared with control, showing an expanded motivational state. The 14-month SM group decreased the number of rearings compared with the 14-month control and EM groups. The number of entries and time spent in the central square of the open field was higher in the 10-month EM group than in the control, revealing an anxiolytic-like behavior. TBARS decreased in the hippocampus and striatum of the 10-month EM group compared with the control. A similar decrease was observed in the striatum of the 10-month SM group. GSH levels were higher in all 14-month treated groups compared with 10-month groups. MPO activity was higher in the 14-month EM group compared with the 14-month control and SM groups, revealing a possible pro-inflammatory status. In conclusion, omega oils induced conflicting alterations in middle-aged mice, contributing to enhanced behavior and anxiolytic and expanded motivational state, but also to increased stress response and pro-inflammatory alterations.

Safety and Efficacy of Combined Low-Dose Lithium and Low-Dose Aspirin: A Pharmacological and Behavioral Proof-of-Concept Study in Rats.

Despite established efficacy in bipolar disorder patients, lithium (Li) therapy has serious side effects, particularly chronic kidney disease. We examined the safety and behavioral effects of combined chronic low-dose aspirin plus low-dose Li in rats to explore the toxicity and therapeutic potential of this treatment. Rats were fed regular or Li-containing food (0.1% [low-dose, LLD-Li] or 0.2% [standard-dose, STD-Li]) for six weeks. Low-dose aspirin (1 mg/kg) was administered alone or together with Li. Renal function and gastric mucosal integrity were assessed. The effects of the combination treatment were evaluated in depression-like and anxiety-like behavioral models. Co-treatment with aspirin did not alter plasma Li levels. Chronic STD-Li treatment resulted in significant polyuria and polydipsia, elevated blood levels of creatinine and cystatin C, and increased levels of kidney nephrin and podocin—all suggestive of impaired renal function. Aspirin co-treatment significantly damped STD-Li-induced impairments in kidney parameters. There were no gastric ulcers or blood loss in any treatment group. Combined aspirin and LLD-Li resulted in a significant increase in sucrose consumption, and in the time spent in the open arms of an elevated plus-maze compared with the LLD-Li only group, suggestive of antidepressant-like and anxiolytic-like effects, respectively. Thus, we demonstrate that low-dose aspirin mitigated the typical renal side effects of STD-Li dose and enhanced the beneficial behavioral effects of LLD-Li therapy without aggravating its toxicity.

Young Plasma Induces Antidepressant-Like Effects in Aged Rats Subjected to Chronic Mild Stress by Suppressing Indoleamine 2,3-Dioxygenase Enzyme and Kynurenine Pathway in the Prefrontal Cortex.

Pathophysiology of depression in elderlies is linked to aging-associated increase in indoleamine 2,3-dioxygenase (IDO) levels and activity and kynurenine (Kyn) metabolites. Moreover, these aging-induced changes may alter the brain's responses to stress. Growing evidence suggested that young plasma can positively affect brain dysfunctions in old age. The present study aimed to investigate whether the antidepressant effects of young plasma administration in aged rats subjected to chronic unpredictable mild stress (CUMS) and underlying mechanisms, focusing on the prefrontal cortex (PFC). Young (3months old) and aged (22months old) male rats were divided into five groups; young control, aged control, aged rats subjected to CUMS (A + CUMS), aged rats subjected to CUMS and treated with young plasma (A + CUMS + YP), and aged rats subjected to CUMS and treated with old plasma (A + CUMS + OP). Plasma was injected (1ml, intravenously) three times per week for four weeks. Young plasma significantly improved CUMS-induced depressive-like behaviors, evidenced by the increased sucrose consumption ratio in the sucrose preference test and the reduced immobility time in the forced swimming test. Furthermore, young plasma markedly reduced the levels of interferon-gamma (IFN-γ), IDO, Kyn, and Kyn to tryptophan (Kyn/Trp) ratio in PFC tissue. Expression levels of the serotonin transporter and growth-associated protein (GAP)-43 were also significantly increased after chronic administration of young plasma. These findings provide evidence for the antidepressant effect of young plasma in old age; however, whether it improves depressive behaviors or faster recovery from stress-induced deficits is required to be elucidated.

Antidepressant like activity of Buspirone but not ondensetron in combination with Fluoxetine or Desipramine in mice

Background: The involvement of one or more 5-HT receptor sub-types in the pathophysiology of depression is still unclear. The study was performed to investigate the effect of ondansetron and buspirone on depression, and their interaction with fluoxetine or desipramine.Methods: The mice were administered ondansetron, buspirone alone and in combinations with fluoxetine or desipramine for 21 days, and the antidepressant effect was assessed by the immobility period and the sucrose consumption, on the tail suspension test (TST) and the chronic mild stress (CMS) models, respectively.Results: Both ondansetron and buspirone when given alone demonstrated slight non-significant decrease in the immobility time. Ondensetron when given in combination with fluoxetine (10 mg/kg; i.p.) and desipramine (15 mg/kg; i.p.), showed significant decrease in immobility time in comparison to the control group only. On the other hand, both the combinations of buspirone, either with fluoxetine or desipramine showed significant decrease in the immobility time when compared to the respective group. In CMS, the fluoxetine, desipramine, ondansetron, and buspirone showed gradual increase in the sucrose consumption, at the end of 4th, 5th, and 6th week, but the significant effect was observed only at the end of 6th week, as compared to the control. The combination of buspirone with desipramine but not with fluoxetine showed significant increase in sucrose consumption when compared to respective group.Conclusions: Therefore, the study indicates that both buspirone and ondansetron have a potential antidepressant like action, although buspirone has shown better antidepressant activity than ondansetron as observed in various combination groups.

Recent, Bioelectricity-Related Articles Selected by Ann M. Rajnicek, Media Editor of Bioelectricity.

Recent, Bioelectricity-Related Articles Selected by Ann M. Rajnicek, Media Editor of Bioelectricity.

Effects of Original Compounds GSB-106, GML-3, and GZK-111 in an Experimental Lipopolysaccharide-Induced Anhedonia Model

Antidepressant activities of the original compounds GSB-106 [bis(N-monosuccinyl-L-seryl-L-lysine) hexamethylenediamide], a mimetic of the fourth loop of brain-derived neurotrophic factor (BDNF); GML-3(N-butyl-N-methyl-1-phenylpyrrolo[1,2-a]pyrazine-3-carboxamide), a ligand of 18 kDa translocator protein (TSPO); and GZK-111 (N-phenylacetylglycyl-L-proline ethyl ester), a substitute dipeptide that is biotransformed into the neuropeptide cyclo-L-prolylglycine that affects AMPA receptors; were previously revealed at V. V. Zakusov Institute of Pharmacology in experimental models of the depressive state caused by unescapable stress conditions. The present article studied the antidepressant effects of GSB-106, GML-3, and GZK-111 in an inflammatory model of the depressive state induced by lipopolysaccharide (LPS) in male C57Bl/6 mice with an assessment of anhedonia based on the consumption of sucrose solution. LPS in a single dose of 0.5 mg/kg intraperitoneally (i.p.) caused a marked decrease of 39% (p ≤ 0.01) in the consumption of 1% sucrose solution as compared to the control group. GSB-106 administered perorally at a dose of 0.5 mg/kg 24 h after LPS increased by 20% (p ≤ 0.05) sucrose consumption reduced by LPS in mice. GML-3 administered once perorally at doses of 0.5 and 1.0 mg/kg increased sucrose consumption by 29 and 21% (p ≤ 0.01), respectively. GZK-111 administered once i.p. at a dose of 1.0 mg/kg increased sucrose consumption by 17% (p ≤ 0.05). The obtained data confirmed the antidepressant properties of GSB-106, GML-3, and GZK-111.

Quercetin alleviates chronic unpredictable mild stress-induced depressive-like behaviors by promoting adult hippocampal neurogenesis via FoxG1/CREB/ BDNF signaling pathway

Quercetin, a naturally occurring flavonoid, has been reported to exert antidepressant effects, however, the underlying mechanisms are still uncertain. Recent studies have demonstrated that Forkhead box transcription factor G1 (FoxG1) regulates the process of adult hippocampal neurogenesis (AHN) and exerts neuroprotective effects. In this study, we explored whether quercetin plays an anti-depressant role via regulation of FoxG1 signaling in mice and revealed the potential mechanisms. To explore the antidepressant effects of quercetin, mice were subjected to behavioral tests after a chronic unpredictable mild stress (CUMS) exposure. We found that chronic quercetin treatment (15 mg/kg, 30 mg/kg) obviously restored the weight loss of mice caused by CUMS and alleviated CUMS-induced depression-like behaviors, such as increased sucrose consumption, improved locomotor activity and shorten immobility time. In addition, to clarify the relationship between quercetin and AHN, we detected neurogenesis markers in the dentate gyrus (DG) of the hippocampus. Furthermore, FoxG1-siRNA was employed and then stimulated with quercetin to further investigate the mechanism by which FoxG1 participates in the antidepressant effects of quercetin. Our results indicate that chronic quercetin treatment dramatically increased the number of doublecortin (DCX)-positive and BrdU/NeuN-double positive cells. Besides, the expression levels of FoxG1, p-CREB and Brain-derived neurotrophic factor (BDNF) were also enhanced by quercetin in the DG. Strikingly, quercetin failed to reverse the levels of p-CREB and BDNF after FoxG1-siRNA was performed in SH-SY5Y cells and Neural Progenitor Cells (NPCs). Our results thus far suggest that quercetin might exert antidepressant effects via promotion of AHN by FoxG1/CREB/ BDNF signaling pathway.

The Antidepressant-Like Effects of Shen Yuan in a Chronic Unpredictable Mild Stress Rat Model.

Depression is a common yet severe neuropsychiatric condition that causes imposes considerable personal, economic, and social burdens worldwide. Medicinal plant species (e.g., Panax ginseng and Polygala tenuifolia) demonstrate potent antidepressant-like effects with less toxicity and other side effects. Shen yuan prescription (SY), composed of Panax ginseng (GT) and Polygala tenuifolia (YT). The present study aimed to elucidate the effects of SY treatment on chronic unpredictable mild stress (CUMS) rats and study the underlying mechanism. Our results indicated that SY (67.5, 135, or 270 mg/kg) significantly reverses the depressive-like behaviors in rats with a 5-week CUMS exposure, as demonstrated by increased sucrose consumption in the sucrose preference test, and decreased immobility time in the tail suspension and forced swim test. Moreover, SY altered serum corticosterone levels, pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α), and oxidative markers (SOD, CAT, and MDA), and increased the levels of hippocampal neurotransmitters (5-HT, DA, and NE) in rats exposed to CUMS. Furthermore, rats treated with SY showed a reduction in the protein expression of BDNF, p-TrkB, p-Akt, and p-mTOR proteins induced by CUMS exposure in the hippocampus. In conclusion, SY prevented depressive-like behaviors in CUMS-exposed rats by preventing hypothalamus-pituitary-adrenal axis dysfunction, decreasing the levels of the neurotransmitters, minimizing oxidative stress, suppressing neuroinflammation, and activating the PI3K/Akt/mTOR-mediated BDNF/TrkB pathway, all of which are the key players in the pathological basis of depression.