Search

Objective: Prader‐Willi syndrome (PWS) is a multisystem genetic disorder. Unfortunately, none of several mouse models carrying PWS mutations emulates the entirety of the human PWS phenotype, including hyperphagia plus obesity. Methods: To determine whether housing at thermoneutrality (TN, 30 °C) permits the development of hyperphagia and obesity in the Snord116del PWS mouse model, the effects of housing three different ages of Snord116del and wild‐type (WT) littermates at TN versus room temperature (RT, 22–24 °C) for 8 weeks were compared. Results: Snord116del mice born and maintained at TN exhibited lower body weight curves, lower percentage fat mass, and lower food intake than WT mice at RT. In 4‐ to 6‐month‐old high‐fat diet–fed female mice, TN raised the Snord116del body weight curve closer to that of RT‐housed WT mice although the TN‐housed Snord116del mice did not gain more adiposity or exhibit greater food intake. In 6‐ to 8‐month‐old high‐fat diet–fed male mice, body weight, adiposity, and food intake of TN‐housed Snord116del mice remained far below levels in RT‐housed WT mice. TN elicited hypotonia in Snord116del adults and exacerbated mortality of Snord116del newborns. Conclusions: In none of three tested TN protocols were greater food intake, body weight, or adiposity induced in Snord116del mice compared with RT‐housed WT mice. [ABSTRACT FROM AUTHOR]

Despite the presence of a multitudinous pharmacotherapy, diabetes-induced depressive disorder remains undertreated. Evidence suggests that brain serotonergic deficits are associated with depressive-like behavior in diabetes and that 5HT 3 receptor (5HT3R) antagonists have serotonergic facilitatory effects. This study examined the effects of a novel 5HT3R antagonist, 4i ( N -(3-chloro-2-methylphenyl)quinoxalin-2-carboxamide), in diabetes-induced depressive phenotypes. Experimentally, (1) to evaluate the effects of 4i, mice with 8-weeks of diabetes (induced by streptozotocin, 200 mg/kg, i.p.) were treated with vehicle, 4i (0.5 and 1 mg/kg/day, i.p.), fluoxetine (10 mg/kg/day, i.p.) for 4-weeks and subjected to neurobehavioral assays, followed by biochemical estimation of serotonin levels in midbrain, prefrontal-cortex and cerebellum. (2) To evaluate the role of 5HT3R in the postulated effect of 4i, diabetic mice were given 4i (1 mg/kg/day, i.p.) after 1 h of 1-( m -chlorophenyl)-biguanide ( m CPBG, a 5HT3R agonist, 10 mg/kg/day, i.p.) treatment and subjected to the same protocol. The results showed that diabetic mice exhibited a significant behavioral deficit, including depression-like behavior in forced swim test, anxiety-like in open field test and sociability deficits in social interaction test, along with a significant decrease in serotonin level in these brain regions. 4i (1 mg/kg), similar to fluoxetine, prevented these behavioral abnormalities and normalized brain serotonin levels. 4i (0.5 mg/kg) ameliorated only diabetes-induced depressive-like behavior and serotonin deficits, but not anxiety-like effects. m CPBG blunted 4i-mediated behavioral response and increase in brain serotonin levels. Altogether, this study suggests that 4i prevents diabetes-induced depressive phenotypes in mice, which may involve antagonism of 5HT3Rs and increase in serotonin levels in discrete brain regions. [ABSTRACT FROM AUTHOR]

Stress in our daily life severely affects the normal physiology of the biological system. Dysregulation of hypothalamic–pituitary–adrenal (HPA) axis has been implicated in the development of depression-like behavior, which remains under diagnosed and poorly treated. Exogenous corticosterone (CORT) administration has been demonstrated to develop a depression model, which has shown to mimic HPA-axis induced depression-like state in rodents. In the present study, the effect of a novel 5HT 3 receptor, 4i was examined on CORT induced depression in mice. CORT (30 mg/kg, subcutaneously) was given for 4-weeks to mice in control group, while mice in drug treated group were given 4i (0.5–1 mg/kg, intraperitoneally)/fluoxetine (as a positive control, 10 mg/kg), for the last 2-weeks of CORT dosing. Repeated CORT dosing caused depression-like behavior in mice as indicated by increased despair effects in forced swim test (FST) and anhedonia in sucrose preference test. In addition, CORT administration induced oxidative load in the brain with significant increase in pro-oxidant (lipid peroxidation and nitrite levels) markers and a substantial decline in anti-oxidant defense (catalase and reduced glutathione levels) system, indicating a direct effect of stress hormones in the induction of the brain oxidative damage. On the other hand, 4i and fluoxetine treatment reversed the CORT induced depressive-like deficits. Furthermore, 4i and fluoxetine prevented CORT induced oxidative brain insults, which may plausibly demonstrate one of the key mechanisms for antidepressant-like effects of the compounds. Thus, the study suggests that 5HT 3 antagonist; 4i may be implicated as pharmacological intervention targeting depressive-like anomaly associated with HPA-axis dysregulation. [ABSTRACT FROM AUTHOR]

Objective: In the last few decades, serotonin type-3 (5-HT3) receptor antagonists have been identified as potential targets for anxiety disorders. In preclinical studies, 5-HT3 antagonists have shown promising antianxiety effects. In this study, a novel 5-HT3 receptor antagonist, QCM-13(N-cyclohexyl-3-methoxyquinoxalin-2-carboxamide) was evaluated for anxiolytic-like activity in rodent behavioral test battery. Materials and Methods: Mice were given QCM-13 (2 and 4 mg/kg, intraperitoneally [i.p.]) or diazepam (2 mg/kg, i.p.) or vehicle and after 30 min, mice were subjected to four validated behavioral test batteries viz. elevated plus maze, hole board, light-dark and open field tests. Interaction study of QCM-13 with m-chlorophenyl piperazine (mCPP) (mCPP, a 5-HT2A/2C receptor agonist, 1 mg/kg, i.p.) and buspirone (BUS, a partial 5-HT1A agonist, 10 mg/kg, i.p.) were performed to assess the pharmacological mechanism of the drug. Results: QCM-13 expressed potential anxiolytic effect with significant (P < 0.05) increase in behavioral parameters measured in aforementioned preliminary models. Besides, QCM-13 was unable to reverse the anxiogenic effect of mCPP, but potentiated anxiolytic affect of BUS. Conclusion: The results suggest that QCM-13 can be a potential therapeutic candidate for the management of anxiety-like disorders and combination doses of novel 5-HT3 receptor antagonist with standard anxiolytics may improve therapeutic efficacy. [ABSTRACT FROM AUTHOR]

Anxiety disorders are widely spread psychiatric illnesses that are a cause of major concern. Despite a consistent increase in anxiolytics, the prevalence of anxiety is static; this necessitates the development of new compounds with potential activity and minimum unwanted effects. A serotonergic (5HT) system plays an important role in pathogenesis of anxiety and predominantly involves 5HT 1A receptor action in mediating anxiety-like behavior; the antagonism of 5HT 1A receptor has demonstrated to produce anxiolytic-like effects. Alverine citrate (AVC) is reported as a 5HT 1A antagonist; however, its effects on anxiety-like behavior are not investigated. Thus, the present study, by utilizing a neurobehavioral approach, examined the anxiolytic-like effects of AVC in experimental mouse models of anxiety. Mice were acutely treated with AVC (5–20 mg/kg, i.p.)/diazepam (DIA, 2 mg/kg, i.p.) and subjected to four validated anxiety models viz. elevated plus-maze (EPM), light/dark (L/D), hole-board (HB) and marble burying (MB) tests. AVC (15–20 mg/kg) and DIA significantly increased open arm activity in EPM, exploration in light chamber in L/D test, exploratory behavior in HB and reduced MB behavior in marble burying test. AVC (5 mg/kg) had no effect on all behavioral tests, while AVC (10 mg/kg) produced partial effects. It revealed anxiolytic-like effects of AVC. Furthermore, anxiolytic-like effects of AVC at higher doses (15–20 mg/kg) were more pronounced than lower doses (10 mg/kg) and were quite similar to the standard drug DIA. The present finding demonstrates, for the first time, the anxiolytic-like effects of AVC, which may be an alternative approach for management of anxiety-related disorders. [ABSTRACT FROM AUTHOR]

Clinical and preclinical data suggest that diabetes is often associated with anxiety. Insulin, a peptide hormone has been reported to have key functions in the brain and in alleviating several psychological impairments, occur as a consequence of diabetes. However, its effects in diabetes-induced anxiety are scanty. The present study examined whether; insulin can reverse the anxiety-like behavior in streptozotocin (STZ)-induced diabetes in mice. After 8-weeks of diabetes induced by STZ (200 mg/kg, intraperitoneally (i.p.)), mice were given insulin (1-2 IU/kg/day, i.p.)/ diazepam (1 mg/kg/day, i.p.)/ vehicle for 14 days and evaluated for behavioral effects in three validated models of anxiety viz. elevated plus maze (EPM), light-dark (L/D) and hole board (HB) tests. STZ-induced diabetic mice elicited significant behavioral effects which include, decreased percentage open arm entries and time in EPM, reduced latency and time spent in light chamber in L/D, decreased number of head dips, squares crossed and rearings in HB tests respectively. Insulin treatment attenuated the behavioral effects evoked by STZ-induced diabetes in mice as indicated by increased open arms activity in EPM, decreased aversion in light chamber during L/D test and increased exploratory behavior in HB test. In conclusion, this study revealed that insulin can reverse anxiety-like behavior in STZ-induced diabetes in mice. [ABSTRACT FROM AUTHOR]

The aim of the present work was to investigate the role of ondansetron on the high fat diet (HFD) induced obese mice for behavioral and biochemical alterations using chronic unpredictable mild stress (CUMS) model of depression. Animals were fed with high fat diet for 14 weeks and subjected to different stress procedures for 4 weeks. Treatment with ondansetron was started on day 15. After day 28 behavioral assays and biochemical estimations were performed. Behavioral paradigms viz. sucrose preference test, locomotor score, forced swim test (FST) and elevated plus maze (EPM), whereas biochemical parameters like plasma glucose, total cholesterol, triglycerides and total proteins were estimated. Results examines that in behavioral assays, ondansetron significantly ( P < 0.05) increased sucrose consumption, reduced immobility time in FST, increased the percent entries and time in open arm in EPM. In biochemical assessments elevated plasma glucose, total cholesterol, triglycerides and total proteins were significantly ( P < 0.05) reversed by ondansetron treatment in HFD obese animals subjected to CUMS. The study indicates that the obese mice subjected to CUMS exhibited severe depressive-like symptoms and ondansetron significantly reversed the behavioral and biochemical alterations. In the present study the plasma glucose level indicates that, it could be 'altered glucose level' playing an important role in depression co-morbid with obesity. Ondansetron through allosteric modulation of serotonergic system elevates the serotonin level and thereby regulates the insulin secretion and hence, reversing the 'altered glucose level', could be the possible antidepressive-like mechanism against depression co-morbid with obesity. [ABSTRACT FROM AUTHOR]

The biological mechanisms that link the development of depression to metabolic disorders such as obesity and diabetes remain ambiguous. In the present study the potential of a selective cyclooxygenase inhibitor celecoxib (15 mg/kg p.o.) was investigated in depression associated with obesity in mice. Behavioral tests used to assess depressive-like behavior were sucrose preference test, forced swim test (FST), tail suspension test (TST) and elevated plus maze (EPM). The basal locomotor score in obese mice was not altered. Furthermore, estimation of biochemical parameters was performed for plasma glucose, total cholesterol, triglycerides and total proteins. Escitalopram (10 mg/kg p.o.) served as reference standard drug. In the results, chronic treatment with celecoxib for 28 days significantly attenuated the behavioral alterations as indicated by increased the sucrose consumption, reduced the immobility time in FST and TST, increased the percent open arm time and entries in EPM in obese mice. In the biochemical parameters celecoxib significantly reversed the increased plasma glucose, total cholesterol, triglycerides and total proteins in obese mice. In conclusion, celecoxib exhibited potential antidepressant-like effect in depression associated with obesity, which to some extent is mediated by reversing the altered plasma glucose in obese mice. [ABSTRACT FROM AUTHOR]

Abstract: Diabetes is a persistent metabolic disorder, which often leads to depression as a result of the impaired neurotransmitter function. Insulin is believed to have antidepressant effects in depression associated with diabetes; however, the mechanism underlying the postulated effect is poorly understood. In the present study, it is hypothesized that insulin mediates an antidepressant effect in streptozotocin (STZ) induced diabetes in mice through modulation of the serotonin system in the brain. Therefore, the current study investigated the antidepressant effect of insulin in STZ induced diabetes in mice and insulin mediated modulation in the brain serotonin system. In addition, the possible pathways that lead to altered serotonin levels as a result of insulin administration were examined. Experimentally, Swiss albino mice of either sex were rendered diabetic by a single intraperitoneal (i.p.) injection of STZ. After one week, diabetic mice received a single dose of either insulin or saline or escitalopram for 14days. Thereafter, behavioral studies were conducted to test the behavioral despair effects using forced swim test (FST) and tail suspension test (TST), followed by biochemical estimations of serotonin concentrations and monoamine oxidase (MAO) activity in the whole brain content. The results demonstrated that, STZ treated diabetic mice exhibited an increased duration of immobility in FST and TST as compared to non-diabetic mice, while insulin treatment significantly reversed the effect. Biochemical assays revealed that administration of insulin attenuated STZ treated diabetes induced neurochemical alterations as indicated by elevated serotonin levels and decreased MAO-A and MAO-B activities in the brain. Collectively, the data indicate that insulin exhibits antidepressant effects in depression associated with STZ induced diabetes in mice through the elevation of the brain serotonin levels. [Copyright &y& Elsevier]

Objectives The inconsistent therapeutic outcome necessitates identifying novel compounds for the treatment of depression. Therefore, the present study is aimed at evaluating the antidepressant-like effects of a novel 5- HT3 receptor antagonist 3-methoxy- N- p-tolylquinoxalin-2-carboxamide ( QCM-4) on chronic unpredictable mild stress ( CUMS) induced behavioral and biochemical alterations in mice. Methods Animals were subjected to different stressors for a period of 28 days. Thereafter, battery tests like locomotor score, sucrose preference test, forced swim test ( FST), tail suspension test ( TST), elevated plus maze ( EPM) and open field test ( OFT) were performed. Biochemical assays like lipid peroxidation, nitrite levels, reduced glutathione ( GSH), catalase and superoxide dismutase ( SOD) were assessed in brain homogenate. Key findings QCM-4 dose dependently reversed the CUMS induced behavioral and biochemical alterations by increasing the sucrose consumption, reducing the immobility time in FST and TST, increasing the percent time in open arm in EPM and increasing the ambulation along with the rearings and decreased number of fecal pellets in OFT. Further, biochemical alterations were attenuated by QCM-4 as indicated by reduced lipid peroxidation and nitrite levels and elevated antioxidant enzyme levels like GSH, catalase and SOD. Conclusions QCM-4 attenuated the behavioral and biochemical derangements induced by CUMS in mice, indicating antidepressant behavior of the novel compound. [ABSTRACT FROM AUTHOR]

Objective: To investigate the anti-anxiety activity of "6k", a novel 5-hydroxytryptamine type 3 (5-HT3) receptor antagonist in in mice. Materials and Methods: Anti-anxiety activity of "6k" (1, 2, and 4 mg/kg, intraperitoneally (i.p.)) was evaluated in mice by behavioral tests such as elevated plus maze (EPM), open field test (OFT), light-dark box (L&D), and hole board test (HBT). Diazepam (2 mg/kg, i.p.) served as reference standard. Results: "6k" significantly (P < 0.05) increased the time and entries in open arm in EPM as compared to vehicle control group. Further, "6k" significantly (P < 0.05) increased the central and peripheral ambulation along with rearings and time in central area; whereas, reduced the fecal pellets in OFT as compared to vehicle control group. There was significant (P < 0.05) reduction in the latency to enter dark chamber; whereas, increased number of crossings and time in light chamber in L&D aversion test by treatment with "6k" as compared to vehicle control group. In HBT, "6k" significantly (P < 0.05) increased the number of head dipping and squares crossed; whereas, reduced the latency for first head dip and number of fecal pellets as compared to vehicle control group. Conclusion: A novel 5-HT3 receptor antagonist has anti-anxiety action. [ABSTRACT FROM AUTHOR]

Previous studies in our laboratory examined the antidepressant potential of 3-methoxy- N - p -tolylquinoxalin-2-carboxamide (QCM-4), a 5-HT 3 receptor antagonist in acute and chronic rodent models of depression. The aim of present study was to investigate the effect of QCM-4 on chronic unpredictable mild stress (CUMS) induced depression in obese mice using behavioral based battery tests and biochemical assessments. Depressive behavior was induced in obese mice by subjecting to different stress procedures for 28 days. The results indicated that the CUMS induced severe depressive behavior in obese mice as demonstrated by a significant decreased sucrose consumption, increased immobility time in forced swim test (FST) and tail suspension test (TST), decreased percent entries and time in open arm in elevated plus maze (EPM). Moreover, CUMS significantly increased the plasma glucose, total cholesterol, triglycerides and total proteins in obese mice. Chronic treatment with QCM-4 (2 mg/kg po) and standard drug escitalopram (10 mg/kg po) significantly reversed the depressive behavioral changes (increased sucrose consumption, decreased immobility time in FST and TST, and increased the percent entries and time in open arm in EPM) and biochemical alterations (reversed the raised levels of plasma glucose, total cholesterol, triglycerides and total proteins) in obese mice subjected to CUMS. No alteration was observed in the locomotor score in obese mice. In conclusion, the results of the present study suggested that QCM-4 attenuated the depression co-morbid with obesity in mice subjected to CUMS which to some extent is mediated by reversing the “insulin resistance” or “altered plasma glucose” in obese mice. [ABSTRACT FROM AUTHOR]