Rodent Models of Depression: Forced Swim and Tail Suspension Behavioral Despair Tests in Rats and Mice

The development of antidepressants requires simple rodent behavioral tests for initial screening before undertaking more complex preclinical tests and clinical evaluation. Presented in the unit are two widely used screening tests used for antidepressants, the forced swim (also termed behavioral despair) test in the rat and mouse, and the tail suspension test in the mouse. These tests have good predictive validity and allow rapid and economical detection of substances with potential antidepressant-like activity. The behavioral despair and the tail suspension tests are based on the same principle: measurement of the duration of immobility when rodents are exposed to an inescapable situation. The majority of clinically used antidepressants decrease the duration of immobility. Antidepressants also increase the latency to immobility, and this additional measure can increase the sensitivity of the behavioral despair test in the mouse for certain classes of antidepressant. Testing of new substances in the behavioral despair and tail suspension tests allows a simple assessment of their potential antidepressant activity by the measurement of their effect on immobility.

The development of antidepressants requires simple rodent behavioral tests for initial screening before undertaking more complex preclinical tests and clinical evaluation. Presented in the unit are two widely used screening tests used for antidepressants, the forced swim (also termed behavioral despair) test in the rat and mouse, and the tail suspension test in the mouse. These tests have good predictive validity and allow rapid and economical detection of substances with potential antidepressant‐like activity. The behavioral despair and the tail suspension tests are based on the same principle, measurement of the duration of immobility occurring following exposure of rodents to an inescapable situation. The majority of clinically used antidepressants decrease the duration of immobility. Testing of new substances in the behavioral despair and tail suspension tests allows a simple assessment of their potential antidepressant activity by the measurement of their effect on immobility. Curr. Protoc. Pharmacol. 38:5.8.1‐5.8.11. © 2007 by John Wiley & Sons, Inc.

Regulation of Monoamine Oxidase A by Circadian-Clock Components Implies Clock Influence on Mood

DEPRESSANT EFFECT OF TRIMYRISTIN AND ITS INHIBITION BY SOME ANTIDEPRESSANTS IN MICE

INTRODUCTION: Indolamine 2,3-dioxygenase 1 (IDO1) is upregulated in tumors. It facilitates catabolism of tryptophan to kynurenine and downstream metabolites, which are associated with psychiatric symptoms. To this point, 20% of patients at our institution developed psychiatric symptoms months before pancreatic cancer (PC) diagnosis. This proportion was threefold greater relative to non-cancer controls (6.7%), supplying indirect evidence of a biochemical link. Herein, we investigate IDO1 as a target in pancreatic cancer-associated depression. METHODS: Human and murine PC cells were used in vitro. Protein levels were assessed using western blotting and cell survival by PicoGreen. For in vivo studies, murine PC cells were injected into the pancreatic tail. Control mice underwent an acellular injection. Mice were treated with epacadostat (an IDO1 inhibitor), escitalopram, or vehicle. To evaluate depressive-like behavior, mice were subjected to the forced swim and tail suspension tests. The open field test was used to monitor mobility. Tumors were analyzed using western blotting and serum metabolites were assessed using LC-MS. RESULTS: Murine and human PC cells had undetectable basal IDO1 protein levels; however, there was a strong induction with interferon-gamma. There was a further increase in IDO1 with added epacadostat. Escitalopram had no effect on IDO1 levels. Epacadostat and escitalopram did not impact PC cell viability. Physical mobility of PC mice was similar to controls over the study period. PC mice were more immobile relative to controls during the forced swim (percent immobile: 16.0% v 8.2%, p<0.001) and tail suspension (24.1% v 15.4%, p=0.003) tests. There was a 2.3-fold increase in serum kynurenine levels in PC mice relative to controls (p<0.001).PC mice treated with epacadostat were less immobile relative to PC mice receiving vehicle in both the forced swim (3.2% v 6.6%, p=0.002) and tail suspension (25.0% v 39.3%, p=0.002) tests. Metabolomics demonstrated a 95% reduction in serum kynurenine levels in mice receiving epacadostat relative to vehicle (p<0.001). Tumors of mice treated with epacadostat exhibited a compensatory upregulation of IDO1. Mice treated with escitalopram performed similarly to vehicle-treated mice on the forced swim (7.6%, p=0.85) and tail suspension (38.7%, p=0.77) tests, and kynurenine levels were similar. CONCLUSION: Mice with PC exhibit depressive-like behavior relative to control mice with an associated increase in kynurenine. Treatment with epacadostat improved depressive-like behavior and dramatically reduced kynurenine. These data provide evidence to trial epacadostat in patients battling pancreatic cancer-associated depression. Citation Format: Jonathan J. Hue, Hallie J. Graor, Mehrdad Zarei, Ali Vaziri-Gohar, Erryk S. Katayama, Karen Ji, Omid Hajihassani, Alexander W. Loftus, Luke D. Rothermel, Jordan M. Winter. IDO1 is a potential target to combat pancreatic cancer-associated depression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2321.

Group housing of mice increases immobility and antidepressant sensitivity in the forced swim and tail suspension tests

Adenosine and its analogues have been shown to induce "behavioral despair" in animal models believed to be relevant to depression. Recent data have shown that selective adenosine A2A receptor antagonists (e.g., SCH 58261, ZM241385, and KW6002) or genetic inactivation of the receptor was effective in reversing signs of behavioral despair in the tail suspension and forced swim tests, two screening procedures predictive of antidepressant activity. A2A antagonists were active in the tail suspension test using either mice previously screened for having high immobility scores or mice that were selectively bred for their spontaneous "helplessness" in this test. At stimulant doses, caffeine, a nonselective A1/A2A receptor antagonist, was effective in the forced swim test. The authors have hypothesized that the antidepressant-like effect of selective A2A antagonists is linked to an interaction with dopaminergic transmission, possibly in the frontal cortex. In support of this idea, administration of the dopamine D2 receptor antagonist haloperidol prevented antidepressant-like effects elicited by SCH 58261 in the forced swim test (putatively involving cortex), whereas it had no effect on stimulant motor effects of SCH 58261 (putatively linked to ventral striatum). The interaction profile of caffeine with haloperidol differed markedly from that of SCH 58261 in the forced swim and motor activity tests. Therefore, a clear-cut antidepressant-like effect could not be ascribed to caffeine. In conclusion, available data support the proposition that a selective blockade of the adenosine A2A receptor may be an interesting target for the development of effective antidepressant agents.

Background: The fruit of Rosa abyssinica Lindley (Rosaceae) is claimed to alleviate depression in folkloric Ethiopian medicine. Nevertheless, the antidepressant-like effect has not been assessed in rodent models of depression. Methods: The test animals were randomly selected and divided into five groups (n = 8). Group I and II received 2% Tween 80 and the standard drug imipramine (30 mg/kg) respectively while Groups III to V received increasing doses of the extracts and duration of immobility at three dose levels of the crude extract and (100, 200, and 400 mg/kg) was the parameter determined to assess the antidepressant-like activity of R. abyssinica in tail suspension test (TST) and forced swimming test (FST). The locomotor activity was also evaluated in terms of number of square crossings using the open field test (OFT) in order to rule out possible psycho-stimulant activity. Results: The crude extract at the doses of 200 mg/kg and 400 mg/kg significantly reduced the time of immobility in the TST and FST. The aqueous fraction at 200 mg/kg displayed a significant reduction of 38% in the duration of immobility in TST which was superior to the effect of imipramine. The methanol fraction displayed a significant reduction in the duration of immobility of 33.93% only at 200 mg/kg. The ethyl acetate fraction was devoid of activity. No significant change in locomotor activity was detected in all the doses of the crude extract and imipramine in OFT. Conclusion: The results of this study suggest that this plant possesses an appreciable antidepressant-like activity.

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

Antidepressant-like actions of an AMPA receptor potentiator (LY392098)

Event Abstract Back to Event Modulation of P2X7 receptor function alters depressive behavior in rodent models of depression Rómeó Andó1*, Flóra Gölöncsér1 and Beáta Sperlágh1 1 Institute of Experimental Medicine Hungarian Academy of Sciences, Laboratory of Molecular Pharmacology, Hungary Introduction: The purinergic P2X7 receptors (P2X7R), play an important role in the modulation of the neurotransmitter release and in the posttranslational processing of the proinflammatory cytokine, IL-1beta ï€ after bacterial endotoxin challenge. Recent gene polymorphism studies indicate significant association of a gain of function mutation of the gene encoding P2X7R with both major depressive disorder and bipolar disorder. We investigated the possible modulatory effects of P2X7 receptor on depressive-like behavior under basal conditions and after lipopolysaccharide (LPS) treatment in rodent models of depression. Methods: Behavioral tests of depression, namely, forced swim test (FST) and automated tail suspension test (TST) were carried out in wild-type and P2X7 receptor knockout B6/6J mice and the time of immobility was measured. The effects of intraperitoneal lipopolysaccharide (LPS) and the effects of acute and chronic treatments with the P2X7R antagonist Brilliant Blue G (BBG) were investigated. Results: P2X7R knockout mice displayed antidepressant phenotype in both behavioral tests, as indicated by the significant decrease in the time of immobility. Lipopolysaccharide (1 mg/kg, i.p.) treatment increased immobility in both behavioural models in the wild-type mice. However, in P2X7 knockout animals, the effects of LPS were significantly attenuated in the TST and reversed in the FST. Acute treatment with BBG was without effect in wild-type mice but chronic treatment for 1 week dose-dependently decreased immobility (25-50 mg/kg i.p.). Acute BBG administration also attenuated the LPS-induced depressive-like behavior in the TST. Conclusions: The antidepressant phenotype of P2X7R KO mice and the attenuation of LPS-induced depressive behavior by the inhibition of P2X7R is an indication for the role of P2X7 receptors in the pathophysiology of depressive disorders, and suggest that P2X7R antagonists may represent a novel target in the therapeutics of depression. Conference: IBRO International Workshop 2010, Pécs, Hungary, 21 Jan - 23 Jan, 2010. Presentation Type: Poster Presentation Topic: Cognition and behavior Citation: Andó R, Gölöncsér F and Sperlágh B (2010). Modulation of P2X7 receptor function alters depressive behavior in rodent models of depression. Front. Neurosci. Conference Abstract: IBRO International Workshop 2010. doi: 10.3389/conf.fnins.2010.10.00141 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 29 Apr 2010; Published Online: 29 Apr 2010. * Correspondence: Rómeó Andó, Institute of Experimental Medicine Hungarian Academy of Sciences, Laboratory of Molecular Pharmacology, Budapest, Hungary, ando@koki.hu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Rómeó Andó Flóra Gölöncsér Beáta Sperlágh Google Rómeó Andó Flóra Gölöncsér Beáta Sperlágh Google Scholar Rómeó Andó Flóra Gölöncsér Beáta Sperlágh PubMed Rómeó Andó Flóra Gölöncsér Beáta Sperlágh Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Silibinin (SIL), a flavolignan extracted from the medicinal plant "silybum marianum (milk thistle)", has traditionally been used to treat liver disease. This phytochemical has displayed neuroprotective properties, its activity against schizophrenia is not elucidated. The present study was designed to evaluate the antipsychotic potential of silibinin and probe its toxic potential. The acute oral toxicity study was assessed as per OECD 425 guidelines. Animals were divided into two groups of female rats (n = 6): one group served as the normal control and the other group received a 2,000mg/kg dose of SIL. We also evaluated the antipsychotic potential of SIL. To this end, animals were divided into six groups (n = 10) of mice for both the preventive and curative protocols. Group I (CMC 1mL/kg) served as the normal control and received CMC 1mL/kg; group II was the diseased group treated with ketamine (10mg/kg) i.p; group III was the standard group treated with clozapine 1mg/kg; groups IV, V, and VI served as the treatment groups, receiving SIL 50, 100, and 200mg/kg, respectively, orally for both protocols. Improvement in positive symptoms of the disease was evaluated by stereotypy and hyperlocomotion, while negative symptoms (behavioral despair) were determined by a forced swim test and a tail suspension test in the mice models. The results suggested that the LD50 of SIL was greater than 2,000mg/kg. Moreover, SIL prevented and reversed ketamine-induced increase in stereotypy (p < 0.001) and behavioral despair in the forced swim and tail suspension tests (p < 0.001). Taken together, the findings suggest that silibinin is a safe drug with low toxicity which demonstrates significant antipsychotic activity against the positive and negative symptoms of schizophrenia.

Chronic stress-related behavioral and synaptic changes require caspase-3 activation in the ventral hippocampus of male mice.

Carvacrol (5-isopropyl-2-methylphenol) is a monoterpenic phenol present in the essential oil of many plants. It is the major component of the essential oil fraction of oregano and thyme. In this study, the effect of carvacrol was investigated in two behavioral models, the forced swimming and tail suspension tests in mice, to investigate the possible antidepressant effect of this substance. Additionally, the mechanisms involved in the antidepressant-like effect of carvacrol in mice were also assessed. Carvacrol (cvc) was administered orally at single doses of 12.5, 25 and 50 mg/kg. The acute treatment of cvc decreased the immobility time in the forced swimming and tail suspension tests without accompanying changes in ambulation in the open-field test. The anti-immobility effect of carvacrol (25 mg/kg) was not prevented by pretreatment of mice with p-chlorophenylalanine, prazosin and yohimbine. On the other hand, the pretreatment of mice with SCH23390 or sulpiride completely blocked the antidepressant-like effect of carvacrol (25 mg/kg) in the forced swimming test. These results show that carvacrol presents antidepressant effects in the forced swimming and tail suspension tests; this effect seems to be dependent on its interaction with the dopaminergic system, but not with the serotonergic and noradrenergic systems. Carvacrol; Antidepressant; Forced swimming; Tail suspension; Dopaminergic system.

Antidepressant–like effects of Acorus calamus in forced swimming and tail suspension test in mice