Involvement of N-methyl-d-aspartate receptors in the antidepressant-like effect of 5-hydroxytryptamine 3 antagonists in mouse forced swimming test and tail suspension test.

Recent evidence indicates that 5-hydroxytryptamine 3 (5-HT3) antagonists such as ondansetron and tropisetron exert positive behavioral effects in animal models of depression. Due to the ionotropic nature of 5-HT3 and N-methyl-d-aspartate (NMDA) receptors, plus their contribution to the pathophysiology of depression, we investigated the possible role of NMDA receptors in the antidepressant-like effect of 5-HT3 receptor antagonists in male mice. In order to evaluate the animals' behavior in response to different treatments, we performed open-field test (OFT), forced swimming test (FST), and tail-suspension test (TST), which are considered as valid tasks for measuring locomotor activity and depressive-like behaviors in mice. Our data revealed that intraperitoneal (i.p.) administration of tropisetron (5, 10, and 30mg/kg) and ondansetron (0.01, and 0.1μg/kg) significantly decreased the immobility time in FST and TST. Also, co-administration of subeffective doses of tropisetron (1mg/kg, i.p.) or ondansetron (0.001μg/kg, i.p.) with subeffective doses of NMDA receptor antagonists, ketamine (1mg/kg, i.p.), MK-801 (0.05mg/kg, i.p.) and magnesium sulfate (10mg/kg, i.p.) resulted in a reduced immobility time both in FST and TST. The subeffective dose of NMDA (NMDA receptor agonist, 75mg/kg, i.p.) abolished the effects of 5-HT3 antagonists in FST and TST, further supporting the presumed interaction between 5-HT3 and NMDA receptors. These treatments did not affect the locomotor behavior of animals in OFT. Finally, the results of our study suggest that the positive effects of 5-HT3 antagonists on the coping behavior of mice in FST and TST are at least partly mediated through NMDA receptors participation

Tropisetron attenuated the anxiogenic effects of social isolation by modulating nitrergic system and mitochondrial function.

Abstract BACKGROUND: Early social isolation stress (SIS) is associated with the occurrence of anxiety behaviors. It seems interaction between the nitrergic system and mitochondrial function plays a role in mediating the anxiety-like behaviors. In this study, we aimed to investigate the anxiolytic effects of tropisetron in animal model of SIS and we try to illustrate the possible role of nitrergic system and mitochondrial function. METHODS: We applied early social isolation paradigm to male NMRI mice. Animals treated with various doses of tropisetron, nitric oxide agents or their combination and anxiety-like behaviors of animals were assessed using valid behavioral tests including elevated plus maze (EPM), open-field test (OFT) and hole-board test (HBT) in their adulthood. Effects of housing conditions and drug treatments on the mitochondrial function were investigated in the hippocampus by assessing the ATP, GSH, ROS and nitrite levels. RESULTS: Anxiogenic effects of early SIS were assessed in the EPM, OFT, and HBT. Also, SIS disrupted mitochondrial function and caused oxidative stress in the hippocampus of stressed animals. Tropisetron showed an anxiolytic effect in the stressed mice. Also, these effects were mediated by nitrergic system by affecting mitochondrial function and modulating the oxidative stress. L-arginine, a nitric oxide precursor, abolished the anxiolytic effects of tropisetron in the behavioral tasks and blocked the protective effects of it against mitochondrial and oxidative challenge. CONCLUSIONS AND GENERAL SIGNIFICANCE: Our results demonstrated tropisetron attenuated the anxiogenic effects of SIS by mitigation of the negative effects of nitric oxide on mitochondrial functio

Involvement of nitric oxide-cyclic guanosine monophosphate pathway in the antidepressant-like effect of tropisetron and ondansetron in mice forced swimming test and tail suspension test.

Antidepressant-like effects of 5-hydroxytryptamine subtype 3 (5-HT3) antagonists including tropisetron and ondansetron have been previously demonstrated in the literature. It was reported that stimulation of 5-HT3 receptors activate the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway, which is involved in regulation of behavioral and emotional functions. In our study, treating animals with tropisetron (5, 10, and 30mg/kg) and ondansetron (0.01 and 0.1µg/kg) significantly decreased the immobility time in forced swimming test (FST) and tail-suspension test (TST). Co-administration of subeffective doses of tropisetron (1mg/kg) and ondansetron (0.001µg/kg) with subeffective dose of l-NAME (10mg/kg, nonselective NO synthase (NOS) inhibitor) and 7-nitroindazole (25mg/kg, neural NOS inhibitor) exerted antidepressant-like effect in FST and TST, while aminoguanidine (50mg/kg, inducible NOS inhibitor) did not enhance the antidepressant-like effect of 5-HT3 antagonists. Besides, l-arginine (750mg/kg, NO precursor) and sildenafil (5mg/kg, phosphodiesterase inhibitor) suppressed the anti-immobility effect of 5-HT3 antagonists. None of the treatments altered the locomotor behavior of mice in open-field test. Also, hippocampal (but not cortical) nitrite level was significantly lower in tropisetron and ondansetron-treated mice compared with saline-injected mice. Also, co-administration of 7-nitroindazole with tropisetron or ondansetron caused a significant decrease in hippocampal nitrite levels. In conclusion, we suggest that antidepressant-like effect of tropisetron and ondansetron are partially mediated by modulation of NO-cGMP pathway

Activation of cannabinoid receptors elicits antidepressant-like effects in a mouse model of social isolation stress

Social isolation stress (SIS) paradigm is a chronic stress procedure able to induce profound behavioral and neurochemical changes in rodents and evokes depressive and anxiety-like behaviors. Recent studies demonstrated that the cannabinoid system plays a key role in behavioral abnormalities such as depression through different pathways; however, there is no evidence showing a relation between SIS and the cannabinoid system. This study investigated the role of the cannabinoid system in depressive-like behavior and anxiety-like behavior of IC animals. For this purpose, NMRI mice were treated with WIN55, 212-2 (non-selective cannabinoid receptor agonist) and AM-251 (cannabinoid receptor type 1 antagonist) and AM-630 (cannabinoid receptor type 2 antagonist). We found that behavioral abnormality followed by SIS was mitigated after administration of WIN55, 212-2. Also, depressive-like effects induced by SIS were significantly increased following administration of AM-251 and AM-630. Co-administration of cannabinoid receptor antagonists (AM-251 and AM-630), significantly reversed the antidepressant effect of WIN55, 212-2 in IC animals. Our findings suggest that the cannabinoid system is involved in depressive-like behaviors induced by SIS. We showed that activation of cannabinoid receptors (type 1 and 2) could mitigate depression-like behavior induced by SIS in a mouse model

Anticonvulsant effect of minocycline on pentylenetetrazole-induced seizure in mice: involvement of nitric oxide and N-methyl-D-aspartate receptor

Anticonvulsant effects of minocycline have been explored recently. This study was designed to examine the anticonvulsant effect of acute administration of minocycline on pentylenetetrazole-induced seizures in mouse considering the possible role of the nitric oxide/N-methyl-D-aspartate (NMDA) pathway. We induced seizure using intravenous administration of pentylenetetrazole. Our results showed that acute administration of minocycline increased the seizure threshold. Furthermore, co-administration of subeffective doses of the nonselective nitric oxide synthase (NOS) inhibitor NG-L-arginine methyl ester (10 mg/kg) and the neuronal NOS inhibitor 7-nitroindazole (40 mg/kg) enhanced the anticonvulsant effect of subeffective doses of minocycline (40 mg/kg). We found that inducible NOS inhibitor aminoguanidine (100 mg/kg) had no effect on the antiseizure effect of minocycline. Moreover, L-arginine (60 mg/kg), as a NOS substrate, reduced the anticonvulsant effect of minocycline. We also demonstrated that pretreatment with the NMDAreceptor antagonists ketamine (0.5 mg/kg) and MK-801 (0.05 mg/kg) increased the anticonvulsant effect of subeffective doses of minocycline. Results showed that minocycline significantly decreased the hippocampal nitrite level. Furthermore, co-administration of a neuronal NOS inhibitor like NMDA receptor antagonists augmented the effect of minocycline on the hippocampal nitrite level. In conclusion, we revealed that anticonvulsant effect of minocycline might be, at least in part, due to a decline in constitutive hippocampal nitric oxide activity as well as inhibition of NMDA receptors

Anxiety- and Depressive-Like Behaviors are Associated with Altered Hippocampal Energy and Inflammatory Status in a Mouse Model of Crohn’s Disease

Abstract—Depression and anxiety are common comorbid disorders observed in patients with inflammatory bowel disease (IBD). Increasing line of evidence indicates that immune-inflammatory responses are involved in cooccurrence of mood disorders and IBD. However, the mechanisms through which immune-inflammatory pathways modulate this comorbidity are not yet understood. This study investigated the role of innate immunity in the development of behavioral abnormalities associated with an animal model of Crohn’s disease (CD). To do this, we induced colitis in male adult mice by intrarectal (i.r.) injection of DNBS (Dinitrobenzene sulfonic acid). After 3 days, we performed behavioral tests for anxiety- and depressive-like behaviors as well as tissue collection. Our results showed that DNBS-induced colonic inflammatory responses were accompanied by infiltration of inflammatory cells, and increased expression of genes involved in toll-like receptor signaling pathway in intestinal tissue. Furthermore, the DNBS-treated mice showed depressive- and anxiety-like behaviors which were associated with increased expression of the inflammatory genes and abnormal mitochondrial function in the hippocampus. These results suggest that peripheral inflammation is able to increase the transcriptional level of the genes in tolllike receptor pathway, induces abnormal mitochondrial function in the hippocampus, and these negative effects may be involved in the co-occurrence of anxiety and depression in early stages of CD. � 2017 IBRO. Published by Elsevier Ltd. All rights reserved

Experiencing neonatal maternal separation increased the seizure threshold in adult male mice: Involvement of the opioid system

Experiencing early-life stress has been considered as a potent risk factor for the development of many of brain disorders, including seizures. Intervening mechanisms through which neonatal maternal separation (MS) alters the seizure susceptibility in adulthood have not been well studied. In the current study, by applying 180 min of MS stress (PND 2–14), we determined the seizure susceptibility and considered the role of the opioid system. Maternal separation increased the seizure threshold, and administration of anticonvulsant/proconvulsant doses of morphine (1 and 30 mg/kg, respectively) reversed the impact of MS. Using tail flick and hot plate tests, we exposed animals to 30 min Restraint stress (RS) and found that MS decreased the pain threshold, suggesting the hyporesponsiveness of the opioid system. These results supported the abnormal seizure activity observed in the MS mice and suggested that abnormalities in the opioid system following MS alter seizure susceptibility in later life

Protective effects of gabapentin against the seizure susceptibility and comorbid behavioral abnormalities in the early socially isolated mice

Adolescence is a pivotal period of brain development during lifespan, which is sensitive to stress exposure. Early social isolation stress (SIS) is known to provoke a variety of psychiatric comorbidities as well as seizure risk. Psychiatric comorbidities present challenging dilemmas for treatment and management in people with seizure disorders. In this study, we aimed to investigate whether gabapentin (GBP) as an anti-epileptic drug is able to alleviate the seizure activity as well as comorbid behavioral abnormalities in socially isolated mice. Results showed that early SIS induced proconvulsant effects along with depressive, aggressive and anxiety-like behaviors. Whereas the administration of both acute and chronic GBP at sub-effective doses produced no alterations in the behavioral profile of socially conditioned counterparts the same treatments effectively reversed the seizure susceptibility to pentylenetetrazole and behavioral deficits in isolated mice. Results of the study indicate that 1) Early SIS could be considered as an animal model of psychosocial stress to investigate the psychiatric comorbidities in seizure disorders, 2) Chronic administration of low dose GBP prevented the shaping of behavioral abnormalities in adulthood, 3) Chronic administration of low dose GBP produced no negative behavioral effects in socially conditioned mice suggesting the safety of the drug, 4) Gabapentin at low doses may be considered as an agent for management of epilepsy in individuals with psychiatric comorbidities

Tropisetron suppresses colitis-associated cancer in a mouse model in the remission stage

Patients with inflammatory bowel disease (IBD) have a high risk for development of colitis-associated cancer (CAC). Serotonin is a neurotransmitter produced by enterochromaffin cells of the intestine. Serotonin and its receptors, mainly 5-HT3 receptor, are overexpressed in IBD and promote development of CAC through production of inflammatory cytokines. In the present study, we demonstrated the in vivo activity of tropisetron, a 5-HT3 receptor antagonist, against experimental CAC. CAC was induced by azoxymethane (AOM)/dextran sodium sulfate (DDS) in BALB/c mice. The histopathology of colon tissue was performed. Beta-catenin and Cox-2 expression was evaluated by immunohistochemistry as well as quantitative reverse transcription-PCR (qRT-PCR). Alterations in the expression of 5-HT3 receptor and inflammatory-associated genes such as Il-1β, Tnf-α, Tlr4 and Myd88 were determined by qRT-PCR. Our results showed that tumor development in tropisetron-treated CAC group was significantly lower than the controls. The qRT-PCR analysis demonstrated that the expression of 5-HT3 receptor was significantly increased following CAC induction. In addition, tropisetron reduced expression of β-catenin and Cox-2 in the CAC experimental group. The levels of Il-1β, Tnf-α, Tlr4 and Myd88 were significantly decreased upon tropisetron treatment in the AOM/DSS group. Taken together, our data show that tropisetron inhibits development of CAC probably by attenuation of inflammatory reactions in the colitis

Levosimendan exerts anticonvulsant properties against PTZ-induced seizures in mice through activation of nNOS/NO pathway: Role for K<inf>ATP</inf> channel

Aims Although approving new anticonvulsants was a major breakthrough in the field of epilepsy control, so far we have met limited success in almost one third of patients suffering from epilepsy and a definite and reliable method is yet to be found. Levosimendan demonstrated neuroprotective effects and reduced mortality in conditions in which seizure can be an etiology of death; however, the underlying neuroprotective mechanisms of levosimendan still eludes us. In the light of evidence suggesting levosimendan can be a KATP channel opener and nitrergic pathway activator, levosimendan may exert antiseizure effects through KATP channels and nitrergic pathway. Main methods In this study, the effects of levosimendan on seizure susceptibility was studied by PTZ-induced seizures model in mice. Key findings Administration of a single effective dose of levosimendan significantly increased seizures threshold and the nitrite level in the hippocampus and temporal cortex. Pretreatment with noneffective doses of glibenclamide (a KATP channel blocker) and L-NAME (a non-selective NOS inhibitor) neutralize the anticonvulsant and nitrite elevating effects of levosimendan. While 7-NI (a neural NOS inhibitor) blocked the anticonvulsant effect of levosimendan, Aminoguanidine (an inducible NOS inhibitor) failed to affect the anticonvulsant effects of levosimendan. Cromakalim (a KATP channel opener) or L-arginine (an NO precursor) augmented the anticonvulsant effects of a subeffective dose of levosimendan. Moreover, co-administration of noneffective doses of Glibenclamide and L-NAME demonstrated a synergistic effect in blocking the anticonvulsant effects of levosimendan. Significance Levosimendan has anticonvulsant effects possibly via KATP/nNOS/NO pathway activation in the hippocampus and temporal corte