Maryam Rahimi-Balaei

Co-occurrence of anxiety and depressive-like behaviors following adolescent social isolation in male mice; possible role of nitrergic system.

Approximately more than 50% of patients with depression have the co-occurrence of anxiety, which complicates the treatment of disease. Recently, social isolation stress (SIS) paradigm has been suggested as an animal model to investigate the underlying mechanism involved in depression-anxiety co-occurrence. In this study, applying six weeks of SIS to adolescent mice, we tested whether nitrergic system plays a role in co-occurrence of depression and anxiety. In this study, comparisons between socially and isolated conditioned (SC and IC) animals showed that SIS induces behaviors relevant to depression and anxiety in IC mice and in addition, nitrergic system is involved in mediating the negative outcomes of SIS. Administration of subeffective doses of aminoguanidine (a specific inducible nitric oxide synthase inhibitor or iNOS, 50mg/kg) and L-NAME (non-specific inhibitor of NOS, 10mg/kg) significantly reversed the negative effects of SIS on behavioral profile as well as nitrite levels in the cortex of IC mice, Although administration of subeffective dose of 7-nitroindazole (a specific neuronal NOS inhibitor, 25mg/kg) decreased the nitrite levels in the hippocampus, but had no effect on depressant and anxiogenic effects of SIS. Results of this study confirmed that SIS is an appropriate animal model to investigate the potential mechanisms in depression-anxiety co-occurrence. We also showed that nitrergic system has contributed to co-occurrence of depression and anxiety in IC mice as an underlying mechanism.

Blockade of NMDA receptors reverses the depressant, but not anxiogenic effect of adolescence social isolation in mice.

Early life social isolation stress (SIS), a well-known chronic stress paradigm, is contributed to a number of pathophysiological and neurochemical changes including depression and anxiety. The underlying mechanisms for these disorders in socially isolated animals have not been fully cleared. Previous studies have shown that N-Methyl-d-aspartate (NMDA) receptor function is changed by social isolation condition. It is now well recognized that NMDA receptor blockade can exhibit antidepressant and anxiolytic actions. In our study, postnatal day 21-25 mice were randomly housed for 4 weeks under either social condition (SC) or isolated condition (IC). Then, animals were subjected to different behavioral experiments to investigate whether blockade of NMDA receptor resulted in behavioral alterations in animals. Social isolation stress induced depressive and anxiety-like behaviors in IC animals in comparison with SC mice. Also, we applied subeffective doses of antagonists including ketamine (1mg/kg), MK-801 (0.05mg/kg), and magnesium sulfate (10mg/kg) to both SC and IC mice prior to behavioral experiments. Administration of a single dose of all mentioned drugs did not affect the SC mice but modulated the depressant effects of SIS on IC mice. Administration of NMDA receptor antagonists decreased the immobility time in the forced swimming test as well as an increase in grooming behavior in splash test. However, anxiety-like behaviors in IC animals remained unchanged in hole-board test and open field test after blockade of NMDA receptors. Taken together, our results showed the possible involvement of the NMDA receptors in the depressive, but not anxiety-like behaviors induced by SIS.

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

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 function.

Lithium attenuated the depressant and anxiogenic effect of juvenile social stress through mitigating the negative impact of interlukin-1β and nitric oxide on hypothalamic–pituitary–adrenal axis function

The neuroimmune-endocrine dysfunction has been accepted as one of fundamental mechanisms contributing to the pathophysiology of psychiatric disorders including depression and anxiety. In this study, we aimed to evaluate the involvement of hypothalamic-pituitary-adrenal (HPA) axis, interleukin-1β, and nitrergic system in mediating the negative behavioral impacts of juvenile social isolation stress (SIS) in male mice. We also investigated the possible protective effects of lithium on behavioral and neurochemical changes in socially isolated animals. Results showed that experiencing 4-weeks of juvenile SIS provoked depressive and anxiety-like behaviors that were associated with hyper responsiveness of HPA axis, upregulation of interleukin-1β, and nitric oxide (NO) overproduction in the pre-frontal cortex and hippocampus. Administration of lithium (10 mg/kg) significantly attenuated the depressant and anxiogenic effects of SIS in behavioral tests. Lithium also restored the negative effects of SIS on cortical and hippocampal interleukin-1β and NO as well as HPA axis deregulation. Unlike the neutralizing effects of l-arginine (NO precursor), administration of l-NAME (3 mg/kg) and aminoguanidine (20 mg/kg) potentiated the positive effects of lithium on the behavioral and neurochemical profile of isolated mice. In conclusion, our results revealed that juvenile SIS-induced behavioral deficits are associated with abnormalities in HPA-immune function. Also, we suggest that alleviating effects of lithium on behavioral profile of isolated mice may be partly mediated by mitigating the negative impact of NO on HPA-immune function.

Involvement of D1 and D2 dopamine receptors in the antidepressant-like effects of selegiline in maternal separation model of mouse.

Mother-infant interactions are known to be associated with the psychological well-being of an individual in adulthood. It is well accepted that emotional stress in early life, such as maternal separation (MS), leads to alterations in the neurotransmission systems of various brain regions, especially the mesolimbic dopaminergic system, and subsequently can increase the risk for development of psychiatric disorders including depression in adulthood. Selegiline is an irreversible monoamine oxidase (MAO) type B inhibitor which increases striatal dopamine levels and exerts an antidepressant effect. In this study, 180min of MS stress was applied to mice at postnatal day (PND) 2-14 followed by behavioral tests for determining depressive-like behaviors, such as forced swimming test (FST), splash test and sucrose preference test (SPT) in adult mice (PND 50). The open field test (OFT) also was applied to validate FST results. We used SCH23390 (D1 antagonist) and sulpiride (D2 antagonist) in order to determine the role of D1 and D2 dopamine receptors in antidepressant-like effects of selegiline. Our results revealed that MS provoked depressive-like behaviors in adult male mice, and the administration of selegiline attenuated depressive-like behaviors in MS mice. Our findings showed that D1 dopamine receptors facilitate the positive effects of selegiline on the passive behavior in the FST. Furthermore, antidepressant effects of selegiline on hedonic difficulties are mediated via D2 receptor in the SPT. The results of the splash test revealed that both D1 and D2 receptors mediate the protective effect of selegiline against motivational and self-care problems. Based on our results, we conclude that both D1 and D2 dopamine receptors are involved in mediating the antidepressant-like effect of selegiline. We found that D1 receptors mediate an effect on despair behavior, D2 receptors mediate an effect on anhedonia, and both D1 and D2 receptors contribute to the protective effects of selegiline on motivational complications.

Attenuation of oxidative and nitrosative stress in cortical area associates with antidepressant-like effects of tropisetron in male mice following social isolation stress

Tropisetron, a 5-HT3 receptor antagonist widely used as an antiemetic, has been reported to have positive effects on mood disorders. Adolescence is a critical period during the development of brain, where exposure to chronic stress during this time is highly associated with the development of depression. In this study, we showed that 4 weeks of juvenile social isolation stress (SIS) provoked depressive-like behaviors in male mice, which was associated with disruption of mitochondrial function and nitric oxide overproduction in the cortical areas. In this study, tropisetron (5mg/kg) reversed the negative behavioral effects of SIS in male mice. We found that the effects of tropisetron were mediated through mitigating the negative activity of inducible nitric oxide synthase (iNOS) on mitochondrial activity. Administration of aminoguanidine (specific iNOS inhibitor, 20mg/kg) augmented the protective effects of tropisetron (1mg/kg) on SIS. Furthermore, l-arginine (nitric oxide precursor, 100mg/kg) abolished the positive effects of tropisetron. These results have increased our knowledge on the pivotal role of mitochondrial function in the pathophysiology of depression, and highlighted the role of 5-HT3 receptors in psychosocial stress response during adolescence. Finally, we observed that tropisetron alleviated the mitochondrial dysfunction through decreased nitrergic system activity in the cerebral cortex.

Mitochondrial dysfunction bridges negative affective disorders and cardiomyopathy in socially isolated rats: Pros and cons of fluoxetine.

Abstract Objectives Depression is tightly associated with cardiovascular comorbidity and accounts for high financial and social burden worldwide. Mitochondrial dysfunction contributes to the pathophysiology of depression and cardiovascular disorders; its contribution to depression-cardiovascular comorbidity has not yet been investigated. Methods Adolescent rats were subjected to 4 weeks of isolation (social isolation stress or SIS) or social conditions (control), and then they were divided into treatment (fluoxetine, 7.5 mg/kg/day for 21 days) and non-treatment groups. After different housing conditions and treatment, animals were evaluated by behavioural tests (n = 6–8) and mitochondrial assessments (n = 3) of brain and cardiac tissues. Results We found that juvenile SIS induced behavioural abnormalities and mitochondrial dysfunction in adulthood. We showed that juvenile SIS was associated with impaired respiratory chain complex, which leads to reactive oxygen species formation, oxidative damage and ATP abatement in both brain and heart. Administration of FLX (7.5 mg/kg/day) during the isolation period attenuated the effects of SIS on the brain mitochondria and behavioural abnormalities, but had little or no effect on SIS-induced mitochondrial dysfunction in cardiac tissue. Conclusions This suggests that juvenile SIS predisposes the co-occurrence of depression and cardiovascular disease through mitochondrial dysfunction and that therapeutic effect of fluoxetine is partly mediated by its effect on mitochondrial function.

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.

Streptozotocin induced oxidative stress, innate immune system responses and behavioral abnormalities in male mice

Recent evidence indicates the involvement of inflammatory factors and mitochondrial dysfunction in the etiology of psychiatric disorders such as anxiety and depression. To investigate the possible role of mitochondrial-induced sterile inflammation in the co-occurrence of anxiety and depression, in this study, we treated adult male mice with the intracerebroventricular (i.c.v.) infusion of a single low dose of streptozotocin (STZ, 0.2mg/mouse). Using valid and qualified behavioral tests for the assessment of depressive and anxiety-like behaviors, we showed that STZ-treated mice exhibited behaviors relevant to anxiety and depression 24h following STZ treatment. We observed that the co-occurrence of anxiety and depressive-like behaviors in animals were associated with abnormal mitochondrial function, nitric oxide overproduction and, the increased activity of cytosolic phospholipase A2 (cPLA2) in the hippocampus. Further, STZ-treated mice had a significant upregulation of genes associated with the innate immune system such as toll-like receptors 2 and 4. Pathological evaluations showed no sign of neurodegeneration in the hippocampus of STZ-treated mice. Results of this study revealed that behavioral abnormalities provoked by STZ, as a cytotoxic agent that targets mitochondria and energy metabolism, are associated with abnormal mitochondrial activity and, consequently the initiation of innate-inflammatory responses in the hippocampus. Our findings highlight the role of mitochondria and innate immunity in the formation of sterile inflammation and behaviors relevant to anxiety and depression. Also, we have shown that STZ injection (i.c.v.) might be an animal model for depression and anxiety disorders based on sterile inflammation.

Proconvulsant effect of post-weaning social isolation stress may be associated with dysregulation of opioid system in the male mice.

Opioid system has been reported to be involved in the consequences of post-weaning social isolation stress (SIS) such as hypoalgesia and social behaviors. Also, previous studies have shown that SIS increases mu opioid receptor expression in the regions of the brain associated with epileptogenesis such as basolateral amygdala and cortex. Interestingly, experiencing SIS increases seizure risk in the adulthood. Regarding the SIS-induced alterations in the opioid system, we hypothesize that increase in opioidergic system activity (mostly by mu receptor) may be associated with increase in vulnerability to seizures. In non-stressed mice, morphine at low doses (1 mg/kg) has an anticonvulsant effect on seizure threshold while higher doses (60 mg/kg) are proconvulsant. To support the hypothesis, we showed that administration of anticonvulsant dose of morphine (1 mg/kg) to socially isolated male mice not only was not able to reverse the negative effect of SIS on seizure susceptibility to pentylenetetrazole but also enhanced it. These results support our hypothesis that proconvulsant effect of post-weaning social isolation stress may be associated with dysregulation of opioid system in the adult male mice.