Abstract
Objective: To investigate the possible nitriergic influence in the compromised antidepressant effect of fluoxetine in stressed mice. Materials and methods: Male swiss albino mice were used in the present study. Mice were stressed by immobilization for 2hrs. Mice subjected to stress were considered as stressed mice and mice not subjected to stress were considered as unstressed mice. All the treatments were administered intraperitoneally (i.p.) at the dose of 10 ml/kg. Depression like behavioral alterations in unstressed and stressed mice was measured by TST followed by FST. To determine the possible nitriergic influence; nitrite levels were measured in brain homogenates. Results: Present study showed that the 2hrs immobilization significantly increased the immobility period of mice in both TST and FST, with the concurrent increase in the levels of nitrite in the brain homogenates as compared to the vehicle treated unstressed mice. Fluoxetine (FLX) (20 mg/kg, i.p.); pyrrolidine dithiocarbamate (PDTC) (100 mg/kg, i.p.) and methylene blue (MB) (100 mg/kg, i.p.) significantly reduced the immobility period of stressed mice in both TST and FST as compared to vehicle treated stressed mice. Pre-treatment with PDTC (100 mg/kg, i.p.) followed by FLX (20 mg/kg, i.p.) did not significantly alter the immobility period and nitrite levels of FLX (20 mg/kg, i.p.) treated stressed mice. Pre-treatment with MB (100 mg/kg, i.p.) followed by FLX (20 mg/kg, i.p.) did not significantly alter the immobility period of mice in TST, but significantly reduced the immobility period of mice in FST as compared to the FLX (20 mg/kg, i.p.) treated stressed mice. Also the pre-treatment with MB (100 mg/kg, i.p.) followed by FLX (20 mg/kg, i.p.) significantly reduced the nitrite levels as compared to the FLX (20 mg/kg, i.p.) treated stressed mice. Conclusion: It has been concluded that nitriergic mechanism plays a significant role in the compromised antidepressant effect of fluoxetine in stressed mice.
Highlights
Stress disturbs the physiological homeostasis of body (Bohus et al, 1993) and precipitates mood disorders such as depression (McEwen, 2000)
Mice subjected to stress were considered as stressed mice and mice not subjected to stress were considered as unstressed mice
Effect of different treatments on the immobility period of unstressed and stressed mice in TST and Forced swim test (FST) was shown in the fig. 1 and fig
Summary
Stress disturbs the physiological homeostasis of body (Bohus et al, 1993) and precipitates mood disorders such as depression (McEwen, 2000). Stress increase the expression of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α in the brain of animals exposed to stress (Wichers and Maes, 2002) and IL-6 activates NMDA receptors (Maj et al, 1992; Qiu et al, 1995). The stress evokes the release of glutamate in the brain that results in the activation of NMDA receptors (Maj et al, 1992); present in linked with the neuronal nitric oxide synthase (nNOS) (Cheah et al, 2006). The activation of NMDA receptors is responsible for the increased expression of nNOS; responsible for the production of nitric oxide (NO) (Cheah et al, 2006). The cytokines such as IL-1 and TNF-α increases the expression of NF-κβ pathway that is responsible for the increase expression of inducible nitric oxide synthase (iNOS) (Cooke et al, 2001; Hua et al, 2008; Alexopoulos and Morimoto, 2011; Madrigal et al, 2002); which once induced continues to produce the larger quantities of NO (Madrigal et al, 2002)
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