Neuropharmacological evaluation of a novel 5-HT3 receptor antagonist (6g) on chronic unpredictable mild stress-induced changes in behavioural and brain oxidative stress parameters in mice

Abstract

Aim: The aim of the study was to evaluate a novel 5 HT3 receptor antagonist (6g) on chronic stress induced changes in behavioural and brain oxidative stress parameter in mice. A complicated relationship exists among stressful stimuli, body's reaction to stress and the onset of clinical depression. Chronic unpredictable stressors can produce a situation similar to human depression, and such animal models can be used for the preclinical evaluation of antidepressants.

Materials and methods: In the present study, a novel and potential 5-HT3 receptor antagonist (4-benzylpiperazin-1-yl)(3-methoxyquinoxalin-2-yl) methanone (6g) with good Log P (3.08) value and pA 2(7.5) values, synthesized in our laboratory was investigated to study the effects on chronic unpredictable mild stress (CUMS)-induced behavioural and biochemical alterations in mice. Mice were subjected to different stress paradigms daily for a period of 28 days to induce depressive-like behaviour.

Results: The results showed that CUMS caused depression-like behaviour in mice, as indicated by the significant (P < 0.05) decrease in sucrose consumption and locomotor activity and increase in immobility the forced swim test. In addition, it was found that lipid peroxidation and nitrite levels were significantly (P < 0.05) increased, whereas glutathione levels, superoxide dismutase and catalase activities decreased in brain tissue of CUMS-treated mice. '6g' (1 and 2 mg/kg, p.o., 21 days) and fluoxetine treatment (20 mg/kg, p.o., 21 days) significantly (P < 0.05) reversed the CUMS-induced behavioural (increased immobility period, reduced sucrose preference and decreased locomotor activity) and biochemical (increased lipid peroxidation; decreased glutathione levels, superoxide dismutase and catalase activities). However fluoxetine treatment (20 mg/kg, p.o., 21 days) significantly decreased the nitrite level in the brain while '6g' (1 and 2 mg/kg, p.o., 21 days) did not show significant (P < 0.05) effect on the nitrite levels in brain.

Conclusion: Compound '6g' exerted antidepressant-like effects in behavioural despair paradigm in chronically stressed mice by restoring antioxidant mechanisms.

Keywords: 5-HT3 receptor antagonist; chronic unpredictable mild stress; depression; oxidative stress.

Figure 1

Effect of ‘6g’ (1 and 2 mg/kg, i.p.) and fluoxetine (20 mg/kg, i.p.) treatment on locomotor scores in stressed mice. Each column represents mean locomotor scores recorded in 8 min observation period. The error bars indicate SEM; n= 8/group. Fluoxetine = Flx

Figure 2

Effect of ‘6g’ (1 and 2 mg/kg, i.p.) and fluoxetine (20 mg/kg, i.p.) treatment on duration of immobility in stressed mice. Each column represents mean duration of immobility(s). The error bar indicates SEM, ^#P < 0.05 when compared with normal control; *P < 0.05 when compared with stress vehicle treated group; n= 8/group. Fluoxetine = Flx

Figure 3

Effect of ‘6g’ (1 and 2 mg/kg, i.p.) and fluoxetine (20 mg/kg, i.p.) treatment on sucrose preference (%) in stressed mice. The error bar indicates SEM, ^#P < 0.05 when compared with normal control; *P < 0.05 when compared with stress vehicle treated group; n= 8/ group. Fluoxetine = Flx