TY - JOUR
T1 - 5HT3 receptor antagonist (ondansetron) reverses depressive behavior evoked by chronic unpredictable stress in mice
T2 - Modulation of hypothalamic-pituitary-adrenocortical and brain serotonergic system
AU - Gupta, Deepali
AU - Radhakrishnan, Mahesh
AU - Kurhe, Yeshwant
N1 - Funding Information:
The authors are thankful to BITS-Pilani and University Grants Commission India 4-1/2006(BSR)/7/32/2007(BSR) for providing support and research facilities to pursue this work.
PY - 2014/9
Y1 - 2014/9
N2 - Chronic stress is one of the major causes of depression, associated with behavioral and biochemical impairments. 5HT3 receptor antagonists (such as ondansetron) have shown alleviation of depressive symptomology in preclinical and in few clinical studies. However, their effects in chronic stress-induced depressive behavior and the underlying mechanism(s) are yet to be known. In the present study, the effects of a 5HT3 receptor antagonist, ondansetron were evaluated in chronic unpredictable stress (CUS)-evoked depressive behavior. In addition, the possible mechanism was determined by measuring plasma corticosterone (CORT) as a marker of hypothalamic-pituitary-adrenocortical (HPA)-axis activity and serotonin levels in the discrete brain regions. Mice were subjected to a battery of unpredictable stressors for 28 days. Ondansetron (0.05, 0.1 and 1 mg/kg, p.o.) and fluoxetine (10 mg/kg, p.o.) were administered during the last 14 days (day 15-28th) of CUS testing paradigm. The results showed that the 4-week CUS produced significant depressive behavior in mice, which included increased despair effects in forced swim test (FST) and reward-related deficits in sucrose preference test. Biochemical assays demonstrated a significant increase in percentage of plasma CORT and decrease in percentage of serotonin levels in the discrete brain regions of CUS mice. Chronic ondansetron treatment, similar to that of positive control fluoxetine, significantly reversed despair effects in FST and reward-related deficits in sucrose preference test. In addition, ondansetron and fluoxetine treatments significantly increased percentage of serotonin levels in the measured brain regions and attenuated HPA-axis hyperactivity, as evidenced by low percentage of plasma CORT levels in CUS mice. These findings indicate the potential role of ondansetron (a 5HT3 receptor antagonist) in reversing CUS-induced depressive behavior, which is possibly mediated by its modulating effects on the HPA-axis and serotonergic system. Further, the study represents that 5HT3 receptor antagonists can be a potential therapeutic candidate for stress-related depressive disorders.
AB - Chronic stress is one of the major causes of depression, associated with behavioral and biochemical impairments. 5HT3 receptor antagonists (such as ondansetron) have shown alleviation of depressive symptomology in preclinical and in few clinical studies. However, their effects in chronic stress-induced depressive behavior and the underlying mechanism(s) are yet to be known. In the present study, the effects of a 5HT3 receptor antagonist, ondansetron were evaluated in chronic unpredictable stress (CUS)-evoked depressive behavior. In addition, the possible mechanism was determined by measuring plasma corticosterone (CORT) as a marker of hypothalamic-pituitary-adrenocortical (HPA)-axis activity and serotonin levels in the discrete brain regions. Mice were subjected to a battery of unpredictable stressors for 28 days. Ondansetron (0.05, 0.1 and 1 mg/kg, p.o.) and fluoxetine (10 mg/kg, p.o.) were administered during the last 14 days (day 15-28th) of CUS testing paradigm. The results showed that the 4-week CUS produced significant depressive behavior in mice, which included increased despair effects in forced swim test (FST) and reward-related deficits in sucrose preference test. Biochemical assays demonstrated a significant increase in percentage of plasma CORT and decrease in percentage of serotonin levels in the discrete brain regions of CUS mice. Chronic ondansetron treatment, similar to that of positive control fluoxetine, significantly reversed despair effects in FST and reward-related deficits in sucrose preference test. In addition, ondansetron and fluoxetine treatments significantly increased percentage of serotonin levels in the measured brain regions and attenuated HPA-axis hyperactivity, as evidenced by low percentage of plasma CORT levels in CUS mice. These findings indicate the potential role of ondansetron (a 5HT3 receptor antagonist) in reversing CUS-induced depressive behavior, which is possibly mediated by its modulating effects on the HPA-axis and serotonergic system. Further, the study represents that 5HT3 receptor antagonists can be a potential therapeutic candidate for stress-related depressive disorders.
KW - Chronic unpredictable stress
KW - Corticosterone
KW - Forced swim test
KW - Serotonin
KW - Sucrose preference test
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U2 - 10.1016/j.pbb.2014.05.024
DO - 10.1016/j.pbb.2014.05.024
M3 - Article
C2 - 24909071
AN - SCOPUS:84903154330
SN - 0091-3057
VL - 124
SP - 129
EP - 136
JO - Pharmacology Biochemistry and Behavior
JF - Pharmacology Biochemistry and Behavior
ER -