Gupta Deepali, Radhakrishnan Mahesh, Kurhe Yeshwant
Department of Pharmacy, Birla Institute of Technology & Science, Pilani, Rajasthan, 333031, India.
Pharmacol Biochem Behav. 2014 Sep;124:129-36. doi: 10.1016/j.pbb.2014.05.024. Epub 2014 Jun 6.
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 1mg/kg, p.o.) and fluoxetine (10mg/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.
慢性应激是抑郁症的主要病因之一，与行为和生化损伤有关。5-羟色胺3（5HT3）受体拮抗剂（如昂丹司琼）在临床前和少数临床研究中已显示出可缓解抑郁症状。然而，它们在慢性应激诱导的抑郁行为中的作用及其潜在机制尚不清楚。在本研究中，评估了5HT3受体拮抗剂昂丹司琼对慢性不可预测应激（CUS）诱发的抑郁行为的影响。此外，通过测量血浆皮质酮（CORT）作为下丘脑-垂体-肾上腺皮质（HPA）轴活动的标志物以及离散脑区中的血清素水平，确定了可能的机制。将小鼠置于一系列不可预测的应激源中28天。在CUS测试范式的最后14天（第15 - 28天）给予昂丹司琼（0.05、0.1和1mg/kg，口服）和氟西汀（10mg/kg，口服）。结果表明，4周的CUS在小鼠中产生了显著的抑郁行为，包括强迫游泳试验（FST）中绝望效应增加以及蔗糖偏好试验中与奖赏相关的缺陷。生化分析表明，CUS小鼠离散脑区中血浆CORT百分比显著增加，血清素水平百分比降低。与阳性对照氟西汀类似，慢性昂丹司琼治疗显著逆转了FST中的绝望效应以及蔗糖偏好试验中与奖赏相关的缺陷。此外，昂丹司琼和氟西汀治疗显著提高了所测脑区中血清素水平的百分比，并减弱了HPA轴的过度活跃，CUS小鼠血浆CORT水平百分比降低证明了这一点。这些发现表明昂丹司琼（一种5HT3受体拮抗剂）在逆转CUS诱导的抑郁行为中具有潜在作用，这可能是由其对HPA轴和血清素能系统的调节作用介导的。此外，该研究表明5HT3受体拮抗剂可能是应激相关抑郁症的潜在治疗候选药物。
