Depression-like phenotype following chronic CB1 receptor antagonism
Depression-like phenotype following chronic CB1 receptor antagonism
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DOI：
10.1016/j.nbd.2010.03.020
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发表时间：
2010-08-01
影响因子：
6.1
通讯作者：
Whiteside, Garth T.
中科院分区：
文献类型：
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作者：
Beyer, Chad E.;Dwyer, Jason M.;Whiteside, Garth T.
利莫那班是第一个临床上市的大麻素（CB）（1）受体拮抗剂开发用于治疗肥胖。不幸的是CB 1受体拮抗剂在患者中产生不良精神事件。为了确定这是否发生在临床前，我们研究了利莫那班在啮齿动物模型中的情绪障碍的影响。利莫那班长期治疗增加了大鼠强迫游泳试验中的不动时间，并减少了假设为快感缺乏模型的试验中蔗糖甜味剂水的消耗。这些反应与这些行为模型中慢性轻度应激引起的效应相似，两者结合在一起，表明了抑郁样表型。此外，利莫那班长期治疗导致额叶皮质5-羟色胺水平降低，海马细胞增殖、存活率和BDNF水平显著降低，促炎细胞因子（包括干扰素γ和TNF α）浓度升高。这些临床前研究结果模拟临床报告，并暗示可能的机制负责不利的精神病事件报告后，长期使用利莫那班。(C)2010年爱思唯尔公司All rights reserved.
Rimonabant was the first clinically marketed cannabinoid (CB)(1) receptor antagonist developed to treat obesity. Unfortunately. CB1 receptor antagonism produced adverse psychiatric events in patients. To determine whether this occurs pre-clinically, we investigated the effects of rimonabant in rodent models of mood disorders. Chronic treatment with rimonabant increased immobility time in the rat forced swim test and reduced the consumption of sucrose-sweetened water in an assay postulated to model anhedonia. These responses were similar to the effects elicited by chronic mild stress in these behavioral models, which, taken together, are indicative of a depression-like phenotype. Additionally, chronic treatment with rimonabant produced decreases in frontal cortex serotonin levels, marked reductions in hippocampal cell proliferation, survival, and BDNF levels, and elevations in the concentrations of pro-inflammatory cytokines including interferon gamma and TNF alpha. These preclinical findings mimic clinical reports and implicate possible mechanisms responsible for the unfavorable psychiatric events reported following chronic rimonabant use. (C) 2010 Elsevier Inc. All rights reserved.