Evaluation of 5-HT7 receptor antagonism for the treatment of anxiety, depression, and schizophrenia through the use of receptor-deficient mice
Evaluation of 5-HT7 receptor antagonism for the treatment of anxiety, depression, and schizophrenia through the use of receptor-deficient mice
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DOI：
10.1016/j.bbr.2018.12.019
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发表时间：
2019-03-15
影响因子：
2.7
通讯作者：
Witkin, Jeffrey M.
中科院分区：
文献类型：
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作者：
Balcer, Olivia M.;Seager, Matthew A.;Witkin, Jeffrey M.
5-HT7受体是由神经递质5-羟色胺激活的5-羟色胺受体家族中最新发现的受体亚型。研究这种受体在包括抑郁、焦虑和精神分裂症在内的精神疾病中的潜在作用一直是人们非常感兴趣的。对5-HT7+/+(野生型或WT)和5-HT7-/-(受体敲除或KO)小鼠的行为进行了10种不同的检测(7种为焦虑症，1种为抑郁症，2种为精神病)，以确定可能表明5-HT7受体拮抗的临床潜力的差异。对KO和WT小鼠的评估表明，在恐惧条件反射、电击探头埋藏、新奇抑制进食、惩罚记忆、强迫游泳试验和d-苯丙胺多动试验中，两种基因型之间存在显著差异。在不同的基因类型或不同的检测方法中，行为效应的方向并不一致。因此，来自这些行为分析的数据并不一致地支持5-HT7受体构成这些精神障碍的重要药物靶点的想法。目前的发现与文献中关于5-HT7-/-小鼠行为的混合结果以及5-HT7受体拮抗剂在检测抗焦虑、抗抑郁和抗精神病作用的啮齿动物模型中的作用的数据基本一致。
The 5-HT7 receptor is the most recently identified receptor subtype within a family of 5-HT receptors activated by the neurotransmitter serotonin. There has been significant interest in investigating the potential role of this receptor in psychiatric disorders including depression, anxiety, and schizophrenia. Behaviors of 5-HT7 +/+ (wild-type or WT) and 5-HT7 -/- (receptor knockout or KO) mice were compared across 10 different assays (7 for anxiety, 1 for depression, 2 for psychosis) to identify differences that could indicate clinical potential for 5-HT7 receptor antagonism. Evaluation of KO vs. WT mice demonstrated significant differences between the genotypes in the fear conditioning, shock-probe burying, novelty-suppressed feeding, punishment memory, forced swim test, and d-amphetamine hyperactivity assays. There was not consistency in either the direction of behavioral effects across genotypes or across assays. Thus, data from these behavioral assays did not uniformly support the idea that 5-HT7 receptors constitute an important drug target for these psychiatric disorders. The present findings are generally congruent with the mixed results in the literature on the behaviors of 5-HT7 -/-mice and with the data on effects of 5-HT7 receptor antagonists in rodent models that detect activity of anxiolytic, antidepressant, and antipsychotic effects.