High-affinity nicotinic acetylcholine receptors are required for antidepressant effects of amitriptyline on behavior and hippocampal cell proliferation
High-affinity nicotinic acetylcholine receptors are required for antidepressant effects of amitriptyline on behavior and hippocampal cell proliferation
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DOI：
10.1016/j.biopsych.2004.08.010
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发表时间：
2004-11-01
影响因子：
10.6
通讯作者：
Picciotto, MR
中科院分区：
文献类型：
--
作者：
Caldarone, BJ;Harrist, A;Picciotto, MR
背景资料：各种各样的抗抑郁药作为烟碱乙酰胆碱受体（nAChRs）的非竞争性拮抗剂，但这种拮抗作用和抗抑郁药的治疗效果之间的关系是unknown.Methods：抗抑郁药的非竞争性nAChR拮抗剂美加明在强迫游泳试验的性质进行了测试，单独和结合三环类抗抑郁药阿米替林。在抗抑郁模型的常见模型中，在阿米替林的三种行为效应中测试缺乏高亲和力nAChR的小鼠，以确定这些受体是否是阿米替林在抗抑郁作用的常见模型中的行为效应所需的。最后，野生型和基因敲除动物的大脑与阿米替林治疗进行了检查，以确定是否需要高亲和力nAChRs抗抑郁药诱导的增加海马细胞proliferation.Results：抑制nAChRs的mecamylamine有抗抑郁药样作用，在强迫游泳试验和加强阿米替林的抗抑郁活性时，两种药物联合使用。缺乏高亲和力nAChRs的小鼠对阿米替林没有表现出行为反应。最后，阿米替林慢性治疗后，nAChR基因敲除小鼠没有表现出增加海马细胞增殖中看到野生型mice.Conclusions：这些数据支持的假设，nAChRs的拮抗作用是抗抑郁药的治疗作用的一个重要组成部分。
Background: A wide variety of antidepressants act as noncompetitive antagonists of nicotinic acetylcholine receptors (nAChRs), but the relationship between this antagonism and the therapeutic effects of antidepressants is unknown.Methods: Antidepressant properties of the noncompetitive nAChR antagonist mecamylamine in the forced swim test were tested alone and in combination with the tricyclic antidepressant amitriptyline. Mice lacking high-affinity nAChRs were tested in three behavioral effects of amitriptyline in common models of antidepressant models to determine whether these receptors are required for behavioral effects of amytriptyline in common models of antideppressant action. Finally, the brains of wild-type and knockout animals treated with amitriptyline were examined to determine whether high-affinity nAChRs are required for antidepressant-induced increases in hippocampal cell proliferation.Results: Inhibition of nAChRs by mecamylamine had antidepressant-like effects in the forced swim test and potentiated the antidepressant activity of amitriptyline when the two drags were used in combination. Mice lacking high-affinity nAChRs showed no behavioral response to amitriptyline. Finally after chronic treatment with amitriptyline, nAChR knockout mice did not show the increase in hippocampal cell proliferation seen in wild-type mice.Conclusions: These data support the hypothesis that antagonism of nAChRs is an essential component of the therapeutic action of antidepressants.