Caldarone Barbara J, Harrist Alexia, Cleary Muriel A, Beech Robert D, King Sarah L, Picciotto Marina R
Department of Psychiatry, Yale University School of Medicine, 34 Park Street, New Haven, CT 06508, USA.
Biol Psychiatry. 2004 Nov 1;56(9):657-64. doi: 10.1016/j.biopsych.2004.08.010.
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.
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 models to determine whether these receptors are required for behavioral effects of amitriptyline in common models of antidepressant 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.
Inhibition of nAChRs by mecamylamine had antidepressant-like effects in the forced swim test and potentiated the antidepressant activity of amitriptyline when the two drugs 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.
These data support the hypothesis that antagonism of nAChRs is an essential component of the therapeutic action of antidepressants.
多种抗抑郁药可作为烟碱型乙酰胆碱受体（nAChRs）的非竞争性拮抗剂，但这种拮抗作用与抗抑郁药治疗效果之间的关系尚不清楚。
在强迫游泳试验中，单独测试非竞争性nAChR拮抗剂美加明的抗抑郁特性，并将其与三环类抗抑郁药阿米替林联合使用进行测试。在三种行为模型中对缺乏高亲和力nAChRs的小鼠进行测试，以确定在常见的抗抑郁作用模型中，这些受体是否是阿米替林行为效应所必需的。最后，检查用阿米替林治疗的野生型和基因敲除动物的大脑，以确定抗抑郁药诱导的海马细胞增殖增加是否需要高亲和力nAChRs。
在强迫游泳试验中，美加明对nAChRs的抑制具有抗抑郁样作用，当两种药物联合使用时，可增强阿米替林的抗抑郁活性。缺乏高亲和力nAChRs的小鼠对阿米替林无行为反应。最后，在阿米替林长期治疗后，nAChR基因敲除小鼠未表现出野生型小鼠海马细胞增殖增加的现象。
这些数据支持以下假设，即nAChRs的拮抗作用是抗抑郁药治疗作用的重要组成部分。
