Antidepressant action of agomelatine (S 20098) in a transgenic mouse model.
Antidepressant action of agomelatine (S 20098) in a transgenic mouse model.
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DOI：
10.1016/j.pnpbp.2005.04.032
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发表时间：
2005-07-01
影响因子：
5.6
通讯作者：
Mocaer, Elisabeth
中科院分区：
文献类型：
--
作者：
Barden, Nicholas;Shink, Eric;Mocaer, Elisabeth
本研究的目的是评价阿戈美拉汀（S 20098）加速逆转抑郁症神经内分泌特征转基因小鼠模型中观察到的神经内分泌、行为和周期性变化的疗效。在糖皮质激素受体（GR）功能低下的转基因小鼠中，在急性应激或诱导相移后评估阿戈美拉汀的作用，并与地昔帕明和褪黑素进行比较。小鼠在黑暗期开始前2小时注射阿戈美拉汀（10 mg/kg，腹膜内），地昔帕明（10 mg/kg，i. p.），褪黑激素（10 mg/kg，i. p.）或溶媒（羟乙基纤维素（HEC）1%），持续21 - 42天。阿戈美拉汀可有效逆转Porsolt强迫游泳试验以及高架十字迷宫中观察到的转基因小鼠行为变化。在转基因小鼠中，高架十字迷宫的开放臂进入的数量和在开放臂中花费的总时间都大大增加。张开双臂的平均时间对阿戈美拉汀和地昔帕明的逆转非常敏感。阿戈美拉汀还显著加速了诱导相移后温度和活动的昼夜节律周期的重新调整。阿戈美拉汀的这一作用上级于褪黑素，而地昔帕明则无此作用。如果在诱导相移前3周开始治疗，阿戈美拉汀的加速作用尤其显著。阿戈美拉汀给药未引起皮质酮或促肾上腺皮质激素（ACTH）浓度或加压素（AVP）、促肾上腺皮质激素释放激素（CRH）、GR和盐皮质激素受体（MR）mRNA水平的任何重大变化，这使得阿戈美拉汀的作用机制不太可能与下丘脑-垂体-肾上腺皮质（HPA）轴变化相关。本研究表明，阿戈美拉汀在转基因小鼠模型中显示出抗抑郁药物作用的一些特征，这些作用可能与其时间生物学特性部分相关。
The aim of this study was to evaluate the efficacy of agomelatine (S 20098) to accelerate reversal of the neuroendocrinological, behavioural and cyclical changes seen in a transgenic mouse model of the neuroendocrine characteristics of depression. The effects of agomelatine were assessed in transgenic mice with low glucocorticoid receptor (GR) function, after acute stress or induced phase shift, and compared to desipramine and melatonin. Mice were injected 2 h before the onset of the dark period with agomelatine (10 mg/kg, i.p.), desipramine (10 mg/kg, i.p.), melatonin (10 mg/kg, i.p.) or vehicle (hydroxy-ethyl-cellulose (HEC) 1%) each day for 21 to 42 days. Agomelatine was effective in reversing the transgenic mouse behavioural changes noted in the Porsolt forced swim test as well as in the elevated plus maze. Both the number of open arm entries and the total time spent in open arms of the elevated plus maze is greatly increased in transgenic mice. The mean time spent in open arms is exquisitely sensitive to reversal by agomelatine and desipramine. Agomelatine also markedly accelerated readjustment of circadian cycles of temperature and activity following an induced phase shift. This action of agomelatine was superior to that of melatonin while desipramine was without effect. The accelerating effect of agomelatine was particularly notable if treatment was started 3 weeks prior to the induced phase shift. Agomelatine treatment did not cause any major change in corticosterone or adrenocorticotropic hormone (ACTH) concentrations nor in vasopressin (AVP), corticotropin-releasing hormone (CRH), GR and mineralocorticoid receptor (MR) mRNAs levels, which make it unlikely that the mechanism of agomelatine action is related to hypothalamic-pituitary-adrenocortical (HPA) axis changes. The present study shows that agomelatine displays some characteristics of antidepressant drug action in the transgenic mouse model, effects that could be partially related to its chronobiotic properties.