The modulation of BDNF expression and signalling dissects the antidepressant from the reinforcing properties of ketamine: Effects of single infusion vs. chronic self-administration in rats
The modulation of BDNF expression and signalling dissects the antidepressant from the reinforcing properties of ketamine: Effects of single infusion vs. chronic self-administration in rats
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DOI：
10.1016/j.phrs.2015.12.014
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发表时间：
2016-02-01
影响因子：
9.3
通讯作者：
Chiamulera, Cristiano
中科院分区：
文献类型：
--
作者：
Caffino, Lucia;Di Chio, Marzia;Chiamulera, Cristiano
氯胺酮是一种滥用药物，具有独特的特征，除了其作为NMDA谷氨酸受体的非竞争性拮抗剂的固有作用机制外，还显示出抗抑郁和增强的特性，我们的研究的主要目的是找到氯胺酮的分子特征，这可能有助于区分其增强和抗抑郁作用。为此，我们将注意力集中在BDNF上，BDNF是一种神经营养因子，已被证明在几种药物的抗抑郁和增强特性中发挥作用。大鼠暴露于自我静脉内（IV）氯胺酮（S/A）43天或接受单次IV氯胺酮0.5 mg/kg或载体输注。虽然我们使用的剂量低于文献报道的剂量，但它产生的C-max值与抗抑郁药治疗后人类达到的C-max值相对应。我们的结果表明，虽然单次输注氯胺酮增加了海马中神经营养因子的表达，同时减少了腹侧纹状体中的神经营养因子表达，这是与其他抗抑郁药共有的特征，重复的自身给药降低了腹侧纹状体和海马中的mBDNF表达及其下游信号传导。此外，我们在这里表明，Akt的磷酸化是由氯胺酮相反的调节，指出这一途径作为中央的药物的不同actions.Taken在一起，我们在这里指出，BDNF及其下游信号通路作为一个微调机制，其调制可能subserve氯胺酮的不同功能。(C)2015爱思唯尔有限公司版权所有。
Ketamine is a drug of abuse with a unique profile, which besides its inherent mechanism of action as a noncompetitive antagonist of the NMDA glutamate receptor, displays both antidepressant and reinforcing properties.The major aim of our study was to find a molecular signature of ketamine that may help in discriminating between its reinforcing and antidepressant effects. To this end, we focused our attention on BDNF, a neurotrophin that has been shown to play a role in both antidepressant and reinforcing properties of several drugs.Rats were exposed to self-administer intravenous (IV) ketamine (S/A) for 43 days or to receive a single IV ketamine 0.5 mg/kg, or vehicle infusion. Although the dose we employed is lower than that reported by the literature, it however yields C-max values that correspond to those achieved in humans after antidepressant treatment.Our results show that while the single infusion of ketamine increased the neurotrophin expression in the hippocampus while reducing it in the ventral striatum, a feature shared with other antidepressants, the repeated self-administration reduced mBDNF expression and its downstream signalling in both ventral striatum and hippocampus. Further, we here show that phosphorylation of Akt is oppositely regulated by ketamine, pointing to this pathway as central to the different actions of the drug.Taken together, we here point to BDNF and its downstream signalling pathway as a finely tuned mechanism whose modulation might subserve the different features of ketamine. (C) 2015 Elsevier Ltd. All rights reserved.