Up-regulation of neurosteroid biosynthesis as a pharmacological strategy to improve behavioural deficits in a putative mouse model of post-traumatic stress disorder.
Up-regulation of neurosteroid biosynthesis as a pharmacological strategy to improve behavioural deficits in a putative mouse model of post-traumatic stress disorder.
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DOI：
10.1111/j.1365-2826.2011.02234.x
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发表时间：
2012-01
影响因子：
3.2
通讯作者：
Rasmusson AM
中科院分区：
文献类型：
--
作者：
Pinna G;Rasmusson AM
苯二氮卓类药物仍然是治疗焦虑谱系障碍最常用的精神药物；然而，它们的使用与耐受性和依赖性的发展有关。另一个主要障碍是它们对许多患者缺乏疗效，包括患有创伤后应激障碍（PTSD）的患者。对于这些无反应者，使用选择性血清素再摄取抑制剂（SSRI）一直是首选疗法。在过去的十年中，临床研究表明，SSRIs的药理作用可能包括这些药物能够使抑郁症和创伤后应激障碍患者脑部神经类固醇水平降低正常化，特别是黄体酮衍生物四氢孕酮，它可以有效地变构调节GABA对GABAA受体的作用。使用社会孤立小鼠作为 PTSD 动物模型的临床前研究表明，氟西汀及其同类药物通过增加皮质边缘四氢孕酮水平，改善此类小鼠表现出的焦虑样行为、恐惧反应和攻击行为。这是一种比 5-HT 再摄取抑制更新颖且更具选择性的机制，半个世纪以来，5-HT 再摄取抑制一直被认为是 SSRI 治疗作用的主要分子机制。重要的是，这一发现可能揭示了 PTSD 和抑郁症患者中 SSRI 耐药率较高的问题，这些疾病的四氢孕酮合成似乎受到阻碍。有几种不同的机制可能会导致这种阻碍，并且 SSRI 可能只能在某些情况下起到纠正作用。因此，皮质边缘神经元中四氢孕酮生物合成的上调可能为新一代治疗焦虑、抑郁和创伤后应激障碍的强效非镇静抗焦虑药物提供新的非传统药理学靶点：选择性脑类固醇激素（SBSS）。
Benzodiazepines remain the most frequently used psychotropic drugs for the treatment of anxiety spectrum disorders; however their use is associated with development of tolerance and dependence. Another major hindrance is represented by their lack of efficacy in many patients, including patients with posttraumatic stress disorder (PTSD). For these non-responders, the use of selective serotonin reuptake inhibitors (SSRIs) has been the therapy of choice. In the past decade, clinical studies have suggested that the pharmacological action of SSRIs may include the ability of these drugs to normalize decreased brain levels of neurosteroids in patients with depression and PTSD, in particular the progesterone derivative allopregnanolone, which potently and allosterically modulates the action of GABA at GABAA receptors. Preclinical studies using the socially isolated mouse as an animal model of PTSD have demonstrated that fluoxetine and congeners ameliorate anxiety-like behavior, fear responses, and aggressive behavior expressed by such mice by increasing corticolimbic levels of allopregnanolone. This is a novel and more selective mechanism than 5-HT reuptake inhibition, which for half a century has been thought to be the main molecular mechanism for the therapeutic action of SSRIs. Importantly, this finding may shed light on the high rates of SSRI resistance among patients with PTSD and depression, disorders in which there appears to be a block in allopregnanolone synthesis. There are several different mechanisms by which such a block may occur, and SSRIs may only be corrective under some conditions. Thus, upregulation of allopregnanolone biosynthesis in corticolimbic neurons may offer a novel non-traditional pharmacological target for a new generation of potent non-sedating, anxiolytic medications for the treatment of anxiety, depression, and PTSD: selective brain steroidogenic stimulants (SBSSs).
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影响因子：
3
作者：
Atack, John R.
通讯作者：
Atack, John R.
影响因子：
4.4
作者：
Berlant JL
通讯作者：
Berlant JL
影响因子：
2.9
作者：
BITRAN, D;HILVERS, RJ;KELLOGG, CK
通讯作者：
KELLOGG, CK
影响因子：
17.7
作者：
Bremner, JD;Innis, RB;Charney, DS
通讯作者：
Charney, DS
影响因子：
2.1
作者：
Brinton, Roberta Diaz;Wang, Jun Ming
通讯作者：
Wang, Jun Ming