In a mouse model relevant for post-traumatic stress disorder, selective brain steroidogenic stimulants (SBSS) improve behavioral deficits by normalizing allopregnanolone biosynthesis.
In a mouse model relevant for post-traumatic stress disorder, selective brain steroidogenic stimulants (SBSS) improve behavioral deficits by normalizing allopregnanolone biosynthesis.
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DOI：
10.1097/fbp.0b013e32833d8ba0
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发表时间：
2010-09
影响因子：
1.6
通讯作者：
Pinna G
中科院分区：
文献类型：
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作者：
Pinna G
神经甾体3α-羟基-5 α-胆甾烷-20-酮（别孕烯醇酮）在神经精神疾病中的病理生理作用在最近的几项研究中得到了强调。例如，在患有创伤后应激障碍（PTSD）和严重单相抑郁症的患者的脑脊液（CSF）中，别孕烯醇酮水平降低。神经类固醇抗抑郁药，包括氟西汀和类似物，纠正这种减少的方式与改善抑郁症状。PTSD样行为功能障碍，包括与皮质边缘别孕烯醇酮含量降低相关的攻击性增强、过度恐惧和焦虑样行为，通过长期的社会隔离应激在小鼠中建模。别孕烯醇酮不仅由主要的多巴胺能神经元和GABA能神经元合成，而且还局部地、有效地、正性地和变构地调节GABA在突触后和突触外GABAA受体处的作用。因此，本文将回顾临床前研究，这些研究表明，在社会隔离的小鼠中，而不是SSRI机制，异孕烯醇酮生物合成在多巴胺能皮质边缘神经元中为氟西汀提供了一个非传统的靶点，以减少攻击迹象，使恐惧反应正常化，并减少焦虑样行为。在低SSRI非活性剂量下，氟西汀和相关同系物通过充当强效选择性脑类固醇生成兴奋剂（SBSS）而有效增加别孕烯醇酮水平，从而促进GABAA受体神经传递并改善行为功能障碍。虽然这些药物作用的确切分子机制尚未完全了解，但来自社会隔离小鼠的研究结果可能最终产生对治疗精神疾病（如焦虑和惊恐障碍，抑郁症和创伤后应激障碍）的新型药物靶点的见解。
The pathophysiological role of the neurosteroid 3α-hydroxy-5α-pregnan-20-one (allopregnanolone) in neuropsychiatric disorders has been highlighted in several recent investigations. For instance, allopregnanolone levels are decreased in the cerebrospinal fluid (CSF) of patients with posttraumatic stress disorder (PTSD) and major unipolar depression. Neurosteroidogenic antidepressants, including fluoxetine and analogs, correct this decrease in a manner that correlates with improved depressive symptoms. PTSD-like behavioral dysfunctions, including heightened aggression, exaggerated fear, and anxiety-like behavior associated with a decrease in corticolimbic allopregnanolone content are modeled in mice by protracted social isolation stress. Allopregnanolone is not only synthesized by principal glutamatergic and GABAergic neurons but also locally, potently, positively, and allosterically modulates GABA action at post- and extra-synaptic GABAA receptors. Hence, this paper will review preclinical studies which show that in socially-isolated mice, rather than SSRI mechanisms, allopregnanolone biosynthesis in glutamatergic corticolimbic neurons offers a non-traditional target for fluoxetine to decrease signs of aggression, normalize fear responses, and decrease anxiety-like behavior. At low SSRI-inactive doses, fluoxetine and related congeners potently increase allopregnanolone levels by acting as potent selective brain steroidogenic stimulants (SBSSs), thereby facilitating GABAA receptor neurotransmission and improving behavioral dysfunctions. Although the precise molecular mechanisms that underlie the action of these drugs are not fully understood, findings from socially-isolated mice may ultimately generate insights into novel drug targets for the treatment of psychiatric disorders, such as anxiety and panic disorders, depression, and PTSD.