Guidotti A, Costa E
Department of Psychiatry, University of Illinois at Chicago, College of Medicine 60612, USA.
Biol Psychiatry. 1998 Nov 1;44(9):865-73. doi: 10.1016/s0006-3223(98)00070-5.
Neurosteroids synthesized in the nervous system are potent modulators of synaptic activity. Allopregnanolone (ALLO) is of great significance for neuropsychiatric research because it binds with high affinity at nanomolar concentration to various gamma-aminobutyric acid (GABA)A receptor subtypes and potently facilitates GABA action at these receptors. Fluoxetine and paroxetine, two selective serotonin reuptake inhibitors (SSRIs), when administered to rats increase brain ALLO content without altering the brain content of other steroids, including ALLO's precursor 5 alpha dihydroprogesterone. Moreover the improvement in depression symptomatology following administration of fluoxetine or fluvoxamine to unipolar depressed patients for 8-10 weeks is related to the increase of ALLO content in cerebrospinal fluid. Because ALLO via its action at GABAA receptors may relieve anxiety and dysphoria, the increase in ALLO brain content elicited by fluoxetine or other SSRIs may participate in the beneficial anxiolytic and antidysphoric clinical action of this class of drugs. Preliminary experiments suggest that the effect of SSRIs on ALLO biosynthesis is independent from serotonin reuptake inhibition and may be due to a specific SSRI action on the enzymes that synthesize ALLO from its precursor.
在神经系统中合成的神经甾体是突触活动的有效调节剂。别孕烯醇酮（ALLO）对神经精神研究具有重要意义，因为它在纳摩尔浓度下以高亲和力与各种γ-氨基丁酸（GABA）A受体亚型结合，并有力地促进GABA在这些受体上的作用。氟西汀和帕罗西汀这两种选择性5-羟色胺再摄取抑制剂（SSRI），在给大鼠用药时会增加脑内ALLO含量，而不会改变其他甾体的脑内含量，包括ALLO的前体5α-二氢孕酮。此外，给单相抑郁症患者服用氟西汀或氟伏沙明8 - 10周后，抑郁症状的改善与脑脊液中ALLO含量的增加有关。由于ALLO通过其对GABAA受体的作用可能缓解焦虑和烦躁不安，氟西汀或其他SSRI引起的脑内ALLO含量增加可能参与了这类药物有益的抗焦虑和抗烦躁不安的临床作用。初步实验表明，SSRI对ALLO生物合成的作用独立于5-羟色胺再摄取抑制，可能是由于SSRI对从其前体合成ALLO的酶具有特定作用。
