Neurosteroid effect

Inhibitory neurosteroids are biosynthesized by the action of two enzymes , 5α-reductase and 3α-hydroxysteroid dehydrogenase (3α-HSD). [1] These enzymes can be inhibited by 5α-reductase inhibitors such as finasteride and dutasteride and by inhibitors of 3α-HSD such as medroxyprogesterone acetate . [2] [3] [4] Contrarily, 3α-HSD is induced by certain selective serotonin reuptake inhibitors (SSRIs), including fluoxetine , fluvoxamine , sertraline , and paroxetine , as well as certain other antidepressants like venlafaxine and mirtazapine , and these antidepressants have been found to increase inhibitory neurosteroid levels. [1] [5] [6] [7] Inhibition of inhibitory neurosteroid biosynthesis by 5α-reductase inhibitors and 3α-HSD inhibitors has been associated with depression , anxiety , irritability , and sexual dysfunction , [2] [4] [8] whereas enhancement of their biosynthesis has been implicated in the antidepressant and anxiolytic effects of some of the SSRIs. [1]

AB - Puberty is characterized by mood swings and anxiety, which are often produced by stress. Here we show that THP (allopregnanolone), a steroid that is released as a result of stress, increases anxiety in pubertal female mice, in contrast to its anxiety-reducing effect in adults. Anxiety is regulated by GABAergic inhibition in limbic circuits. Although this inhibition is increased by THP administration before puberty and in adults, during puberty THP reduces the tonic inhibition of pyramidal cells in hippocampal region CA1, leading to increased excitability. This paradoxical effect of THP results from inhibition of α4βδ GABAA receptors. These receptors are normally expressed at very low levels, but at puberty, their expression is increased in hippocampal area CA1, where they generate outward currents. THP also decreases the outward current at recombinant α4β2δ receptors, and this effect depends on arginine 353 in the α4 subunit, a putative site for modulation by Cl-. Therefore, inhibition of α4β2δ GABAA receptors by THP provides a mechanism for the generation of anxiety at puberty.

In the mid 1980s, the neuroactive steroids 3α,5α-tetrahydroprogesterone or allopregnanolone (3α,5α-THP) and 3α,5α- tetrahydrodeoxycorticosterone (3α,5α-THDOC) were shown to modulate neuronal excitability via their interaction with GABA A receptors. The steroids 3α,5α-THP and 3α,5α-THDOC were able to enhance the GABA-elicited Cl − current. [13] In addition, these steroids might enhance the binding of muscimol and benzodiazepines to GABA A receptors. [30] Structure- activity studies (SAR) showed that the 3alpha-OH group is essential for the anesthetic actions of these steroids, [31] they also have an optimally-placed hydrogen bond accepting group on the β face of the steroid at the C-17 position. The four steroid rings form a rigid framework for positioning these hydrogen groups in three-dimensional space. [32] Analogues 5 and 6 (Figure 10) are weak modulators of GABA A receptor function because the flexible side chains in these analogues do not have the conformations required for high biological activity. [33]

Neurosteroid effect

neurosteroid effect


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