Neurosteroids, GABAA receptors and neurosteroid based drugs: are we witnessing the dawn of the new psychiatric drugs?

In broad biological terms, neurosteroids can be defined as a class of endogenous steroids synthesized in the brain or in peripheral steroidogenic tissues having potent and relatively selective activity on brain gamma-aminobutyric acid A (GABAA) receptors. In this regard, the most important neurosteroids are allopregnanolone and allotetrahydrodeoxycorticosterone (allo THDOC). These α-reduced derivatives of pregnenolone and progesterone act as positive allosteric modulators of GABAA receptors. As such, they potentiate the inhibitory action of GABA on GABAA receptors and produce a wide spectrum of behavioral actions ranging from anxiolytic, anticonvulsive, sedative, hypnotic, amnestic (loss of memory), myorelaxant, and anesthetic effects. Sulfated derivatives of pregnenolone and dehydroepiandrosterone ,pregnenolone sulfate (PS) and dehydroepianddrosterone sulfate (DHEAS), are also very important neurosteroids. In contrast to allopregnolone and alloTHDOC, PS and DHEAS induce excitatory effect on neurons because they facilitate the block of GABAA receptors. The spectrum of behavioral effects of PS and DHEAS consists of analeptic, anxiogenic, proconvulsive, and anamnestic (cognitive enhancing). The purpose of this review paper is to analyze recent research in the field of neurosteroids and neurosteroid-based drugs with emphasis on interaction of neurosteroids with brain GABAA receptors. This article also provides an overview of neurosteroids-based strategies for the development of innovative therapeutic approaches. GABAA receptor modulating steroids (GAMS), GABAA receptor modulating steroid antagonists (GAMSA), and translocator protein (TSPO) activators are examples of innovative therapeutic approaches in treating clinically important neurological and psychiatric diseases. Consequently, the therapeutic potential of GAMS, GAMSA, and TSPO activators will be briefly evaluated.