Abstract
New perspectives in neurosteroid action: open questions for future research.
Highlights
Neurosteroids are still a hot topic in cellular and systemic neuroscience the first report on anaesthetic actions of progesterone from Selye was published already in 1941 (Selye, 1941)
What is the exact site of interaction of such neurosteroids with GABAA receptors? Is it really a binding site with clear saturable binding kinetics or rather an interaction site? Recent studies show that photolabeling of amino acids in the third transmembrane domain of the β3 subunit of the GABAA receptor by neurosteroid analogs is feasible (Chen et al, 2012) but does this really prove a binding site? What makes the difference in the regulation of GABAergic neurotransmission between the modulation by a 3α-reduced neurosteroid such as allopregnanolone and a benzodiazepine? Both are positive allosteric modulators of GABAA receptors and enhance GABAergic neurotransmission but there appear to be great differences with regard to abuse liability and tolerance development (Rupprecht et al, 2009)
It has been shown that negative mood symptoms may occur in women with premenstrual dysphoric disorder (PMDD) during the luteal phase of the menstrual cycle when progesterone and allopregnanolone levels usually are high (Bäckström et al, 2014) which has to be reconciled with the known anxiolytic effects of moderate to high concentrations of allopregnanolone
Summary
Neurosteroids are still a hot topic in cellular and systemic neuroscience the first report on anaesthetic actions of progesterone from Selye was published already in 1941 (Selye, 1941). It is a fascinating concept that endogenous metabolites of progesterone such as allopregnanolone and pregnanolone are powerful allosteric modulators of γ-aminobutyric acid type A (GABAA) receptors.
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