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Abstract
Neuroactive steroids are natural or synthetic steroids that rapidly alter the excitability
of neurons by binding to membrane-bound receptors such as those for inhibitory and
(or) excitatory neurotransmitters. The best-studied neuroactive steroids are a series
of sedative-hypnotic 3 alpha-hydroxy ring A-reduced pregnane steroids that include
the major metabolites of progesterone and deoxycorticosterone, 3 alpha-hydroxy-5 alpha-pregnan-20-one
(allopregnanolone) and 3 alpha,21-dihydroxy-5 alpha-pregnan-20-one (allotetrahydroDOC),
respectively. These 3 alpha-hydroxysteroids do not interact with classical intracellular
steroid receptors but bind stereoselectively and with high affinity to receptors for
the major inhibitory neurotransmitter in brain, gamma-amino-butyric acid (GABA). Biochemical
and electrophysiological studies have shown that these steroids markedly augment GABA-activated
chloride ion currents in a manner similar (but not identical) to that of anesthetic
barbiturates. Several steroids have also been observed to have convulsant or proconvulsant
properties, including the synthetic amidine 3 alpha-hydroxy-16-imino-5 beta-17-azaandrostan-11-one
(RU5135) and the natural sulfate esters of pregnenolone and dehydroepiandrosterone.
Several of these have been shown to be bicuculline or picrotoxin-like GABAA receptor
antagonists. Examples of steroids that alter neuronal excitability rapidly by augmenting
or inhibiting excitatory amino acid receptor-mediated responses have also been reported.
Recently, allopregnanolone and allotetrahydroDOC have also been measured in brain
and plasma where their levels have been shown to fluctuate in response to stress and
during the estrous and menstrual cycles of rats and humans, respectively. Although
the major fraction of allopregnanolone in tissue, including brain, is of adrenal and/or
ovarian origin, appreciable levels of allopregnanolone can still be measured in the
brains of adrenalectomized and/or oophorectomized animals. Receptor-active neurosteroids
may represent an important class of neuromodulators that can rapidly alter central
nervous system excitability via novel nongenomic mechanisms.