Neuroactive Steroid Actions at the GABAA Receptor

Abstract

Neuroactive steroids are a new class of steroids that do not interact with any of the classical cytosolic hormonal steroid receptors. The most well-documented examples are those that interact with the γ-aminobutyric acidA (GABAA) receptor/chloride channel complex in the central nervous system. The GABAA receptors are known to contain allosteric modulatory sites for therapeutically useful drugs such as benzodiazepines (BZs) and barbiturates. The interaction of neuroactive steroids with the GABAA receptor is specific to a site on the receptor complex distinct from the benzodiazepine and barbiturate modulatory sites. Neuroactive steroids exist endogenously; the examples are metabolites of progesterone and deoxycorticosterone, 3α-hydroxy-5α-pregnane-20-one, and 5α-pregnane-3α, 21α-dihydroxy-20-one, respectively, and their 5/3 stereoisomers. The GABAA receptor agonist-like effects that these neuroactive steroids produce in vivo are similar, but not identical, to those of BZs and barbiturates. Representatives of all three classes of modulators are active as sedative-hypnotics, anticonvulsants, and anxiolytics in animal models. Because of the heterogeneity of GABAA receptors and their differential distribution in the brain, dissimilar in vivo pharmacological profiles displayed by BZs, barbiturates and neuroactive steroids are not surprising. Studies of neuroactive steroid interactions with the GABAA receptor revealed a unique subset of these steroids that modulate the receptor with limited efficacy. Another endogenously occurring progesterone metabolite, 5αpregnane-3α,20α-diol, is an example of this subset of neuroactive steroids. At present, it is not clear whether the observed limited efficacy is due to receptor subtype selectivity, partial agonist activity or both. Nevertheless, data from recombinantly expressed GABAA receptors suggests that receptor subunit composition influences the recognition properties of the neuroactive steroid site. Collectively, biochemical, pharmacological, and physiological studies support the existence of a novel binding site for neuroactive steroids on membrane-bound GABAA receptor complexes in the mammalian brain. The physiological role of this binding site and its endogenously occurring ligands may provide additional insight into how hormonal steroids may affect brain excitability in a non-genomic fashion.