Potentiation and inhibition of GABA_A receptor function by neuroactive steroids

Certain steroids have long been known to rapidly and potently influence nervous system function1,2 through mechanisms unrelated to intracellular steroid receptor activation and associated transcriptional activity.3-5 In this chapter, synthetic and endogenous steroids that possess these rapid actions will be termed neuroactive steroids.6 Our more specific focus will be on steroids with actions at GABA_A receptors, which we will refer to as GABA-active steroids. As addressed in other chapters, there are two main classes of GABA-active steroids. The first class potentiates GABAA receptor function. A second class inhibits GABAA receptor function. Representatives of both GABA-potentiating and GABA-inhibiting GABA-active steroids are synthesized endogenously and may tonically regulate receptor function. Additionally, exogenous representatives of both classes may have clinical applications. After a brief review of the two classes of GABA-active steroids, the actions of neuroactive steroids at other potentially relevant molecular targets, and the potential clinical utility of neuroactive steroids, this chapter will focus on recent attempts by our groups and others to understand structure-activity relationships of GABApotentiating and GABA-inhibiting steroids. We also review our studies of interactions between the two classes and recent studies of the mechanism of GABAinhibiting steroids.