Neuroactive steroid modulation of [3H]muscimol binding to the GABAA receptor complex in rat cortex.

Epalons are a subclass of neuroactive steroids which are positive allosteric modulators of the GABAA receptor acting via a unique site on the receptor complex. Enhancement of [3H]muscimol binding to the GABA recognition site was observed to be either full (> 150%) or limited (110-135%) and specific for epalons. Both one and two component modulation was observed. Saturation studies performed in the presence of 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha,5 alpha-P) showed that 3 alpha, 5 alpha-P increased the density of high affinity [3H]muscimol sites and doubled the affinity of low affinity sites. 3 alpha,5 alpha-P had no effect on the affinity of the high affinity site or the density of the low affinity site. These data indicate that: (1) epalons are potent, stereoselective enhancers of [3H]muscimol binding; (2) epalons display varying levels of efficacy and some exhibit two-component enhancement; and (3) 3 alpha,5 alpha-P enhancement of [3H]muscimol binding results from both an increased density of high affinity sites and an increased affinity for low affinity sites.