NEUROACTIVE STEROID MODULATION OF [H-3] MUSCIMOL BINDING TO THE GABA(A) RECEPTOR COMPLEX IN RAT CORTEX

Epalons are a subclass of neuroactive steroids which are positive allo steric modulators of the GABA(A) receptor acting via a unique site on the receptor complex. Enhancement of [H-3]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 modulat ion was observed. Saturation studies performed in the presence of 3 al pha-hydroxy-5 alpha-pregnan-20-one (3 alpha,5 alpha-P) showed that 3 a lpha,5 alpha-P increased the density of high affinity [H-3]muscimol si tes 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 p otent, stereoselective enhancers of [H-3]muscimol binding; (2) epalons display varying levels of efficacy and some exhibit two-component enh ancement; and (3) 3 alpha,5 alpha-P enhancement of [H-3]muscimol bindi ng results from both an increased density of high affinity sites and a n increased affinity for low affinity sites.