CHRONIC ETHANOL ADMINISTRATION ALTERS THE MODULATORY EFFECT OF 50-ALPHA-PREGNAN-3-ALPHA-OL-20-ONE ON THE BINDING CHARACTERISTICS OF VARIOUSRADIOLIGANDS OF GABA(A) RECEPTORS

in this study, we investigated the modulatory effect of 5 alpha-pregna n-3 alpha-ol-20-one, a neurosteroid, on the binding characteristics of [H-3]flunitrazepam (2 nM). [H-3]muscimol (5 nM), and 4 nM [S-35]t-but ylbicyclophosphorothionate (TBPS) in cerebral cortex, cerebellum, and hippocampus of control, ethanol-dependent, and ethanol-withdrawn rats. 5 alpha-Pregnan-3 alpha-ol-20-one potentiated the binding of [H-3]flu nitrazepam and [H-3]muscimol in all the rat brain regions investigated in this study. There was a significant increase in the maximal potent iation of [H-3]flunitrazepam as well as [H-3]muscimol binding (E-max) in the ethanol-dependent rat cerebellum as compared to control group ( p < 0.025). Furthermore, 5 alpha-pregnan-3 alpha-al-20-one elicited a biphasic response, i.e., it potentiated the binding of [S-35]TBPS at l ower concentrations (less than or equal to 100 nM) and inhibited the b inding at higher concentrations (> 100 nM). There was a significant hi gher inhibition of [S-35]TBPS binding(-E-max) by 5 alpha-pregnan-3 alp ha-ol-20-one in the hippocampus of ethanol-dependent as well as ethano l-withdrawn rats (p < 0.025). These observations suggest that the neur osteroid binding site associated with the gamma-aminobutyric acid(A) ( GABA(A)) receptors in cerebellum and hippocampus plays an important ro le during ethanol-dependence and ethanol-withdrawal, and some of the c hanges following ethanol dependence and its withdrawal may be mediated through the neurosteroid binding site. (C) 1998 Elsevier Science B.V. All rights reserved.