Unsulfated and sulfated neurosteroids differentially modulate the binding characteristics of various radioligands of GABA_A receptors following chronic ethanol administration

Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) inhibited the binding of [³H]flunitrazepam (2 nM), [³H]muscimol (5 nM) and 4 nM [³⁵S]t-butylbicyclophosphorothionate [³⁵S]TBPS in the rat cerebellum as well as cerebral cortex. DHEAS-induced inhibition of binding of these radioligands (62% to 100%) was more pronounced as compared to that in the case of DHEA (5% to 31%). DHEAS, unlike DHEA, inhibited [³H]flunitrazepam binding significantly to a lesser extent in the cerebellum of ethanol-dependent rats as compared to the control group (I_max: 82±1 vs. 92±2%, p<0.005). However, DHEA, unlike DHEAS, inhibited [³⁵S]TBPS binding to a greater extent in the ethanol-dependent rat cerebellum as compared to the control group (I_max: 31±2 vs. 19±2%, p<0.005). Furthermore, DHEA was more potent in inhibiting [³⁵S]TBPS binding in the cerebellum (IC₅₀:55±5 vs. 74±7 μM, p<0.05) and cerebral cortex (IC₅₀: 26±4 vs. 64±9 μM, p<0.05) of ethanol-dependent rats as compared to the control group. These observations indicate that unsulfated and sulfated androstane-steroids modulate the GABA_A receptors in the control as well as the ethanol-dependent rats differentially, and also suggest that the androstane-steroid binding sites associated with the GABA_A receptors play an important role during ethanol dependence.