Epipregnanolone Acts as a Partial Agonist on a Common Neurosteroid Modulatory Site of the GABAA Receptor Complex in Avian CNS

Neurosteroid modulatory sites present in the GABA_A receptor complex in chick optic lobe were investigated, in order to evaluate whether allopregnanolone and alphaxalone act through a common site of action. Results showed that either allopregnanolone or alphaxalone present a single-component enhancement of [³H]flunitrazepam binding with EC₅₀ of 1.18 ± 0.12 and 6.56 ± 0.86 M and E_max of 82.18 ± 5.80 and 62.98 ± 3.73 %, respectively. Epipregnanolone behaved as a partial agonist of these steroid modulatory sites with EC₅₀ of 0.49 ± 0.15 M and E_max 12.34 ± 1.03%. Moreover, the addition of 16 M epipregnanolone to either allopregnanolone or alphaxalone decreased EC₅₀ values to 0.54 ± 0,09 and 1.24 ± 0.25 M respectively, while E_max values were not significantly affected. On the other hand, additivity experiments disclosed that a maximal concentration (16 M) of alphaxalone in the presence of allopregnanolone failed to enhance [³H]flunitrazepam binding in excess of that produced by allopregnanolone alone. Results indicate that not only allopregnanolone and alphaxalone act through a common site of action, but such site is highly stereospeciflc with regard to the neurosteroid spatial configuration.