Benz[e]indenes (Bis) are tricyclic molecules that can be envisioned as steroids without an A-ring. Because certain steroids are known to alter γ-aminobutyric acid (GABA) responses in central neurons, we examined the effects of a substituted BI resembling 3α-hydroxy-5α-pregnan-20-one (Sa-OH-DHP) on GABA-gated chloride currents in cultured postnatal rat hippocampal neurons. The compound, BI-1, reversibly potentiated GABA currents at concentrations of >10 nM, with an EC50 value of 0.2 μM. BI-1 increased the apparent affinity of GABA for its receptor, decreasing the GABA EC50 from 9 μM to 3 μM. BI-1 had no effect on the shape of the GABA current-voltage relationship and did not alter the GABA reversal potential. The effects of BI-1 were not altered by benzodiazepine or picrotoxin site antagonists. At concentrations up to 10 μM, where maximal effects on GABA currents were seen, BI-1 did not directly activate a membrane current. This contrasts with the effects of Sa-OH-DHP, which activated chloride currents at concentrations that were subsaturating for GABA potentiation. These results suggest that the BIs may be useful for determining the mechanisms by which steroids potentiate GABA responses and directly gate chloride channels.
|Number of pages||6|
|State||Published - Dec 1992|